Circular Guidelines for risk based inspections of manufacturing facilities

GUIDANCE DOCUMENT FOR RISK BASED INSPECTION OF DRUG MANUFACTURING SITES CENTRAL DRUGS STANDARD CONTROL ORGANIZATION DIRECTORATE GENERAL OF HEALTH SERVICES MINISTRY OF HEALTH & FAMILY WELFARE GOVT. OF INDIA Page 1 of 15Contents Introduction .......................................................................................................................... 4 Background .......................................................................................................................... 5 Objective ............................................................................................................................... 5 Purpose: ................................................................................................................................ 6 Scope: .................................................................................................................................... 7 Types of Inspection ............................................................................................................ 7 Conduct During Inspection .............................................................................................. 7 Steps in conduct of inspection ....................................................................................... 8 Selection of Site for Risk Based Inspection: .............................................................. 8 Planning of Inspection: ..................................................................................................... 9 Conduct of Inspection: .................................................................................................... 10 Areas to be covered during inspection ...................................................................... 11 Page 2 of 15Findings: ............................................................................................................................. 12 Classification of Findings of Risk Based Inspection: ............................................ 13 Outcome of inspection:................................................................................................... 14 Annexures: ......................................................................................................................... 15 References: ........................................................................................................................ 15 Page 3 of 151. Introduction  Ensuring the quality, safety, and efficacy of medicines is a critical aspect which contributes significantly to strengthening the assurance in public health systems including healthcare professionals and other stakeholders.  Enforcement is one of the key components in the regulatory system to ensure that the safe, quality and efficacious drugs reach the patients.  Schedule M to the Drugs Rules,1945 provides requirements for Good Manufacturing Practices (GMP) and requirements of plant and equipment for manufacture of drugs.  It specifies in detail the requirements of premises, surroundings, personnel, sanitation, storage of raw materials, documentation and records, self- inspections and quality control systems and site master files etc.  The manufacturer is required to comply with the requirements of Good Manufacturing Practices prescribed in Schedule M under the conditions of the licence so as to ensure that the drugs manufacturers in the country conform to the standards prescribed for them.  In the Indian context, the enforcement in drug regulation is designed as a control system in which the quality of the drugs manufactured are mainly monitored through random sampling, testing of the products and in case of quality failure, regulatory actions are taken through administrative measures by way of suspension, cancellation or launching prosecution depending on the nature and criticality of the product quality failure.  While, the Indian drug industry is spread out in the various States and Union Territories, the enforcement has been found to be of varying level among the states. Non-uniformity in the interpretation of the provisions of the law and their implementation, lack of adequate infrastructure and varying level of the competence of the regulatory officials have resulted in less than satisfactory performance in many States.  Compliance to the Good Manufacturing Practices (GMP) is checked through inspections that are undertaken predominantly in a routine manner. In contrast to this other well regulated country like the USA and the EU which follow a risk-based approach to inspections. They identify the facilities that need to be Page 4 of 15inspected based on history of inspection, risk associated with the product and findings of past inspections. Such risk-based inspections result in optimization of allocation of resources ensuring better quality products. 2. Background  Risk Based Inspection is a methodology that is based upon the concept of rating manufacturing sites on the basis of an estimated risk that they may pose to patients, consumers, animals and users of medicines. The methodology also takes into account the risk to product quality.  A risk based approach to inspection planning will improve the depth of GMP inspections and will allow effective implementation of the provisions of Schedule M of Drugs Rules 1945 for maintaining a high level of patient safety.  Risk-based approach makes the best use of surveillance and enforcement resources.  The principles of Quality Risk Management are employed while planning the risk-based inspection of the pharmaceutical manufacturing sites. 3. Objective  The Central Drugs Standard Control Organization is responsible for laying down the standards of drugs, cosmetics, diagnostics and devices and enforcing the rules of Good Manufacturing Practice (GMP) in India for manufacturers of Finished Pharmaceuticals Products (FPP) and Active Pharmaceutical Ingredients (API).  The objective of the drug regulation is to ensure safety, efficacy and quality of the drugs available in the country.  The objective of this document is to provide uniform enforcement procedures for onsite inspections to evaluate compliance of the quality system and infrastructure with nationally & internationally accepted GMP Standards (based on the reference document as prescribed in the D & C Act & Rules and WHO-GMP/TRS guidelines) Page 5 of 15 The Competent Authority may also carry out unannounced inspections at the premises of manufacturers of active substances used as starting materials or at the premises of manufacturing License Holders whenever it considers that there are grounds for suspecting non-compliance with the principles and guidelines of good manufacturing practice.  A risk based approach to inspection planning will enable the frequency, depth and breadth of inspections to be determined accordingly. This will allow flexible and effective administration and supervision whilst maintaining a high level of patient safety. This document sets out a simple and flexible Quality Risk Management tool that may be used by GMP Pharmaceutical Inspectorates when planning the frequency and scope of GMP inspections. It is a methodology that is based upon the concept of rating manufacturing sites on the basis of an estimated risk that they may pose to patients, consumers, animals and users of medicines. The methodology also takes into account the risk to product quality. 4. Purpose:  This document outlines recommendations for a risk based planning system according to which sites that fall under regulatory supervision are subject to inspection.  It is intended that each GMP Pharmaceutical Inspectorate uses the document as the basis for developing and implementing its own annual Inspection programme.  The purpose of this document is to provide a simple and qualitative Quality Risk Management tool that may be of use to GMP Pharmaceutical Inspectorates to priorities sites for inspections when planning the frequency and scope of GMP inspections. Page 6 of 155. Scope:  The planning of routine GMP inspections of active substance and drug product manufacturers by the Competent Authorities;  The planning of routine GMP inspections of Vaccines, New Drugs, Subsequent New drug etc. manufacturers by the Competent Authorities.  Follow-up activities, such as assigning a new risk rating to the site following the receipt of new information about the site or its products. (Note: the types of new information might include information on quality defects, product recalls, market surveillance test results, etc.  The scope of this document does not extend to the planning of inspections at new manufacturers before any inspection has taken place.  A useful rule of thumb to use is that the tool should not be applied to a site until the site has been granted a Manufacturing Authorisation and/or a GMP Certificate, as these actions indicate that the site will have been assessed from a compliance perspective. 6. Typesof Inspection A. Routine Inspection i. Inspections for grant/renewal of licenses under CLAA Scheme. ii. Inspections for issuance / revalidation of COPPs as per WHO Certification Scheme for use in international commerce only. iii. Inspections for approval of Testing Laboratories. iv. Risk based inspections B. Follow up inspection i. Compliance verification inspection for verification of corrective & preventive actions. 7. Conduct During Inspection  The inspectors are public servant within the meaning of Sec. 21 of IPC. Inspector shall act according to the procedures for handling of confidential information. All information observed or passed to the inspector is confidential and shall not be disclosed to anybody other than his controlling authority. Page 7 of 15 Inspector shall neither carry with him any written or printed materials relating to other units nor disclose any information relating to another company.  The inspector’s task is not only to point out deficiencies but also to provide guidance based on scientific evidence. 8. Steps in conduct of inspection Identification of risk There are two different kinds of risk –risk factor A. An intrinsic risk: The intrinsic risk estimated for a site reflects the complexity of the site, its processes and products, the criticality of the products or services provided by the site including from a supply perspective as well as status of sample drawn and tested. B. Compliance-related risk: The compliance-related risk reflects the GMP compliance status of the site immediately following the most recent routine inspection at the site. The details of Quality Risk Management Tool for Risk Rating based on the intrinsic risk and compliance risk and Guidance on How to Score the Intrinsic Risk Factors is annexed as Annexure I and II respectively 9. Selection of Site for Risk Based Inspection: a) Complexity refers to the complexity of the site, its manufacturing processes, and its products. b) Criticality relates to how critical the availability of the products manufactured at the site is from a supply perspective, or how critical the services provided by the site. c) Compliance reflects the compliance status of the site following the most recent routine inspection at the site. When this risk is being estimated, the classification and number of deficiencies identified at the last inspection are taken into account. Page 8 of 15Following criteria should be applied for site selection for risk based inspection:  The compliance history of the establishment;  Complaints  History of “Not of Standard Quality” drugs  The record, history, and nature of recalls linked to the establishment;  The inherent risk of the drug manufactured, prepared, propagated, compounded, or processed at the establishment;  The inspection frequency and history of the establishment;  Whether the establishment has been inspected by a foreign government or an agency of a foreign government  The level of competence demonstrated by staff at the site  The major changes at the site since the last inspection  The criticality of the products manufactured/wholesaled by the site, and the criticality of the analytical tests used by the site  Any other criteria deemed necessary and appropriate 10. Planning of Inspection:  The planning of the RBI will be done as per the risk criteria.  The risk based inspection will be conducted in accordance with Risk Based Inspection checklist as per Annexure III and IV  The Risk Based Inspection checklist encompasses of the GMP provisions of the Schedule M of the Drugs Rules, 1945 and WHO TRS. A general schedule of Inspection is to be followed by the Inspection team.  Receipt of File of the firm to the deputed inspection team member(s).  A review should be made relating to the firm to be visited from the documents available in the office file. This may include: - o Drug Manufacturing License. o Product permission for the applied products. o Site Master File o Evaluation of: - i. Product records (process validation and stability studies), ii. Reports of adverse Drugs reaction, Page 9 of 15iii. Market complaint, iv. Product recall record, v. NSQ reports available in the office file, vi. Discrepancies pointed out in previous inspection reports. Preparation of the day wise inspection plan (1-3 days) Communication with the Local Authority for access to the site of inspection and regarding the Schedule of inspection. 11. Conduct of Inspection:  There will be a preliminary tour of the site to allow the inspectors to get a general orientation of the site. It is recommended that the inspecting team start the plant tour as soon as possible after arrival. It is advisable to follow the inspection plan as per material flow.  Over the course of the inspection the inspectors shall review all procedures, production and laboratory records, validations and any other record or documentation relating to production and control of the production process.  It is advisable to check the items that are specific to certain areas of the facility, such as, Sampling /Dispensing of RM/PM, in process testing and working documents at the point of operation.  The inspection shall also include detailed tours of all production facilities, laboratories, stores, utilities, the plant’s record and documentation centre. The following specific issues shall be investigated, a) The suitability of the facility for its purpose, including the orderliness of its Lay-out for man and material movement, equipment and cleanliness; b) The production equipment – its qualification/validation, calibration and cleanliness, preventive maintenance, daily equipment usage logs. Whether production records are fully maintained and in real time. c) Critical systems: HVAC, water system, filtered compressed air, drainage. ETP and any other relevant systems. d) The documents such as master formulae, test specifications, Standard Operating Procedures, batch records (including protocols of analysis and Page 10 of 15documents relating to the control of printed material and labelling operations) requires close verification.  The inspection team may adopt the additional and other plan for areas of inspection based on the need of particular inspection for the required purpose. 12. Areas to be covered during inspection To cover following areas as per SOP, Checklist benchmarks etc. provided in the Guidance document available on CDSCO website under Public notices vide F. No. DCG(I)/Misc/2016(60) dated 26-05-2016 1. Building and premises 2. Ancillary areas 3. Security system 4. Water & Compressed air system 5. Disposal of waste(Ambient protection) 6. Health, clothing and sanitation of workers 7. Training 8. Warehousing Area 9. Raw Materials 10. Production Area for Non Sterile preparation 11. Air Handling Systems (HVAC 12. Cleaning validation 13. Manufacturing Operations and Controls: 14. Precautions against mix-up and cross-contaminations 15. Sanitation in the Manufacturing areas: 16. Equipment 17. Production Area for Sterile Preparation Page 11 of 1518. Air Handling System (Central Air Conditioning) 19. Environmental Monitoring 20. Garments 21. Sanitation 22. Equipment 23. Manufacturing Process 13. Findings: How to write a Deficiencies / Non-compliance statements: a) The non-compliance statement should include the requirement (R), evidence (E) and deficiency (D). b) Example: (R) The relevant cleaning records and source data should be kept in cleaning validation reports; (E) the source of three samples taken for recovery testing during the process equipment validation was not traceable; (D) cleaning validation reports did not include sufficient data. c) Deficiencies/noncompliance statements should distinguish whether the defect lies in the system itself or in a failure to comply with the system. For instance, when cleaning is found to be suboptimal, it is important to know whether the standard operating procedures (SOPs) are inadequate or lacking, or whether adequate written procedures exist but are not being followed by personnel. d) Where more than one deficiency relates to the same basic quality system failure, the deficiencies should be grouped and listed as a single observation, under a heading that reflects the basic system failure. e) Deficiencies should be reported with a focus on risk to patient health and/or need for corrective and preventive action (CAPA). Recommendations should relate to recommended regulatory action as appropriate. f) Each deficiency should be classified as critical, major or other, according to the following definitions, which may be adapted according to the national or regional legal context. The report should not include comments that could be construed as proposed specific solutions to issues raised. Page 12 of 1514. Classification of Findings of Risk Based Inspection: Classification of a deficiency is based on the assessed risk level and may vary depending on the nature of the products manufactured, e.g. in some circumstances an example of another deficiency may be categorized as major. A deficiency that was reported at a previous inspection and was not corrected may be reported with a higher classification. One-off minor lapses or less significant issues are usually not formally reported, but are brought to the attention of the manufacturer during the inspection. a) Critical deficiency A critical deficiency may be defined as an observation that has produced, or may result in a significant risk of producing, a product that is harmful to the user. Item/area/system/knowledge is missing or of such nature to warrant serious quality/compliance concerns. b) Major deficiency A major deficiency may be defined as a non-critical observation that: a) has produced or may produce a product that does not comply with its condition of licence b) indicates a major deviation from the GMP guidelines; c) indicates a failure to carry out satisfactory procedures for release of batches; d) indicates a failure of the person responsible for quality assurance/quality control to fulfil his or her duties; e) consists of several other deficiencies, none of which on its own may be major, but which together may represent a major deficiency and should be explained and reported as such. c) Other deficiency A deficiency may be classified as other if it cannot be classified as either critical or major, but indicates a departure from GMP. A deficiency may be other either because it is judged as minor or because there is insufficient information to classify it as major or critical. Page 13 of 1515. Outcome of inspection: Based on the number of the critical and major observations regulatory action like issuance of show cause notice or cancel a licence or suspend a licence for period as licensing authority thinks fit either wholly or in respect of any of the drugs or other actions as deemed fir under the provisions of D & C Act, 1940. 16. Action to be taken based on inspection findings: a) When there is one or more critical or several major deficiencies (e.g.≥6): I. The site is considered to be operating at an unacceptable level of compliance with Good Manufacturing Practices (GMP) guidelines. II. Administrative (Show cause notice followed by Stop production order, Cancellation of product permission, Cancellation of manufacturing license) and/or legal enforcement actions (prosecution) as necessary. III. Another inspection will normally be required. IV. This action will continue till satisfactory resolution of the non compliance after joint verification by CDSCO& State. b) When there are few major deficiencies (e.g.<6) and other deficiencies: I. The site shall submit compliance report after rectification of deficiencies and the same shall be verified for determination of compliance to GMP. CAPAs for all deficiencies to include actions implemented and/or planned, timelines and documented evidence of completion, as appropriate. II. CAPAs are to be evaluated on paper and shall include an on-site inspection for verification of compliance submitted by the site. c) When there are other deficiencies only: I. The site is considered to be operating at an acceptable level of GMP compliance. II. The manufacture is expected to provide CAPAs. CAPAs for all deficiencies to include actions Implemented and/or planned, timelines and documented evidence of completion, as appropriate. Page 14 of 15III. CAPAs are to be evaluated on paper and followed up during the next routine inspection. Annexures: Annexure I- Quality Risk Management Tool for Risk Rating based on the intrinsic risk and compliance risk Annexure II- Guidance on How to Score the Intrinsic Risk Factors Annexure III- Risk Based Inspection checklist Annexure IV- Risk Based Inspection Benchmark tool References: 1. PICS document on “A Recommended Model for Risk-Based Inspection Planning in The GMPEnvironment” 2. USFDA documents on “Understanding CDER’s Risk-Based Site Selection Model” 3. WHO TRS 981, Annex 2 “WHO guidelines on quality risk management” ******* Page 15 of 15Annexure-I Quality Risk Management Tool for Risk Rating based on the intrinsic risk and compliance risk A. The Intrinsic Risk Associated with the Site B. The Compliance-related Risk based on the last Inspection C. The Risk-Rating assigned to the SiteAnnexure II Guidance on How to Score the Intrinsic Risk Factors No Intrinsic Risk Factor & Scoring Mechanism 1 Complexity: This concerns the complexity of the site, its processes and its products. (Note: The Site Master File (if available) and the last GMP inspection report can be useful sources of information on which to assign the Complexity score.) There are three possible scores here, 1, 2 and 3. Sites with a low risk factor score in this area are known to have a low level of complexity in the design of the site, in its products and processes. When scoring this Risk Factor, it is useful to consider the following: General but useful indicators of site complexity are: • The size of the site – large sites are rated more complex than smaller sites • The number of different manufacturing or distribution processes that are in use at the site – larger numbers generally give rise to more complexity • The level of dedication of equipment and facilities (e.g. Air Handling Units) that is in place at the site – sites with a low level of dedication are considered more complex than other sites • The number of staff at the site – larger numbers generally give rise to more complexity • The number of commercial markets/countries supplied by the site - larger numbers generally give rise to more complexity • The number of customers supplied by the site - larger numbers generally give rise to more complexity • If the site is a contract manufacturer or contract laboratory, the site can be regarded as being relatively complex General but useful indicators of process complexity are: • Sterile and aseptic manufacturing processes – these are always considered highly complex processes. • Parametric release activities – these are usually considered highly complex processes. • The number of critical steps that must be controlled within a process – generally, processes with a high number of critical steps can be considered to be more complex processes. • The type of products manufactured – some product types such as low concentration/high potency dosage forms and sustained released dosage forms can be more complex to manufacture thanother types of products (such as immediate release tablets) and the complexity of their manufacturing process should be rated more highly here. • The number of unit operations in a non-sterile manufacturing process – larger numbers generally give rise to more complexity. • Repackaging activities - repackaging an already packaged batch can be considered a moderately to highly complex process. • The extent of reprocessing or reworking taking place at the site: these activities can add complexity to the process • Biological processes • The extent of subcontracting in use by the site - a significant use of contract manufacturers, off-site distribution sites or contract laboratories generally gives rise to complexity. • In case of importers, the complexity of importation, batch release and product distribution processes – sometimes the arrangements in place for importation can be quite complex. General but useful indicators of product complexity are: • The number of components that make up any one product pack - larger numbers of components in a pack generally give rise to more product complexity. For example, a pack of an injectable product may have 4 components within it (a lyophilised vial, a diluent vial, a transfer needle and a technical leaflet, whereas a pack of a tablet product may have just a blister strip and a patient information leaflet within it.) • Products requiring special storage and distribution: (e.g. cold chain products and short-shelf-life products such as radiopharmaceuticals can be complex to manage.) Scoring Guideline: Assign a score of 1 to sites with a low overall level of Complexity Assign a score of 2 to sites with a moderate overall level of Complexity Assign a score of 3 to sites with a high overall level of Complexity Note: When assigning the overall complexity rating, the rating (1, 2 or 3) which most reflects the various individual complexity ratings that were assigned to site, process and product complexity should be chosen. This is similar to taking an average of all of the individual complexity ratings that were assigned. In cases where there is insufficient information or knowledge about the complexity associated with the site, its processes and products, a medium score of 2 should be assigned. 2 Criticality: This concerns how critical the availability of the products manufactured by the site are from a supply perspective, or howcritical the services provided by the site are. An example of a critical service provided by a site may be an analytical testing service performed for several other companies. (Note: The Site Master File (if available) and the last GMP inspection report can be useful sources of information on which to assign the Criticality score.) There are three possible scores here, 1, 2 and 3. Scoring Guideline: Assign a high score (of 3) for the sites where “Not of Standard Quality” are more than 5 per year. Assign a high score (of 3) to sites that are known to manufacture essential products or that are known to be sites that provide an essential service that is not readily available elsewhere. • These may be sites that are the major or sole supplier of an essential product (such as an important vaccine, a critical blood product, etc.). Note: it is recognised that being the major or the sole supplier of an essential product does not present any risk to product quality; rather, it presents a risk to product availability. • The test methods (and related equipment) used by these sites cannot easily or readily be performed or used by other laboratories. • These may be sites that provide a contract manufacturing or testing service to a number of other manufacturers and a disruption in such services would have a significant impact on product availability. Assign a low score (of 1) to sites that are known to manufacture only non-essential products or that are known to be sites that do not provide an essential service. Assign a high score (of 1) for the sites where “Not of Standard Quality” are 0-3 per year • These may be sites that are not the sole supplier of any important products (such as an important vaccine, a critical blood product, etc.). • The test methods (and related equipment) used by these sites are not such that they cannot be readily performed or used by other laboratories. • These are not sites that provide a contract manufacturing or testing service to many other manufacturers, where a disruption in such services would have a significant impact on product availability.Assign a medium score (of 2) to sites that are in between the above types of sites. Assign a high score (of 2) for the sites where “Not of Standard Quality” are 3-5 per year Note: In cases where there is insufficient information or knowledge about the criticality associated with the site, a medium score of 2 should be assigned.Risk Based Joint Inspection Report Name of the manufacturing unit Address Mfg. Lic. no. Validity of License. Constitution of the firm List of Directors/Partners/Proprietor License issuing authority Categories of drugs permitted to be manufactured Specify whether COPP has been issued to the firm Name and Designation of the Inspecting team members Site Specific Data No. of Products manufactured at site (during last year) No. of manufacturing blocks No. of Technical Personnel in Manufacturing No. of Technical Personnel in QA No. of Technical Personnel in QC No. of Technical Personnel in Microbiology No. of Technical Personnel from other Department No. of Technical Personnel in R&D Page 1 of 55Risk Based Joint Inspection Report No. Of technical personnel in Formulation development No. of Samples drawn by QC (during last year) No. of Samples declared OOS (during last year) No. of samples declared NSQ by Govt. Analyst (during last year). Collect reasons for such failures and annexe with this checklist Observations should be descriptive without ambiguity and answer like "Yes" or "No" should be avoided 1 Building and premises: - Observations Rating Specify whether the whole facility is separated, 1.1 Sch-M dedicated and is not a part of any other non-drug facility. Specify whether the surroundings of manufacturing 1.2 Sch-M area is clean and as per the SOP prescribed in this regard. (Mention the SOP nos.) Describe the pest, insects, birds and rodents control system followed in the premises. Specify pest control 1.3 Sch-M schedule- area wise, along with materials and methods used. What measures have been taken to make Interior surface (of walls, floors, and ceilings) smooth and free from cracks, and to permit easy cleaning Specify material of construction and finish for walls, ceiling, 1.4 Sch-M floor, coving etc. i.e. whether Epoxy or PU coated, kota / granite stone with epoxy sealed joints, solid / GI / gypsum / cal. Silicate board ceiling with epoxy, PU or any other pre-fabricated panel (GRP, powder coated SS or Aluminium etc.) paint. Page 2 of 55Risk Based Joint Inspection Report Specify the lux level maintained in various parts of the 1.5 Sch-M, premise (Storage area, manufacturing area specially visual inspection, Laboratory areas etc.). Specify the air handling system used in various areas 1.6 Sch-M, i.e. stores, production, packing, QC areas. Specify drainage system which prevents back flow and 1.7 Sch-M, entry of insects and rodents into the premises. Specify number and location of drains installed. 2 Ancillary areas: - Specify the position of rest and refreshment rooms and 2.1 Sch-M, mention whether they are separated and not leading directly to the manufacturing and warehouse areas. Are there general change rooms in plant? specify 2.2 Sch-M, number of washing station & toilets provided for number of users. Specify whether primary clean garments are provided 2.3 Sch-M, for each personnel entering the factory premises. Is there in-house general laundry for garment washing 2.4 Sch-M, / cleaning? If not how garment washing is carried out and monitored. Sch-M, Whether change room facilities separated for both 2.5 Para sexes. Sch-M, Whether maintenance workshop is separated and 2.6 Para away from production. 3 Security system:- Is the men & material movement inside the factory 3.1 WHO TRS premises, observed & checked through security system. Is CCTV available to control the Entry & Exit from 3.2 WHO TRS Factory premises? Is there a system for identifying persons visiting the 3.3 WHO TRS factory ? How? Page 3 of 55Risk Based Joint Inspection Report What is the precautionary activity taken for the 3.4 WHO TRS movement of carriers i.e. vehicles? 4 Water & Compressed air system: - Verify whether a current drawing of the water system Sch-M, 4.1 showing all equipment in the system from inlet to the Para points of use is available. Sch-M, Specify the MOC of the water storage tank (Both PW 4.1.1 Para & WFI) and its pipe line. Sch-M, Specify weather storage tank for WFI is steam 4.1.2 Para jacketed. Specify whether water system validation/qualification Sch-M, 4.2 has been carried out as per protocol and reports have Para been prepared and maintained. Whether IQ protocol include at least facility review, equipment specification vs. design, welding roughness testing on pipelines, absence of dead points / section in the pipelines, pipe and tank passivation, drawings, WHO 4.3 SOP for operations, cleaning, sanitation, maintenance TRS-970 and calibration of gadgets. Whether its report includes Conclusion / Summary, Data tables, Results, Conclusions, Protocol reference, Revision and approval signatures. Whether OQ protocol includes at least System production capacity (L/min), Flow type and water rate, Valve operation, Alarm system operation and Controls WHO 4.4 operation? Whether its report includes Conclusion / TRS-970 Summary, operations performed Data tables, Results, Conclusions, Protocol reference, Revision and approval signatures. WHO Please specify whether Phase 1, Phase 2 and Phase 4.5 TRS-970 3 studies carried as part of PQ stages? WHO Phase 1: Whether the operations parameters, cleaning 4.6 TRS-970 and sanitation procedures & frequencies defined. Page 4 of 55Risk Based Joint Inspection Report Whether daily sampling records for every pre- treatment point and usage point for a period of 2 to 4 weeks maintained and SOP’s prepared. PHASE 2: Whether daily sampling records for every WHO 4.7 pre-treatment point and usage point for a period of 4 to TRS-970 5 weeks after Phase 1 maintained and reviewed. WHO PHASE 3: Whether weekly sampling records available 4.8 TRS-970 of every usage point for a one-year period. Specify source of raw water and give details of treatment processes, sampling points, distribution and 4.9 Sch-M storage system for raw and purified water. Verify whether the Raw Water holding tank was sanitised as per specified SOP. Verify whether the softener column is regenerated as 4.10 Sch-M per the specified SOP. Specify whether the quality of potable water used for 4.11 Sch-M the preparation of purified water meets the requirement of Schedule M in respect of microbiological limit. Specify whether the quality of Purified Water used for 4.12 Sch-M the preparation of WFI meets the requirement of IP/BP/USP. What is the process for preparation of Water for 4.13 Sch-M Injection (WFI)? Specify the process of sanitisation of SS storage tank 4.14 Sch-M of WFI. Specify whether the quality of WFI meets the 4.15 Sch-M requirement of IP/BP/USP & Schedule M. Specify whether WFI is used for: 1) Bulk preparations of liquid injections 4.16 Sch-M 2) Final rinse of product containers for sterile preparations. 3) Final rinse of machine parts (for sterile preparations) Page 5 of 55Risk Based Joint Inspection Report 4) Preparation of disinfectant solutions for use in critical areas (for sterile preparations.) How bio burden in purified water & WFI are controlled 4.17 Sch-M / reduced (Mention the SOP no. followed in this regard). Specify whether WFI has been stored and circulated 4.17.1 Sch-M above 70 degree centigrade. Verify whether the circulation rate of purified water & WHO 4.18 WFI is at least twice the storage capacity of the holding TRS-970 vessels per hour. WHO Verify the Dead leg of non returned valve at the 4.19 TRS-970 discharge point. WHO Specify how the circulation loop is sanitised. Verify the 4.20 TRS-970 SOP. WHO Specify whether spray ball is used to wet the surface 4.21 TRS-970 of head space in the storage vessel. WHO Specify whether pressure release valves are provided 4.22 TRS-970 in the storage vessel. How water tanks are cleaned periodically and records 4.23 Sch-M maintained thereof. WHO Specify whether on line TOC test is available for WFI 4.24 TRS-970 & PW. Specify whether replacement of Air Vent filters on the purified/WFI water tank is carried out as per relevant PIC/S 4.25 SOP. Guidelines Whether the provision to keep dry the vent filter is made. Specify the arrangement for preparation of pure steam 4.26 Sch-M & its use. Specify whether pure steam (condensate) used in production meets the microbiological specification of 4.27 Sch-M not more than 10 cfu/100ml and IP/BP/USP specifications of WFI. Page 6 of 55Risk Based Joint Inspection Report WHO 4.28 Verify PQ of the PSG. TRS-970 Specify the system in place for the compressed gases 4.29 Sch-M / air used in the facility. Verify the qualification documents of compressed air 4.30 ISO/PICS system specially where it comes in contact with product or primary container. Specify whether action and alert limits are followed WHO 4.31 based on qualification of water and compressed Air TRS-970 system. 5 Disposal of waste(Ambient protection):- Specify the system of disposal of sewage, and effluents (solid, liquid, and gas) from the manufacturing 5.1 Sch-M site.(Enclosed the copy of NOC obtained from State Pollution control board in this regard.) Mention the procedure for storage and disposal of 5.2 Sch-M rejected drugs and applicable SOP. Whether adequate records are maintained for the 5.3 Sch-M disposal of waste. Whether provision for disposal of bio-medical waste 5.4 Sch-M made as per the provisions of the Bio Medical Waste (Management and Handling) Rules 1996. 6 Health, clothing and sanitation of workers: - Whether all personnel prior to employment have undergone medical examination including eye 6.1 Sch-M examination and are all free from Tuberculosis, skin and other communicable or contagious diseases & thereafter at regular intervals. Whether investigational reports, e.g. of X rays etc. preserved. 6.2 Sch-M Whether records of such medical examination are maintained thereof Page 7 of 55Risk Based Joint Inspection Report Specify whether employees report their illness to the 6.3 Sch-M supervising authority before entering into the production area. Specify whether person from infectious disease is 6.4 Sch-M barred to enter into production area. Specify if any unhygienic practise is observed within 6.5 Sch-M the manufacturing areas. Whether all personnel are trained to ensure high level 6.6 Sch-M of personal hygiene. Mention the SOP no. followed in this regard. Specify whether cross over bench is in place in the 6.7 Sch-M change room and if so whether it rules out the possibility of dust particle entering the clean side. Whether arrangements provided for cleaning of 6.8 Sch-M outside dust and dirt from foot. 7 Training:- Specify whether basic training on GMP is provided to 7.1 Sch-M all personnel attached to production and quality control activity at the time of induction. Specify whether specific training related to the job duty 7.2 Sch-M are provided to all personnel at the time of induction. WHO 7.3 Specify whether continuous training is provided. TRS-986 WHO Specify whether concept of QA and its importance is 7.4 TRS-986 part of training session. Are all the persons associated with various production activities properly trained as per guidelines provided in WHO 7.5 WHO working document. Verify the assessment TRS-986 records of the training of few selected people who are associated with critical operations and procedure 8 Warehousing Area:- WHO Is access to the area restricted to authorised personnel 8.1 TRS-986 only. Page 8 of 55Risk Based Joint Inspection Report Whether adequate areas have been allocated for warehousing of Raw Materials, intermediates, Packaging Material, products in quarantine, finish 8.2 Sch-M products, rejected or returned products. How are these areas marked or segregated. Please specify the total area provided for warehousing. How the warehousing areas being maintained to have 8.3 Sch-M good storage conditions. Are they clean and dry and maintained within specified temperature limits? Is there any SOP defining maximum exposure time at WHO 8.4 room temperature for thermo labile materials i.e. prior TRS-986 to storage in a refrigerator. Specify the storage arrangement provided for materials which are sensitive to temperature, humidity 8.5 Sch-M and light and how the parameters are monitored. Is cold room or deep freezers required for storage of goods? WHO Verify the Thermal mapping of the cold rooms or deep 8.6 TRS-986 freezers Whether receiving and dispatch bays are maintained 8.7 Sch-M to protect in coming and out going materials. How incoming materials are treated and cleaned before entry into the plant. 8.8 Sch-M Please specify the cleaning system for the outer surface of the container. How quarantined materials are segregated from other 8.9 Sch-M materials. How access to quarantined area is restricted. Specify the system followed for storing passed raw 8.10 Sch-M materials. Whether proper racks, bins and platforms have been 8.11 Sch-M provided for the storage. Page 9 of 55Risk Based Joint Inspection Report What is the control on entry of material and men into WHO the sampling area? Whether reverse LAF have been 8.12 TRS-986 provided for sampling. Whether log book for sampling booth maintained. Specify the storage arrangement provided for primary 8.13 Sch-M packaging materials. Specify the arrangements provided to sample the 8.14 Sch-M primary packaging materials foils, bottles, etc. which are used as such. WHO 8.15 Specify sampling plan used. TRS-986 WHO Which type of sampling tools are used and how they 8.16 TRS-986 are cleaned, dried and maintained. How containers are cleaned before and after sampling. WHO 8.17 (Specify whether the sampling is carried out as per the TRS-986 current SOP). What provisions have been made for segregated 8.18 Sch-M storage of rejected, recalled or returned materials or products. How is the access to these areas restricted? How printed secondary packaging materials are stored 8.19 Sch-M in safe, separate and in secure manner. How printed packaging materials, product leaflets etc. 8.20 Sch-M are stored separately to avoid chances of mix-up? How labels, cartons, boxes, circulars, inserts and 8.21 Sch-M leaflets are controlled. ? How records of receipt of all labelling and packaging 8.22 Sch-M materials are maintained. Whether unused packaging materials return to the 8.23 Sch-M store or destroyed. How returned/unused packaging material like foils is 8.24 Sch-M controlled so as to prevent contamination and cross- contamination. Page 10 of 55Risk Based Joint Inspection Report Specify the arrangement provided for dispensing of 8.25 Sch-M starting materials. What is the control on entry of material and men into WHO the dispensing area? Whether reverse LAF have been 8.26 TRS-986 provided for dispensing with back ground clean air supply. WHO Whether pressure differential is maintained between 8.27 TRS-986 the dispensing and adjacent areas. WHO 8.28 Specify the pressure differential maintained. TRS-986 Examine the record of the daily check of balances in 8.29 Sch-M the dispensing area. WHO How containers are cleaned before and after 8.30 TRS-986 dispensing. Who carries out the dispensing? Specify whether appropriate air velocity is maintained WHO in sampling & dispensing areas which rule out any 8.31 TRS-986 influence in the balance readings placed inside the RLAFs Benches. Specify whether the dispensing is carried out as per the 8.32 Sch-M current SOP. Specify whether dispensed material for each batch of 8.33 Sch-M final product are kept together and conspicuously labelled. What steps are taken against spillage, breakage and 8.34 Sch-M leakage of containers? How highly hazardous, poisonous and explosive materials, narcotics, and psychotropic drugs are 8.35 Sch-M handled and stored. How these areas are safe and secure. 9 Raw Materials: - Please specify the procedures followed for receiving 9.1 Sch-M and processing of in-coming materials (Starting materials and packing material). Verify the SOP. Page 11 of 55Risk Based Joint Inspection Report Whether first in / first out or first expiry principal has 9.2 Sch-M been adopted. How they are labelled and stored as per their status – 9.3 Sch-M Under Test, Approved and Rejected Whether incoming materials are purchased from 9.4 Sch-M approved vendors. Whether list of approved vendors is available to the 9.5 Sch-M user. WHO 9.6 Specify the norms of vendor qualification. TRS-986 How damaged containers are identified recorded and 9.7 Sch-M segregated Whether each batch of a consignment is considered for 9.8 Sch-M sampling, testing and release. WHO Whether all the containers of each batch of starting 9.9 TRS-986 materials sampled for identification test. Whether labels of raw material in the storage area have information like; a) designated name of the product and the internal code reference, where applicable, and analytical reference number; 9.10 Sch-M b) manufacturer’s name, address and batch number; c) the status of the contents (e.g. quarantine, under test, released, approved, rejected); and d) The manufacturing date, expiry date and re-test date. Whether separate areas are provided for under test, 9.11 Sch-M approved and rejected materials. How the containers from which samples have been 9.12 Sch-M drawn labelled. Please specify the procedures by which it is ensured 9.13 Sch-M that the raw materials which has been released by the Page 12 of 55Risk Based Joint Inspection Report Quality Control Department and which are within their shelf life are going to be used in the product. 10 Production Area for Non Sterile preparation:- WHO Verify whether access to production area is restricted 10.1 TRS-986 to authorised personnel only. Whether the facility is provided with a well-sealed WHO 10.2 structure with no air leakage through ceilings, cracks TRS-986 or service penetrations. Whether entry and exit doors, for materials and WHO personnel, have an interlock mechanism or other 10.3 TRS-986 appropriate system to prevent the opening of more than one door at a time. WHO Specify the procedures for entry of maintenance 10.4 TRS-986 people into the production area. WHO Whether the change rooms have an arrangement with 10.5 TRS-986 step-over/cross-over bench. 10.6 Sch-M Is there any cris cross flow of materials and men? Whether the premises and equipment are 10.7 Sch-M appropriately designed and installed to facilitate cleaning and decontamination. WHO Specify the position of IPQC lab in the manufacturing 10.8 TRS-986 area. Specify whether non storage areas are used for 10.9 Sch-M storage of any material. WHO Specify the provisions for storage of dirty, washed and 10.10 TRS-986 cleaned equipment in process areas. Specify how service lines are identified for nature of 10.1 Sch-M supply and direction of the flow. Whether service lines in production areas are through WHO 10.12 service pendants. If not, how they are placed so as to TRS-986 avoid accumulation of dust. 11 Air Handling Systems (HVAC):- Page 13 of 55Risk Based Joint Inspection Report Please specify whether following parameters are qualified:  (IQ,OQ,PQ)  Temperature  Relative humidity  supply air quantities for all diffusers  return air or exhaust air quantities  room air change rates WHO  room pressures (pressure differentials) 11.1 TRS-986  room airflow patterns  unidirectional flow velocities  filter penetration tests (HEPA)  room particle counts  room clean-up rates  microbiological air and surface counts where appropriate  operation of de-dusting  warning/alarm systems WHO 11.2 Verify the SOPs for AHUs operation and cleaning. TRS-986 Specify whether the facilities and premises have following basic air-handling characteristics: a) The absence of direct venting of air to the outside. b) Whether the facility is maintained at a negative air pressure to the environment. WHO c) The precaution taken to prevent the infiltration into 11.3 TRS-986 the core areas. d) Whether appropriate air pressure alarm systems as well as alert and action limit is provided. e) The type of HEPA filters used in the HVAC system f) Whether the change rooms are supplied with same quality of air as supplied to the working area. Page 14 of 55Risk Based Joint Inspection Report g) The measures taken to prevent air flow from the primary packing area to the secondary packing area. Whether HVAC system description includes: 1) Schematic drawings detailing the filters and their WHO 11.4 specifications TRS-986 2) Number of air changes per hour 3) pressure gradients WHO Specify the emergency power systems in case of 11.5 TRS-986 power failure. WHO Specify whether recirculated air is used. If yes, specify 11.6 TRS-986 the proportion of fresh air supplied. Whether risk assessment study has been carried out in WHO 11.7 case of return air/ recirculated air system. Verify the TRS-986 records thereof. WHO Specify what precaution has been taken during filter 11.8 TRS-986 change of AHUs. Whether all exhaust systems from the facility, including dust extraction systems, vacuum system exhaust, fluid WHO 11.9 bed drier exhaust, coating pan exhaust, etc., are TRS-986 passed through safe change filter housings and wet scrubber before being exhausted to the atmosphere. Whether all exhaust points outside the building are WHO located as far as possible from air entry points, exit 11.10 TRS-986 points and at a high level, to minimize the possibility of re-entrainment of exhaust air. WHO Whether the return air ducts are checked periodically 11.1 TRS-986 for dust accumulation. Whether the dust collectors are located in a room 11.11 Sch-M maintained at a negative pressure. WHO Whether the filters cleaning facility is maintained at 11.12 TRS-986 negative pressure. Page 15 of 55Risk Based Joint Inspection Report WHO Whether records for safe disposal of all contaminated 11.13 TRS-986 filters and dust are maintained. Specify whether total No. of AHUs used to cover the WHO 11.15 whole production Area is commensurate with the TRS-986 requirements WHO 11.16 Specify the Terminal Air Filter of various core areas. TRS-986 WHO Specify the no. of Air Change maintained in various 11.17 TRS-986 core areas. WHO Specify the pressure balancing to segregate different 11.18 TRS-986 areas. WHO Are the returns risers cleaned during Product Change 11.19 TRS-986 Over? Verify if the AHU's / HVAC systems have been shut WHO down. If yes the reasons there of such as cleaning & 11.20 TRS-986 maintenance & the procedures for re-initiation / re-start of the systems 12 Cleaning Validation:- Is a validation performed to confirm cleaning 12.1 Sch-M effectiveness? Does the protocol define the selection criteria for WHO 12.2 products or groups of products subject to cleaning TRS-986 validation? WHO Is data produced supporting the conclusion that 12.3 TRS-986 residues were removed to an acceptable level? Specify whether the validation is implemented to verify cleaning of: WHO 12.4 1) Surfaces in contact with the product TRS-986 2) After a change in product 3) Between shift batches. WHO Specify whether the Validation Strategy include 12.5 TRS-986 contamination risks & equipment storage time. Page 16 of 55Risk Based Joint Inspection Report WHO Whether Quality Control responsible of the sampling 12.6 TRS-986 for cleaning verification? WHO Whether personnel engaged in cleaning, sampling etc. 12.7 TRS-986 trained. Specify whether acceptance limits been set for cleaning verification and are based on following WHO criteria: 12.8 TRS-986 1) Visually clean. 2) 10 ppm in another product. 3) 0.1% of the therapeutic dose? WHO Specify whether detergent residues and degradation 12.9 TRS-986 products are investigated during validation. Whether validation records include: Recovery study data, Analytical method, Acceptance WHO Criteria, Swab recovery test, Signatures of the Quality 12.10 TRS-986 Assurance Manager, Signature of the employee in charge of cleaning verification from Production and Quality Control. 13 Manufacturing Operations and Controls:- Whether the contents of all vessels and containers used in manufacture and storage is conspicuously 13.1 Sch-M labelled with the name of the products. Batch no, Batch Size, and stage of manufacture along with signature of technical staff. Whether the products not prepared under aseptic 13.2 Sch-M conditions are free from pathogens like Salmonella, Escherichia coli, Pyocyanea etc. If yes, pls give brief account of measures taken to 13.3 Sch-M assure freedom from pathogens. WHO Verify whether handling of materials and products are 13.4 TRS-986 carried out in accordance with the relevant SOP’S. WHO Specify Whether any deviation is approved in writing 13.5 TRS-986 by a designated person and recorded. Page 17 of 55Risk Based Joint Inspection Report WHO 13.6 Is there an approved SOP for In process check? TRS-986 WHO Is the personnel clothing clean, unstained & dust free, 13.7 TRS-986 including shoes? WHO Is there a cleaning SOP for slippers or shoes that is 13.8 TRS-986 being used in the manufacturing area? WHO Whether process hold time studies has been carried 13.9 TRS-986 out for various stages of production 14 Precautions against mix-up and cross-contaminations:- Whether proper AHU, pressure differential, segregation, status labelling have been provided to 14.1 Sch-M prevent mix-up and cross-contamination in manufacturing area Pls specify the areas of dust generation and 14.2 Sch-M mechanism involved in controlling the dust Do all the areas have their own independent air locks 14.3 Sch-M separately for men and material entry. What criterion of pressure differential has been set for 14.4 Sch-M production v/s adjoining areas. Whether processing of sensitive drugs like Beta lactam Antibiotics and Sex Hormones is done in segregated 14.5 Sch-M areas with independent AHU and proper pressure differentials along with demonstration of effective segregation of these areas with records. Please specify what measures has been taken to 14.6 Sch-M prevent contamination of products with Beta Lactam Antibiotics, Sex hormones and cyto toxic substances. What measures has been taken to prevent mix-ups 14.7 Sch-M during various stages of production. Whether equipments use for production are labelled 14.8 Sch-M with their current status. Whether packaging lines are independent and 14.9 Sch-M adequately segregated. Page 18 of 55Risk Based Joint Inspection Report How line clearance is performed. Whether records of 14.10 Sch-M line clearance is maintained according to appropriate checklist. Whether separate carton coding area has been 14.11 Sch-M provided or online carton coding is performed How carton coding procedure is controlled. Please specify how temperature, humidity and air 14.12 Sch-M filtration are controlled in the areas where raw material and/or products are exposed and handled How access of authorized persons to manufacturing 14.13 Sch-M areas including packaging is controlled. Whether separate gowning provision is followed before 14.14 Sch-M entering the core areas. Whether segregated secured areas for recall or 14.15 Sch-M rejected materials or for such material which are to be processed or recovered are provided. Whether various operations are carried out in 14.16 Sch-M segregated areas. Are doors of all core areas closed at all times with 14.17 Sch-M interlock arrangements? Specify whether any SOP is followed to verify the 14.18 Sch-M effectiveness for prevention of cross contamination. WHO Specify whether critical operations are carried out in 14.19 TRS-986 closed system. WHO 14.20 Specify the methods followed for product change-over. TRS-986 15 Sanitation in the Manufacturing areas:- Specify the cleaning procedure of the manufacturing 15.1 Sch-M areas and verify with the SOP in this regard. 15.2 Sch-M Whether cleaning procedure is validated. 15.3 Sch-M Whether a routine sanitation program is in place. 15.4 Sch-M Verify the SOP & the records in this regard. Page 19 of 55Risk Based Joint Inspection Report Does the location facilitate cleaning of equipment as 15.5 Sch-M well as the cleaning of the areas in which they are installed? 15.6 Sch-M Whether production area is adequately lit. Mention lux levels observed in production, visual 15.7 Sch-M inspection and other areas. Specify in detail the procedure followed during product 15.8 Sch-M changeover. 16 Equipment: - Whether the equipment are designed aiming to minimize risk of error and permit effective cleaning and 16.1 Sch-M maintenance in order to avoid cross contamination & build up of dust. 16.2 Sch-M Whether all equipment are provided with log book. Please specify the procedures to clean the equipment 16.3 Sch-M after each batch production. Whether validity period for use after the cleaning of 16.4 Sch-M equipment is specified. Whether separate area is provided for storage of 16.5 Sch-M machine parts etc. Whether balances and other measuring equipments with appropriate range are available in the Raw 16.6 Sch-M Material stores & production areas and they are calibrated in accordance with SOP maintained. Specify the calibration schedule of the balances. Specify material of construction of contact parts of the 16.7 Sch-M production equipments. Which types of lubricants are used in the equipment. 16.8 Sch-M Specify the quality and control reference No. of these lubricants Specify the procedures to remove defective 16.9 Sch-M equipments from production areas. Page 20 of 55Risk Based Joint Inspection Report WHO Verify whether washing and cleaning of equipment are 16.10 TRS-986 not a source of contamination. 16.11 Sch-M Whether all equipment is provided with an ID NO. WHO Specify the procedures to clean the equipment after 16.12 TRS-986 each batch production and verify with the SOP. WHO 16.13 Specify whether CIP or SIP is in place. TRS-986 WHO 16.14 Specify whether the CIP / SIP system is qualified TRS-986 Are there cleaning agent labelled with a catalogue no. WHO 16.15 indicating that they were received through the TRS-986 warehouse. WHO 16.16 Are there records for preparation of cleaning agent? TRS-986 17 Production Area for Sterile Preparation 17.1 Building and Facilities:- Specify the building is devoid of cracks especially in the 17.2 Sch-M Critical solutions preparation rooms, Filling rooms, Sealing rooms. Are the locations of services like water, steam, gases 17.3 Sch-M etc. Such that the servicing or repairs can be carried out without any threat to the integrity of the facility Specify water lines pose any threat of leakage to the 17.4 Sch-M critical area Specify the manufacturing areas clearly separated into following Support Areas: 1) Washing of containers & closures 17.5 Sch-M 2) Storage of washed containers & closures 3) Sterilization of containers & closures 4) Preparation of bulk solution ( critical/non critical) 5) Change room Page 21 of 55Risk Based Joint Inspection Report Specify de-cartoning areas to remove outer cardboard 17.6 Sch-M wrappings of primary packaging materials segregated from the washing areas. Specify whether particle shedding materials like 17.7 Sch-M wooden pallets, fibre board drums, cardboards etc. are taken into the preparation areas. Specify in the classified areas: 1) Walls are flat, smooth and devoid of recesses. 2) Surface joints like electric sockets, gas points flushed with walls. 3) Joints in the ceiling are properly sealed 17.8 Sch-M 4) Air grills and lights flushed with the ceiling. 5) Grade A & B areas devoid of sinks and drains. 6) Doors and windows made up of non shedding materials. 7) Doors open towards higher pressure areas and close automatically due to air pressure. WHO Is there a glass panel between critical area & support TRS-961 17.16 area so that all operations in Grade A & B areas can ANNEXE- be supervised from support areas? 06 WHO TRS-961 Fire extinguishers are suitably fastened to the walls 17.17 ANNEXE- without gaps. 06 Quality of the furniture used is smooth & washable and 17.18 Sch-M made of SS316. Change rooms entrance provided with air locks before 17.19 Sch-M entry to the sterile product manufacturing areas. How many change rooms are provided to enter into the 17.20 Sch-M critical areas? Page 22 of 55Risk Based Joint Inspection Report WHO Specify an appropriate inter- locking system with visual TRS-961 17.2 and/or audible warning system installed to prevent the ANNEXE- opening of more than one door at a time. 06 Are the critical and support areas provided with 17.2 Sch-M intercom telephones or speak phones for communication purposes. Specify the critical areas and support areas provided 17.2 Sch-M with suitable air- locks or pass boxes with proper interlocking arrangements for material transfer. WHO TRS-961 Specify whether dynamic pass box is used for material 17.2 ANNEXE- transfer between two different air class. 06 Specify the method of transfer of sterile rubber bungs 17.3 Sch-M & aluminum caps to the aseptic area. Specify whether grade A/B area is devoid of sinks and 17.3 Sch-M drains. 18 Air Handling System (Central Air Conditioning):- Specify whether the Air Handling Units for sterile 18.1 Sch-M product manufacturing area are separated from those for other areas Give the Background Grade of air for following critical areas: 1) Aseptic filling area 2) Sterilized components unloading area for aseptic 18.2 Sch-M filling. 3) Batch manufacturing area for aseptic filling preparations. 4) Component washing and preparation area. 5) Change rooms to enter into Critical area. Page 23 of 55Risk Based Joint Inspection Report WHO Specify the steps taken in air handling system to TRS-961 18.3 achieve the Grade A, B, C and D of air as per ANNEXE- designated classified areas. 06 Specify the recovery time of B & C zone from the time 18.4 Sch-M of personnel leaving the room after completion of operations and verify the records in this regard. Specify whether filling operations are challenged 18.5 Sch-M initially and there after periodically by simulation trials including sterile media fill. WHO TRS-961 Specify the procedure followed for medial fill and the 18.6 ANNEXE- acceptance criteria. 06 WHO Whether the medial fill trial is based on worst case TRS-961 situation taking into consideration all interventions, 18.7 ANNEXE- activities occurring during normal activity as well as 06 worst case. WHO Whether simulation tests are repeated at defined TRS-961 18.8 intervals and after any significant modification to HVAC ANNEXE- system, equipment or process. 06 Specify the number of air changes in Grade A/B and 18.9 Sch-M Grade C areas. Specify the air velocity maintained in Grade A Laminar 18.10 Sch-M Air Flow stations Specify the differential pressure between areas of 18.1 Sch-M different environmental standards. Specify type of manometer installed for measurement 18.1 Sch-M and verification of Air Pressure Differential. WHO Specify the air classification in final change room to 18.13 TRS-961 enter A/B area. Page 24 of 55Risk Based Joint Inspection Report ANNEXE- 06 19 Environmental Monitoring:- Specify the temperature and humidity maintained in the 19.1 Sch-M critical areas. Verify the area qualification records and specify whether the following were taken into consideration: 1) No. of Persons 2) ACPH (Air Changes per hours) WHO 3) Particle count (Static & Dynamic) TRS-961 4) Viable count (Static & Dynamic) 19.2 ANNEXE- 5) Temperature & Humidity 06 6) Air Sampling location and interpretation of results (Both viable and non-viable) 7) Whether the above method is in compliance with ISO 14644-1 8) Action and Alert limits for all the above parameters Mention the periodic monitoring frequencies of the followings: 9) Particulate Counts 10) HEPA filters integrity testing 19.3 Sch-M 11) Air Change rates 12) Air pressure differentials 13) Temperature and Humidity 14) Microbiological monitoring by settle plates and/ or swabs in Critical areas & Other areas Does a written Environmental Monitoring Program 19.4 Sch-M exist? How long the settle plates are exposed in Grade A and 19.5 Sch-M other areas. Verify the records of microbiological results also 19.6 Sch-M specify whether alert and actions limits are followed or not. Page 25 of 55Risk Based Joint Inspection Report What action is taken in case particulate and 19.7 Sch-M microbiological monitoring counts exceed the limits? WHO Specify what parameters are reassessed and TRS-961 approved before starting production and in case of 19.8 ANNEXE- major engineering modifications being carried out to 06 the HVAC system of any area. 20 Garments: 20.1 Sch-M Specify type of garments used in critical areas? 20.2 Sch-M Specify type of Zips used in garments 20.3 Sch-M Whether garments used in critical areas are sterile. Specify the process of sterilization of the garments & 20.4 Sch-M the practice followed to carry the sterilised garments to the final change room. Are garments, masks, gloves are changed at every 20.5 Sch-M work session? Are the gloves used made of latex or other suitable 20.6 Sch-M plastic material 20.7 Sch-M Are powder free gloves used in clean rooms Are the gloves long enough to cover the wrists 20.8 Sch-M completely and allow the over-all cuff to be tucked in Are the foot-wear used made of plastic or rubber 20.9 Sch-M material 20.10 Sch-M Are the foot-wear daily cleaned with a bactericide Does the safety goggles / numbered glasses worn 20.1 Sch-M inside the critical areas have side extensions 20.1 Sch-M Are safety goggles sanitized by a suitable method 20.1 Sch-M Specify the garment changing procedure documented Specify whether operators are trained in garment 20.1 Sch-M changing procedure. Specify a full size mirror been provided in the final 20.2 Sch-M change room to ascertain that the operator has appropriately attired in the garments. Page 26 of 55Risk Based Joint Inspection Report WHO TRS-961 Specify how the garments used in clean areas are 20.2 ANNEXE- cleaned and sterilized. 06 21 Sanitation: Specify the SOP followed for sanitation of sterile 21.1 Sch-M processing facilities and mention the SOP nos. Specify whether employees carrying out the sanitation 21.2 Sch-M of critical areas are specially trained for this purpose. 21.3 Sch-M Verify the training records. 21.4 Sch-M Specify the sanitizing agent/s used. Specify the quality of water used for preparation of 21.5 Sch-M sanitising solution. 21.6 Sch-M Specify the disinfectant used for hand sprays? Specify whether disinfectant solutions are filtered 21.7 Sch-M through membrane into suitable sterile containers or sterilized before use? Specify whether the diluted disinfectants bear ‘use 21.8 Sch-M before’ labels based on microbiological establishment of their germicidal properties & verify the records Specify whether fumigation is carried out in critical 21.9 Sch-M areas. If yes, specify fumigating agent and its conc. used. Specify whether any SOP exist for the purpose of 21.10 Sch-M fumigation if so mentioned the SOP nos. 21.1 Sch-M Specify the cleaning procedure of critical areas. WHO Specify whether particle monitoring in Grade A zones TRS-961 21.1 is undertaken for the full duration of critical processing ANNEXE- including equipment assembly. 06 WHO Specify whether particle monitoring in Grade B zones 21.1 TRS-961 is undertaken for the full duration of critical processing. Page 27 of 55Risk Based Joint Inspection Report ANNEXE- 06 Whether more than one sanitizing agent is used in 21.1 Sch-M rotation. If yes list the sanitizing agents their concentration and frequency. 22 Equipment: Specify whether the unit- sterilizers are double ended 22.1 Sch-M with suitable inter-locking between the doors. Specify the initial effectiveness of sterilization process 22.2 Sch-M established by using microbial spore indicators. Specify whether thermal Mapping of heat sterilizers is 22.3 Sch-M carried out on regular basis. Check records. Specify suitable vent filters and recording 22.4 Sch-M thermographs provided in autoclaves & dry sterilizers. Specify HEPA filters for cooling air and recording 22.5 Sch-M thermographs provided in DHS/Tunnel. WHO TRS-961 22.6 Specify whether provisions of CIP or SIP are available. ANNEXE- 06 22.7 Sch-M Specify whether pure steams are in use. Specify filter integrity test carried out before and after 22.8 Sch-M the filtration process. Specify the material of construction of the equipment & 22.9 Sch-M glass containers. 22.10 Sch-M Specify the tubing used in critical areas 22.1 Sch-M Specify the qualifications of critical equipment. WHO TRS-961 Verify the qualification, protocol and reports for the 22.1 ANNEXE- critical equipment. 06 Specify SOPs available for each equipment for its 22.1 Sch-M operation and cleaning. Page 28 of 55Risk Based Joint Inspection Report Specify whether the measuring devices attached to 22.1 Sch-M equipment calibrated at suitable intervals. Specify whether a written calibration program is 22.2 Sch-M available Specify whether calibration status documented and 22.2 Sch-M displayed on the equipment and the gauges 23 Manufacturing Process Specify whether the bulk raw materials and bulk 23.1 Sch-M solutions monitored for bio-burden periodically (solutions not to contain more than 100 cfu/ml). Specify the minimum possible time between the preparation of the solution and its sterilization or 23.2 Sch-M filtration through microorganism retaining filters followed. Specify the porosity of the filters when any external 23.3 Sch-M gases are coming into contact with the sterile product. Specify whether gas cylinders are kept out side of the 23.4 Sch-M critical areas. Specify the procedure of sterilization of washed 23.5 Sch-M containers. Specify whether the sterilized containers not used 23.6 Sch-M within an established time, rinsed with WFI and re- sterilized. Is each lot of the finished product filled in one 23.7 Sch-M continuation operation? Specify whether all critical process is validated. Verify 23.8 Sch-M the records. WHO TRS-961 Verify the process validation protocol and reports for 23.9 ANNEXE- the critical operation. 06 WHO Specify whether critical operations are carried out in 23.10 TRS-961 closed system. Page 29 of 55Risk Based Joint Inspection Report ANNEXE- 06 24. Aseptic processing and sterilization by filtration: Specify whether the filling area is of Grade A 24.1 Sch-M environment with Grade B background. Specify the room classification of solutions preparation 24.2 Sch-M area which is sterilized by filtration. Specify the filter used for sterilization of solution by 24.3 Sch-M filtration. WHO TRS-961 Specify the maximum possible time used for filtration 24.4 ANNEXE- process. 06 Specify whether integrity of the sterilizing filters is 24.5 Sch-M verified before and after use. If so, by which method. WHO Specify whether the personal working in the aseptic TRS-961 24.6 area is qualified for clean room procedure or not. If so ANNEXE- verify the training records. 06 25 Product Containers & Closures:- Specify whether the containers and closures used 25.1 Sch-M comply with pharmacopoeia or other specific requirements. Specify whether Specifications, Test methods, Cleaning procedures, Sterilizing procedures etc. are 25.2 Sch-M available of the containers/ closures and other component parts of drug packages. Specify whether the container & closures are 25.3 Sch-M compatible with the product without affecting its quality and purity. Verify the records. Specify whether containers and the closures are finally 25.4 Sch-M washed with WFI before sterilization. Page 30 of 55Risk Based Joint Inspection Report Specify whether a written procedure exist for washing 25.5 Sch-M of glass ampoules/vials. Specify whether the material quality of the stoppers 25.6 Sch-M and closures ensures that it does not affect the quality of the product and avoids the risk of toxicity. 26 Sterilization Whether the sterilizing processes have been validated 26.1 Sch-M (Dry heat, Moist heat, filtration, ETO, ionizations whichever applicable. Whether the validity of the process verified at regular 26.2 Sch-M intervals (at least annually) Whether the terminal sterilizer’s capacity is sufficient to sterilize one batch completely at one time. If not 26.3 Sch-M specify controls and measures taken in lot sterilizations. Whether biological indicators used in monitoring of 26.4 Sch-M sterilization. WHO TRS-961 Verify that the probe is placed at the coolest point on 26.5 ANNEXE- the basis of validation studies 06 WHO TRS-961 Verify the qualification, protocol and reports for the 26.6 ANNEXE- sterilizers 06 Whether the biological indicators stored and used as 26.7 Sch-M per manufacturer’s instructions. Whether quality of BI’s checked by positive controls. Whether a clear means of differentiating ‘sterilized’ 26.8 Sch-M from ‘unsterilized‘ products is in place. Specify. Whether the label on the basket / tray or other carrier 26.9 Sch-M of product / component clearly states:  Name of the material Page 31 of 55Risk Based Joint Inspection Report  Its batch number  Its sterilization status  Indicator (in case it has passed through sterilization process) Whether sterilization records including thermographs 26.10 Sch-M and sterilization monitoring slips attached with the Batch Production Record 27 Sterilization (By Dry Heat) Whether the sterilization cycle recording device of 27.1 Sch-M suitable size and precision provided in DHS./ Tunnel Whether the position of temperature probes used for controlling and / or recording determined during 27.2 Sch-M validation and (where applicable) been checked against a second independent temperature probe located in the same position 27.3 Sch-M Whether the chart forms a part of the batch record. Whether sterilization cycle validated only by biological 27.4 Sch-M indicator and chemical indicators or physical validation is also carried out Whether the time allowed reaching the required temperature before commencing the measurement of 27.5 Sch-M sterilizing time, separately determined for each type of load. Are adequate precautions taken to protect the load 27.6 Sch-M during cooling after it has gone through the high temperature phase of a heat sterilization cycle In case the cooling is affected with any fluid or gas in 27.7 Sch-M contact with the product , is it sterilized. Whether the equipment air inlet and outlets been 27.8 Sch-M provided with bacteria retaining filters In the process of sterilization by dry heat, does the 27.9 Sch-M equipment have: 1) Air circulation facility within the chambers Page 32 of 55Risk Based Joint Inspection Report 2) Positive pressure to prevent entry of non-sterile air WHO TRS-961 Verify the sterilizer loading pattern & whether is 27.10 ANNEXE- complied with the validated loading pattern. 06 Whether the process of dry heat sterilization intended to remove the pyrogens. 27.1 Sch-M If so, has the validation been done with challenge tests using endo-toxins 28.Sterilization (By Moist Heat) Whether recording of both temperature and pressure 28.1 Sch-M carried out to monitor the process Whether the control instrumentation independent of 28.2 Sch-M the monitoring instrumentation and recording charts. Whether the equipment has automated control and 28.3 Sch-M monitoring system, if so, have these been validated to ensure that critical process requirements are met. Whether the system and cycle faults are recorded 28.4 Sch-M inbuilt and also observed by the operator and record maintained. Whether the readings of the thermograph during sterilization cycling are routinely checked by the 28.5 Sch-M operator against the reading shown by the dial thermometer fitted with autoclave. Whether the sterilizer fitted with a drain at the bottom of the chamber If so, does the record of temperature at 28.6 Sch-M this position is recorded throughout the sterilizing period Are frequent leak tests conducted on the chamber of 28.7 Sch-M the autoclave on each day of operation. Whether all items to be sterilized (other than sealed 28.8 Sch-M containers) are wrapped for sterilization. Page 33 of 55Risk Based Joint Inspection Report Whether the wrapping material allows removal of air and penetration of steam ensuring contact with the 28.9 Sch-M sterilizing agent at the required temperature for required time Whether the wrapping prevent contamination after 28.10 Sch-M sterilization Whether the steam used for sterilization is of suitable quality and doesn’t contain additives at a level which 28.1 Sch-M could cause contamination of the product or equipment 29. Others Specify whether products released only after complete 29.1 Sch-M filling and testing. Specify whether result of the tests relating to sterility, 29.2 Sch-M bacterial endo-toxins are maintained in the analytical records WHO TRS-961 Whether process hold time studies has been carried 29.3 ANNEXE- out for various stages of production 06 30. Documentation and Records Whether all daily documents are filled correctly and 30.1 Sch-M timely. How the documents are designed, prepared, reviewed 30.2 Sch-M and controlled to provide an audit trail. Whether documents are approved signed and dated by 30.3 Sch-M appropriate and authorized person. 30.4 Sch-M Whether documents specify title, nature and purpose. Whether documents are regularly reviewed and kept 30.5 Sch-M up to date. Whether the records are made at the time of each 30.6 Sch-M operation in such a way that all significant activities concerning to the production are traceable. Page 34 of 55Risk Based Joint Inspection Report Whether data is recorded by electronic data processing system or by other means. If by electronic data 30.7 Sch-M processing system then how access is controlled to enter, modify etc. the data. Whether master formula and detailed operating 30.8 Sch-M procedures for each product are available? Specify the duration of retaining the documents after Sch-M the expiry of the respective product and who is responsible for its maintenance. Do the manufacturing records pertaining to manufacture of Sterile & Non- Sterile products indicate the following details: Serial number of Batch Manufacturing ,Record ,Name of the product, Reference to Master Formula Record, Batch/ Lot number, Batch/ Lot size, Date of commencement and completion of manufacture, Date of manufacture and assigned date of expiry, Date of each step in manufacturing, Names of all ingredients with reference number given by the quality control department ,Quantity of all ingredients, Time and duration of blending, mixing etc. where ever applicable, PH of solutions whenever applicable, Filter integrity 30.9 testing records, Temperature and humidity records whenever applicable, Records of plate-counts whenever applicable, Results of bacterial endo-toxin and toxicity, Records of weight or volume of drug filled in containers, Bio burden records before sterilisation, Leak test records, Inspection records, Sterilization records including load details, date, duration, temperature, pressure etc. Container washing & testing records, Total number of containers filled, Total number of containers rejected at each stage, Theoretical yield, permissible yield, actual yield and variation there of, Clarification for variation in yield ,beyond permissible yield, Reference number of relevant analytical reports, Details of re-processing, if any, Names of all operators carrying out different activities, Environmental monitoring records, Specimens of different packaging material, Records of destruction of rejected containers and packaging Page 35 of 55Risk Based Joint Inspection Report material, and Signature of the competent technical staff responsible for manufacture and testing. 31 Labels and Other Printed Materials:- Whether the printing is in bright colour and legible on 31.1 Sch-M labels and other printed materials? How printed labels (art work) are approved. Verify the 31.2 Sch-M SOP. WHO 31.3 Specify whether cut labels or rolled labels are used. TRS-986 Whether the labels comply with requirements of Rule 31.4 Sch-M 96 & 97 & other relevant provisions 32 Master Formula Records: - How master formula records for each product are 32.1 Sch-M prepared, authorized and controlled. 32.2 Sch-M Whether master formula is batch size specific. Whether master formula record covers all the points as 32.3 Sch-M prescribed in Schedule ‘M’. WHO Whether master formula record covered all the points 32.4 TRS-986 as prescribed in WHO-TRS 986 & PIC/S guidelines 33 Batch Processing / Manufacturing Records:- Whether the BPR/BMR for each product is prepared on 33.1 Sch-M the basis of currently approved master formula. Whether BPR / BMR covered all the points as 33.2 Sch-M prescribed in Schedule ‘M’ WHO Whether BPR / BMR covered all the points as 33.3 TRS-986 prescribed in WHO-TRS 986 & PIC/S Whether all the documents generated during Batch 33.4 Sch-M production are attached with the BPR /BMR 34 Batch Packaging Records: - Whether authorized packaging instructions for each 34.1 Sch-M product of various pack size and type are maintained and complied with. Page 36 of 55Risk Based Joint Inspection Report Specify whether all material, equipment, rooms and 34.2 Sch-M packaging lines are labelled with an indication of product being processed with batch no. Whether packaging lines are independent and 34.3 Sch-M adequately segregated. How line clearance is performed. Whether records of 34.4 Sch-M line clearance is maintained according to appropriate checklist. 34.5 Sch-M Do the packaging materials arrive on a covered trolley? Are packaging materials verified against a master set 34.6 Sch-M to ensure that they are the most recent edition and the correct materials for the batch? Are the quantities of packaging materials verified 34.7 Sch-M against the amounts stated as dispensed from the warehouse? WHO Specify the monitoring code (bar code, pinholes etc.) 34.8 TRS-986 for final packing materials. Is the batch yield calculated immediately upon 34.9 Sch-M completion of packaging operation & prior to the introduction of a new batch into the area? Is the yield calculation independently verified by 34.10 Sch-M second individual and whether any significant deviation from accepted yield is recorded and investigated? Is any excess printed packaging material destroyed on 34.11 Sch-M completion of the batch? Is there a provision in the department for the separation 34.12 Sch-M of printed packaging material for destruction & rejected product? Whether Batch packaging record covered all the 34.13 Sch-M points as prescribed in Schedule ‘M’ WHO Whether Batch packaging record covered all the 34.14 TRS-986 points as prescribed in WHO-TRS 986 & PIC/S Page 37 of 55Risk Based Joint Inspection Report Whether all the documents generated during 34.15 Sch-M packaging are attached with the Batch packaging record. Whether BPR are based on current master formula 34.16 Sch-M record. 35 Standard Operating Procedure and Records: - Verify the List of SOPs and mention total number of 35.1 Sch-M SOPs followed by the firm. 35.2 Sch-M Has all the SOPs been displayed. 35.3 Sch-M The formats, logs & SOPs are current 35.4 Sch-M Is any obsolete copy seen in the Area? 36 Reprocessing and Recoveries:- 36.1 Sch-M Verify the SOP for reprocessing. WHO Whether reprocessed batch is subjected to stability 36.2 TRS-986 evaluation. Whether the recoveries are added into the subsequent 36.3 Sch-M batches. If yes specify the procedures. 37 Finished Product:- Specify whether finished products are held in 37.1 Sch-M quarantine until their final release. Specify the storage arrangement of finished products 37.2 Sch-M after final release by QA 38 Quality Control Area: - Specify whether QC area is independent of production 38.1 Sch-M area. 38.2 Sch-M Specify the working space provided for QC: Specify the procedure followed for approval/rejection of raw materials, packaging materials, intermediate 38.3 Sch-M products and finished products. Verify the SOP and record. Specify the arrangement provided to protect sensitive 38.4 Sch-L1 electronic balances from vibrations, electrical interference, humidity etc. Page 38 of 55Risk Based Joint Inspection Report Specify the safety measures taken to avoid any 38.5 Sch-L1 accidental hazards in the QC department. Specify whether separate washing and drying area is 38.6 Sch-M provided for glassware Specify which grade of glassware is used in assay 38.7 Sch-L1 procedures and whether they are certified/calibrated. Verify the certificates and calibration records. Specify whether any particular test is outsourced. If so 38.8 Sch-M mention the name of laboratory and verify the contract made in this regard. 39 Microbiology Lab Whether separate AHU's are provided for 39.1 Sch-M microbiological testing areas. Whether support areas are under same AHU which is 39.2 Sch-M used for sterile area. Briefly describe layout of the microbiology lab (attach 39.3 Sch-M copy of the layout if available) Whether entry to the sterile area is through three air 39.4 Sch-M lock systems with separate exit WHO Specify whether access in sterile area is controlled, 39.5 TRS-986 and if so the system followed in this regard Verify the list of equipment used in the microbiological 39.6 Sch-M lab and also specify whether these are placed logically and function accurately Specify whether operators are trained in gowning 39.7 Sch-M procedures. Verify the training records. Specify the gowning procedure to enter the sterile 39.8 Sch-L1 area. Verify the entry and exit records. Specify the air class of sterile areas and whether 39.9 Sch-L1 pressure difference is maintained. Verify the records. WHO Specify whether an environmental monitoring 39.10 TRS-986 programme is followed with alert and action limit. Page 39 of 55Risk Based Joint Inspection Report Specify whether a documented cleaning and 39.1 Sch-M disinfection programme is in place. WHO Specify whether a procedure for dealing with spillages 39.1 TRS-986 in sterile area is in place. WHO Whether separate areas provided for sterility testing, 39.1 TRS-986 assay of antibiotics & vitamins and MLT in sterile area. Specify the type of workstations (LAF) provided in the 39.1 Sch-M sterile area. Whether double door autoclave is provided for 39.2 Sch-M transferring of materials from unclassified area to sterile area. WHO 39.2 Verify the area qualification document for sterile area. TRS-986 Verify the procedure for selection of sampling location and interpretation of results for environmental WHO 39.2 monitoring of sterile area along with the SOP and TRS-986 documents. (Specify whether the method is in compliance with ISO 14644-1). Specify whether qualification of all equipment and 39.2 Sch-L1 instruments used in this department is covered under VMP. Verify the qualification document of major equipment 39.2 Sch-L1 like autoclave/incubator, hot air oven, refrigerator, LAF etc. Specify the Calibration procedure of temperature measurement devices used in autoclave and 39.20 Sch-L1 incubator. Verify whether it is traceable to standard temperature. Verify the procedure for the handling and disposal of 39.2 Sch-M chemical and microbial waste. WHO Specify the procedure followed to verify the validity of 39.2 TRS-986 the test in case of antibiotic potency testing. Page 40 of 55Risk Based Joint Inspection Report WHO Specify whether there is separate autoclave for 39.2 TRS-986 decontamination. WHO Specify whether the Vendors for dehydrated media is 39.2 TRS-986 approved and qualified. WHO Specify whether GPT is carried out for dehydrated 39.3 TRS-986 / media. IP Specify whether performance of culture media 39.3 Sch-L1 (recovery or survival maintenance) is carried out and the results meet acceptance criteria. Specify the source of procurement of reference culture 39.3 Sch-L1 and its maintenance. Specify the Air Grades for following areas: —Sterility testing room 39.3 Sch-L1 —Microbiological Assay room —MLT room —Airlocks (entry and exit both) Verify the following records: —Log book for the entry/exit in the sterile area 39.3 Sch-M —media preparation record —records for water testing (micro) —records for MLT Verify how the concentration of the inoculums is 39.30 IP determined. Whether firm has provided microbiology lab for MLT 39.3 Sch-M test for nonsterile dosage form. If no how this test is complied. 40 Quality Control System: - Specify the source of procurement of various reference 40.1 Sch-L1 standards How the reference standards are stored, evaluated and 40.2 Sch-L1 maintained. Page 41 of 55Risk Based Joint Inspection Report WHO Specify whether authorized access system is followed 40.3 TRS-986 for reference standards. Verify the SOP and records for preparation of working 40.4 Sch-L1 standard from the reference standard. Verify the SOP and records for destruction of unused 40.5 Sch-L1 working standard Verify the sampling SOPs and records for:  starting materials  primary packaging materials  secondary packaging materials  in process materials 40.6 Sch-M  finished products  water analysis  wash water analysis  swab analysis  wash water analysis of cleaned garments Specify whether approved specifications are available for all:  starting materials  primary packaging materials  secondary packaging materials 40.7 Sch-M  in process materials  finished products  water analysis  wash water analysis  swab analysis  wash water analysis of cleaned garments Verify whether all approved specifications are based 40.8 Sch-L1 on validation. WHO Is there any SOP for handling of OOS product (out of 40.9 TRS-986 specification)? Page 42 of 55Risk Based Joint Inspection Report WHO Specify the procedure for review of test data & 40.10 TRS-986 calculations. Specify whether a designated person is responsible for 40.1 Sch-L1 receipt of samples for testing. Specify the procedure followed for receiving and 40.1 Sch-L1 recording (logging in). Verify the SOP and records Specify the procedure for storage and distribution of 40.1 Sch-L1 received samples to different analyst. Is there a maximum time limit for retention of sample in 40.1 Sch-L1 the laboratory prior to testing? Specify the procedure followed for preparation, 40.2 Sch-L1 consumption & destruction of volumetric solution. Verify the SOP and records. Specify whether there is a log book for the preparations of the reagent including name of the analyst, name of 40.2 Sch-L1 the reagent, Calculations, Date of preparation & expiration. Specify the procedure followed for using GR, LR and 40.2 Sch-L1 AR grade of chemicals / solvents used for calibration & sample testing. Specify whether respective STP is followed by the 40.2 Sch-L1 analyst for analysis. Specify the procedure of reporting the result of analysis 40.2 Sch-L1 by the analyst to QC Head. Specify the procedure followed for storage of samples 40.20 Sch-L1 after testing. Specify the procedure for retention of samples after 40.2 Sch-L1 testing is completed. 40.2 Sch-L1 Specify the procedure followed for issuance of COA. Specify procedures for safe removal of waste from the 40.2 Sch-L1 laboratory. 41 Analytical Method Validation (AMV):- Page 43 of 55Risk Based Joint Inspection Report Specify whether following Characteristics are considered during validation of analytical methods:  Specificity  Linearity  Range  Accuracy 41.1 IP  Precision  Detection  Limit  Quantification  Limit  Robustness.  Solution Stability/Filter Study 42 HPLC Calibration Verify the records of calibration of following parameters:  Calibration of pump.  Calibration of Gradient proportionate valve (GPV).  Calibration of Auto injector. 42.1 IP  Calibration of Detector.  Temperature calibration for Column oven and  Sample Trays compartment.  Auto Sampler Carry over.  Manual injector calibration  System suitability 43 Dissolution Apparatus Calibration Verify the records of calibration of following parameters:  Checking of RPM 43.1 IP  Checking of Temperature  Checking of distance between inside bottom of the vessel & paddle Page 44 of 55Risk Based Joint Inspection Report  Checking of distance between inside bottom of the vessel & Basket  Checking Wobbling of paddle  Checking of Wobbling of Basket  Checking of Timer: Calibrate against standard stop watch  Performance verification test [Verify whether dissolution is calibrated against standard prednisolone tablets] 44 UV-VIS Verify the records of calibration of following parameters:  Control of wavelengths (Wavelength accuracy)  Control of absorbance (Photometric accuracy)  Limit Of Stray Light  Resolution Power 44.1 IP  Resolution (second order derivative spectrum)  CELLS Verification  I0 flatness  Calibration of Visible Wavelength  Calibration of absorbance reproducibility for visible wavelength  Photometric linearity at 430nm 46 FTIR Verify the records of calibration of following parameters: 46.1 IP  Verification of the wave number scale  Control of resolution performance 47 TOC Analyser+ Verify the records of calibration of following 47.1 USP parameters:  System suitability: Page 45 of 55Risk Based Joint Inspection Report  Calibration (Four point calibration) 48 Stability Studies Specify whether stability study is carried out in the QC and if so, is there separate area for Stability Chamber for stability studies. How many Stability Chambers 48.1 Sch-M have been provided? Specify whether shelf life of the product is fixed on the basis of stability studies. WHO Verify the qualification documents of all the stability 48.2 TRS-986 chambers. WHO Specify whether a written programme for ongoing 48.3 TRS-986 stability determination is in place. WHO Specify whether a complete description of stability 48.4 TRS-986 study is available. WHO Verify the stability calendar along with stability protocol 48.5 TRS-986 and documents. Attach the copy of stability calendar WHO Specify whether the stability protocol indicates 48.6 TRS-986 complete set of testing parameters and methods. WHO Specify whether summary of all generated data from 48.7 TRS-986 the study are retained. WHO 48.8 Specify the testing schedule for each product TRS-986 Specify whether stability study is performed after any WHO 48.9 significant changes in process equipment, packaging TRS-986 materials etc. WHO 48.10 Specify the validation method for stability chambers TRS-986 Specify the Temperature and humidity for real times WHO 48.1 studies carried out for fixing shelf life of drug in the TRS-986 country. 49 Quality assurance:- Mention the documents prepared and maintained by 49.1 Sch-M QA department Page 46 of 55Risk Based Joint Inspection Report 49.2 Sch-M Specify the responsibility of the QA Head. Specify the procedure followed by QA department to 49.3 Sch-M ensure the implementation of all SOPs in the plant. Verify the total list of SOPs maintained by QA and how 49.4 Sch-M QA ensure that no obsolete SOP is in circulation. Specify whether any procedure is followed for WHO preparation of SOPs and its circulation to all 49.5 TRS-986 concerned. How master, controlled and uncontrolled copy of SOPs are processed. WHO Mention the change control procedures & examine 49.6 TRS-986 three recent change control forms. Specify the procedures followed to ensure CAPA WHO 49.7 process. Verify the SOP and three recent records in TRS-986 this regard. How deviation are controlled. Verify SOP and three WHO 49.8 recent deviations. Specify whether all deviations are TRS-986 reported and records maintained. Is the production batch record and release test results 49.9 Sch-M reviewed for accuracy and completeness before a batch/lot of finished product is released? 49.10 Sch-M Verify the checklist and SOP in this regard. Whether QA is involved in control of starting materials, 49.1 Sch-M intermediate products, bulk products, process controls, calibrations, validation and release of finish goods. 50 Annual Product Quality Review (APQR):- WHO Specify Whether Annual Product Quality review is 50.1 TRS-986 carried out for each product Specify whether following criteria are considered for review: WHO  Starting materials and packaging materials 50.2 TRS-987  Critical in-process controls and finished product results;  All significant deviations or non-conformance Page 47 of 55Risk Based Joint Inspection Report  All changes made to the processes or analytical methods;  Results of the stability monitoring programme and any adverse trends  All quality-related returns, complaints and recalls and the investigations performed at the time  Adequacy of any other previous corrective actions on product process or equipment  The qualification status of relevant equipment and utilities e.g. HVAC, water, or compressed gases WHO Verify whether Cp and CpK values are calculated and 50.3 TRS-988 what is the acceptance criteria fixed. 51 Product Recalls:- 51.1 Sch-M Specify the product recall system. Verify the procedure followed to handle the recalled 51.2 Sch-M products Are distribution records available for a prompt recall of 51.3 Sch-M products from the market? Verify the SOP for recall of products clearly defining 51.4 Sch-M responsibility, procedure reporting, reconciliation etc. 52 Complaints and Adverse Reactions:- Are complaints, whether received in oral or written 52.1 Sch-M form, documented in writing, and retained in a designated file? WHO Are complaints reviewed on a timely basis by the 52.2 TRS-988 Quality Assurance unit? WHO Is CAPA process followed in response to each 52.3 TRS-988 complaint documented? Specify whether system of route cause analysis is WHO 52.4 followed by the firm on the complaint of adverse drug TRS-988 reaction. Specify the review system for complaints concerning 52.5 Sch-M the quality of products. Page 48 of 55Risk Based Joint Inspection Report How records of complaint and adverse reactions 52.6 Sch-M maintained. Whether the firm has provided Pharmacovigilance Draft 52.7 department for analysing complaints of adverse drugs Rules reactions resulting from the use of a drug. Are there any criteria for action to be taken on the basis 52.8 Sch-M of nature of complaint / adverse reaction? 53 Site Master File:- Whether all the relevant information has been included 53.1 Sch-M in the site master file. Whether quality policy has been included in the site 53.2 Sch-M master file. 53.3 Sch-M Verify whether all information as per schedule M WHO Verify whether all information as per WHO TRS 986 53.4 TRS-988 and PIC/S document. 54 Validation WHO 54.1 Specify the validation policy of the company TRS-988 WHO 54.2 Whether a Validation Master Plan has been prepared. TRS-988 Verify resources and those responsible for its 54.3 Sch-M implementation. WHO Identify the systems and processes to be validated as 54.4 TRS-988 per VMP Verify whether documentation, standard operating WHO procedures (SOPs), Work Instructions and Standards 54.5 TRS-988 (applicable for national and international) are incorporated in VMP WHO Validation list for facilities/equipment, processes / 54.6 TRS-988 procedure and products. Specify whether key approval criteria are mentioned in WHO 54.7 the VMP & how record and conclusion of such TRS-988 validation studies are prepared and maintained. Page 49 of 55Risk Based Joint Inspection Report Verify Protocol format for each validation activity, WHO including re-validation and reasonable unforeseen 54.8 TRS-988 events (power failures, system crash and recovery, filter integrity failure. WHO 54.9 Whether validation calendar is specified in VMP. TRS-988 Specify whether the critical processes validated 54.10 Sch-M Prospectively, retrospectively or concurrently. WHO In case electronic data processing systems are used, 54.1 TRS-988 are these validated? WHO Please specify whether periodical challenge tests 54.1 TRS-988 performed on the system to verify reliability. Are the validation studies performed according to pre- 54.1 Sch-M defined protocols? Is a written report summarized, results and conclusions 54.1 Sch-M prepared and maintained? WHO Is the validity of the critical processes and procedures 54.2 TRS-988 established based on a validation study? WHO Are criteria established to assess the changes 54.2 TRS-988 originating a revalidation? Are trend analyses performed to assess the need to re- WHO 54.2 validate in order to assure the processes and TRS-988 procedures continue to obtain the desired results? 55 Internal Quality / GMP Audit Programme Does a formal auditing function exist in the Quality 55.1 Sch-M Assurance department? Does a written SOP specify who shall conduct audits 55.2 Sch-M and qualifications (education, training, and experience) for those who conduct audits? Does a written SOP specify the scope and frequency 55.3 Sch-M of audits and how such audits are to be documented? Page 50 of 55Risk Based Joint Inspection Report Specify whether record is maintained for CAPA on the WHO 55.4 basis of self quality audit / inspection and whether TRS-988 same is reviewed by the management 56 Pharmaceutical Development ICH/Q-8- Whether there is Research and Development facility 56.1 PICS available. ICH/Q-8- Whether formulation development facility up to 56.2 PICS development of exhibit batches available. ICH/Q-8- Whether firm hires consultants for technology transfer. 56.3 PICS If so details thereof. ICH/Q-8- Whether firm has adopted latest tools (quality by 56.4 PICS design) to develop new products. 57 Quality Risk Assessment System:- Whether the firm has adopted QRM principle to ICH/Q-9- mitigate risk involved in pharmaceutical development, 57.1 PICS manufacturing and distribution. If yes specify which guidelines are followed in this regard. ICH/Q-9- Whether firm has policy document on QRM. Specify 57.2 PICS document number and its effective date. ICH/Q-9- Which known principles have been adopted to analyse 57.3 PICS risks e.g. FMEA, HAZOP, HACCP, FTA etc. Whether risk priority number (RPN) is calculated based ICH/Q-9- 57.4 on severity, probability and detectability. If so, what is PICS the criteria of acceptance. ICH/Q-9- How many products, process etc. have been analysed 57.5 PICS for risk. Give brief. 58 Data Integrity Whether the records are completed at the time of the 58.1 Sch-M operation and are legible maintained with raw data if applicable. Whether the firm has software based manufacturing 58.2 Sch-L1 and testing equipment Page 51 of 55Risk Based Joint Inspection Report Whether the individuals are provided log in IDs for 58.3 Sch-L1 access. All login and logout information should be available. Whether rights to work, amend, modify, delete are 58.4 Sch-L1 specified in written document. Whether right to access and modify are with two 58.5 Sch-L1 different individuals. If yes how QA is involved in modification of data. Whether audit trails related to project creation (study 58.6 Sch-L1 creation), project (study) modification, deletion etc. are available. Whether the data is backed up at regular intervals. If 58.7 Sch-L1 yes what is the written back up policy. The data backup must be server based. How Excel sheets are validated if calculation are done 58.8 Sch-L1 in Excel sheet. Whether the firm has QA SOP for review of data 58.9 Sch-L1 integrity or audit trail. If yes how the modification and deletions are reviewed. 59 Pharmaceutical Quality Management System (PQS) WHO Specify the management responsibility defined as per 59.1 TRS-986 the quality manual Specify the Procedures followed for continual WHO 59.2 improvement of process performance and product TRS-986 quality Specify the performance indicators presently followed WHO by the firm to monitor the effectiveness of PQS like 59.3 TRS-986 product quality monitoring, CAPA, change management and management review WHO 59.4 whether purchases are also included under PQS TRS-987 WHO 59.5 Specify whether life cycle approach is followed TRS-986 Page 52 of 55Risk Based Joint Inspection Report WHO Give synopsis of last to management review meeting 59.6 TRS-986 held by the firm List of Observations/Deficiencies: 1) Critical: 1.1: 1.2: 2) Major: 2.1: 2.2: 3) Others: 3.1: 3.2: 3.3: Page 53 of 55Risk Based Joint Inspection Report Page 54 of 55Risk Based Joint Inspection Report Concluding Remarks: Name and Signatures of the Inspecting officials: Page 55 of 55Quality Rating S.No Reference 2 1 0 X 1 Building and premises: - 1.1 Sch-M, Specify whether the whole facility is separated, the whole facility was found the whole facility was found separated, Non drug items like nutraceuticals 1) The manufacturing dedicated and is not a part of any other non-drug separated, dedicated and is not a dedicated and is not a part of any other was found manufactured along facilities for potent drugs facility. part of any other non-drug facility. non-drug facility. with general drug item such as sex hormones, Even no other category of drugs beta-lactam and cytotoxic like sex hormones, beta lactam, are common with general cyto-toxic, spore forming are drugs. manufactured in the same campus 2) Some of the critical areas of manufacturing are exposed directly with the environment 1.2 Sch-M, Specify whether the surroundings of Situated in eco-friendly zone with Situated in industrial area and not Situated in industrial area and manufacturing area is clean and as per the SOP less than 50% FAR with the effected by other industries. obnoxiou fumes, smoke is prescribed in this regard. (Mention the SOP nos.) surroundings in the campus is free produced in the surroundings. from dust and planned greeneries. NA 1.3 Sch-M, Describe the pest, insects, birds and rodents NA Agreement copy and SOP in place. Neither agreement copy nor SOP Pest infestation, rodents control system followed in the premises. Specify available. and birds found in the pest control schedule- area wise, along with manufacturing premises materials and methods used. 1.4 Sch-M, What measures have been taken to make Interior Made of RCC and layout is such Made of RCC and interior surfaces are Cracks are observed at many surface (of walls, floors, and ceilings) smooth and so that uni-flow system of man and smooth, free from cracks and permits places of non critical areas of free from cracks, and to permit easy cleaning material is maintained and interior easy cleaning. manufactured Specify material of construction and finish for surfaces are smooth, free from walls, ceiling, floor, coving etc. i.e. whether cracks and permits easy cleaning. Epoxy or PU coated, kota / granite stone with Maintenance of hygienic conditions epoxy sealed joints, solid / GI / gypsum / cal. is excellent and proper documents Silicate board ceiling with epoxy, PU or any other are available. All the pre-fabricated panel (GRP, powder coated SS or manufacturing and surrounding Aluminium etc.) paint. corridors including change rooms are made of epoxy flooring and interior surfaces are free from any cracks or joints. 1Quality Rating S.No Reference 2 1 0 X 11 .B5uildingS acnhd- Mpr,e mises: S-pecify the lux level maintained in various parts 400-500 lux in the processing area 400-500 lux in the processing area Less then 500 lux in inspection of the premise (Storage area, manufacturing area 300-400 lux in ancillary areas 300-400 lux in ancillary areas areas specially visual inspection, Laboratory areas etc.). 200-300 lux in storage area 200-300 lux in storage area Less then 400 lux in processing More then 500 lux in inspection More then 500 lux in inspection areas area areas NA For photo sensitive products monochromatic light is used 1.6 Sch-M, Specify the air handling system used in various Totally dedicated AHU for each Separate AHU for critical area. All manufacturing and ancillary No AHU is provided in areas i.e. stores, production, packing, QC areas. operation. areas is under same AHU the manufacturing areas or where raw materials and/or products are exposed. 1.7 Sch-M, Specify drainage system which prevents back flow GMP drains with cleaning records GMP drains with cleaning records and No GMP drain in the critical areas There are open drain(s) and entry of insects and rodents into the premises. and SOP in place. Drawing is also SOP in place. in the critical areas where Specify number and location of drains installed. available specifying the number the products are and location of drains. exposed. 2 Ancillary areas: - 2.1 Sch-M, Specify the position of rest and refreshment Separate and outside the Inside the manufacturing area rooms and mention whether they are separated manufacturing area NA NA and not leading directly to the manufacturing and warehouse areas. 2.2 Sch-M, Are there general change rooms in plant? specify Separate and outside the Inside the manufacturing area number of washing station & toilets provided for NA manufacturing area NA number of users. Separate for male and female 2.3 Sch-M, Specify whether primary clean garments are Clean Garments are provided to all Factory Garments are provided to No Clean Garments are provided provided for each personnel entering the factory employees as well as visitors with employees only as primary gowning NA premises. proper Identification 2.4 Sch-M, Is there in-house general laundry for garment In House Laundry facility is in place In House / out source Laundry facility No proper Cleaning facility (use of washing / cleaning? If not how garment washing is with proper SOP, monitoring and specific for pharmaceuticals garments common washer man) NA carried out and monitored. audit facility is in place 2.5 Sch-M, Para Whether change room facilities separated for both Change room facilities was found Change room facilities was found sexes. NA separated for both sexes. not separated for both sexes. NA 2.6 Sch-M, Para Whether maintenance workshop is separated and Maintenance workshop is separated Maintenance workshop is away from production. NA and far away from production separated but adjacent to the NA production area 3 Security system:- 3.1 WHO TRS Is the men & material movement inside the factory Written security policy was found premises, observed & checked through security maintained with SOP. system. NA NA NA 3.2 WHO TRS Is CCTV available to control the Entry & Exit from CCTV is available to control the Factory premises? Entry & Exit from Factory premises NA NA NA and is regularly monitored 2Quality Rating S.No Reference 2 1 0 X 13 .B3uildingW anHdO p rTeRmSises:I s- there a system for identifying persons visiting Persons are identified through to the factory ? How? photo and Biometrics NA NA NA 3.4 WHO TRS What is the precautionary activity taken for the Movement of carriers inside the movement of carriers i.e. vehicles? plant is guided and controlled by NA NA NA the security persons 4 Water & Compressed air system: - 4.1 Sch-M, Para Verify whether a current drawing of the water Schematic drawing of water Schematic drawing of water system No schematic drawing of water system showing all equipment in the system from system was found in the PW was found in the PW generation area system was found in place inlet to the points of use is available. generation area showing all the but not showing location of various NA equipment and location of various sampling and users’ points. sampling and users’ points. 4.1.1 Sch-M, Para Specify the MOC of the water storage tank (Both MOC of the holding vessels & MOC of the holding vessels & MOC of the holding vessels & PW & WFI) and its pipe line. circulation pipelines of purified circulation pipelines of purified water circulation pipelines of purified water was found of SS316L with was found of SS316 with certification water was found of SS316 NA certification 4.1.2 Sch-M, Para Specify weather storage tank for WFI is steam WFI storage tank was found steam WFI storage tank was found jacketed. NA jacketed. without steam jacketed. NA 4.2 Sch-M, Para Specify whether water system Water system qualification (IQ, OQ & Water system qualification (IQ, OQ 1) Purified water system validation/qualification has been carried out as per PQ) was found carried out and records & PQ) was not found carried out. is ill maintained and data protocol and reports have been prepared and maintained. in respect of its quality is maintained. falsified. NA 2) WFI system and pure steam system of parenteral unit are ill maintained and data in respect of their quality is falsified. 4.3 WHO TRS- Whether IQ protocol include at least facility review, All the details were found in the IQ 970 equipment specification vs. design, welding protocol and records found roughness testing on pipelines, absence of dead maintained points / section in the pipelines, pipe and tank passivation, drawings, SOP for operations, cleaning, sanitation, maintenance and calibration NA NA NA of gadgets. Whether its report includes Conclusion / Summary, Data tables, Results, Conclusions, Protocol reference, Revision and approval signatures. 4.4 WHO TRS- Whether OQ protocol includes at least System All the details were found in the 970 production capacity (L/min), Flow type and water OQ protocol and records found rate, Valve operation, Alarm system operation and maintained Controls operation? Whether its report includes NA NA NA Conclusion / Summary, operations performed Data tables, Results, Conclusions, Protocol reference, Revision and approval signatures. 3Quality Rating S.No Reference 2 1 0 X 14 .B5uildingW anHdO p rTeRmSis-es:P -lease specify whether Phase 1, Phase 2 and Phase 1, Phase 2 and Phase 3 970 Phase 3 studies carried as part of PQ stages? studies were found carried out as part of PQ stages NA NA NA 4.6 WHO TRS- Phase 1: Whether the operations parameters, Operations parameters, cleaning & 970 cleaning and sanitation procedures & frequencies sanitation procedures and defined. Whether daily sampling records for every frequencies was found defined. pre-treatment point and usage point for a period of Daily sampling records for every 2 to 4 weeks maintained and SOP’s prepared. pre-treatment point and usage NA NA NA point for a period of 2 to 4 weeks maintained and SOP’s prepared. 4.7 WHO TRS- PHASE 2: Whether daily sampling records for Daily sampling records for every 970 every pre-treatment point and usage point for a pre-treatment point and usage period of 4 to 5 weeks after Phase 1 maintained point for a period of 4 to 5 weeks and reviewed. after Phase 1 was found NA NA NA maintained and reviewed. 4.8 WHO TRS- PHASE 3: Whether weekly sampling records Weekly sampling records of every 970 available of every usage point for a one-year usage point for a one-year period NA NA NA period. was available. 4.9 Sch-M Specify source of raw water and give details of Following treatment processes are Following treatment processes are in Following treatment processes are Potable water was found treatment processes, sampling points, distribution in the water purification system for the water purification system for PW: in the water purification system for outsourced without any and storage system for raw and purified water. PW: —Raw water storage PW: records/validation Verify whether the Raw Water holding tank was —Raw water storage —Sodium hypochlorite dosing —Raw water storage regarding any further sanitised as per specified SOP. —Sodium hypochlorite dosing —Multimedia filtration —Sodium hypochlorite dosing treatment and/or analysis —Multimedia filtration —Softener — Sand and Charcoal filter before use. —Softener (2 nos, one for standby) —Soft water storage tank —Softener —Soft water storage tank —cartridge filter 150 micron —Ion exchange treatment —cartridge filter 150 micron —SMBS dosing, — PW storage tank —SMBS dosing, —ADH dosing ( for anti scaling), —ADH dosing ( for anti scaling), —Auto pH correction (using NAOH), —Auto pH correction (using Mixed Bed NAOH), — PW storage tank —Double pass RO —EDI —Ultra Filtration — PW storage tank with vent filter Provisions for—cartridge filter 5 micron, UV disinfection was found placed in the circulation loop. 4.10 Sch-M Verify whether the softener column is regenerated Column generation as per written Column generation without any as per the specified SOP. NA criteria written criteria NA 4Quality Rating S.No Reference 2 1 0 X 14 .B1u1ildingS acnhd- Mpremises:S -pecify whether the quality of potable water used The quality of water was found The quality of water was found No records were available for the preparation of purified water meets the assessed for seasonal variation for complies with the requirement of requirement of Schedule M in respect of microbiological limit and records schedule M for microbiological limit microbiological limit. found maintained and complies and records found maintained. NA with the requirement of schedule M 4.12 Sch-M Specify whether the quality of Purified Water used Quality of Purified Water used for the No records were available for the preparation of WFI meets the requirement preparation of WFI was found comply NA NA of IP/BP/USP. with the requirement of IP/BP/USP. 4.13 Sch-M What is the process for preparation of Water for Purified water is fed in to Purified water is fed in to multicolumn Purified water is fed in to Injection (WFI)? multicolumn distillation plant fitted distillation plant and the WFI so multicolumn distillation plant and with on line TOC analyser and obtained is stored in steam jacketed the WFI so obtained is stored in conductivity meter with PLC SS316 vessel. SS316 vessel. control. The WFI so obtained is NA stored in steam jacketed SS316L vessel with constant circulation loop at elevated temperature. 4.14 Sch-M Specify the process of sanitisation of SS storage Raw Water holding tank was found No SOP was found in this regard tank of WFI. NA cleaned by passing pure steam for 1/2 NA hour as per SOP 4.15 Sch-M Specify whether the quality of WFI meets the Quality of WFI meets the requirement No records were available requirement of IP/BP/USP & Schedule M. of IP/BP/USP & Schedule M and NA NA records found maintained 4.16 Sch-M Specify whether WFI is used for: It was observed that WFI is used for: It was observed that WFI is used 1) Bulk preparations of liquid injections 1) Bulk preparations of liquid injections for only Bulk preparations of liquid 2) Final rinse of product containers for sterile 2) Final rinse of product containers for injections preparations. sterile preparations. 3) Final rinse of machine parts (for sterile 3) Final rinse of machine parts (for preparations) sterile preparations) NA NA 4) Preparation of disinfectant solutions for use in 4) Preparation of disinfectant solutions critical areas (for sterile preparations.) for use in critical areas (for sterile preparations.) 4.17 Sch-M How bio burden in purified water & WFI are Bio Burden in purified water was Bio Burden in purified water was found No control regarding Bio Burden in controlled / reduced (Mention the SOP no. found controlled by passing controlled by passing through UV purified water was found. followed in this regard). through UV radiation in addition radiation. NA maintaining recirculation through loop system. 4.17.1 Sch-M Specify whether WFI has been stored and It was observed that WFI is stored and It was observed that WFI is not circulated above 70 degree centigrade. NA circulated above 70 degree centigrade. stored and circulated above 70 NA degree centigrade. 5Quality Rating S.No Reference 2 1 0 X 14 .B1u8ildingW anHdO p rTeRmSis-es:V -erify whether the circulation rate of purified water Circulation rate of purified water & 970 & WFI is at least twice the storage capacity of the WFI was found more then twice holding vessels per hour. the storage capacity of the holding NA NA NA vessels per hour and the pump capacity is commensurate with the circulation rate. 4.19 WHO TRS- Verify the Dead leg of non returned valve at the Less than 3D NA NA NA 970 discharge point. 4.20 WHO TRS- Specify how the circulation loop is sanitised. Verify Circulation loop is sanitised by 970 the SOP. passing pure steam for 15 to 30 NA NA NA minutes. 4.21 WHO TRS- Specify whether spray ball is used to wet the Spray ball is used to wet the 970 surface of head space in the storage vessel. surface of head space in the NA NA NA storage vessel. 4.22 WHO TRS- Specify whether pressure release valves are pressure release valves are NA NA NA 970 provided in the storage vessel. provided in the storage vessel. 4.23 Sch-M How water tanks are cleaned periodically and Water tanks were found cleaned No records were available records maintained thereof. NA periodically and records found NA maintained thereof. 4.24 WHO TRS- Specify whether on line TOC test is available for On line TOC analyser is available 970 WFI & PW. for WFI and PW NA NA NA 4.25 PIC/S Specify whether replacement of Air Vent filters on Replacement of Air Vent filters on Guidelines the purified/WFI water tank is carried out as per the purified water/WFI tank was relevant SOP. found carried out as per relevant Whether the provision to keep dry the vent filter is SOP. NA NA NA made. 4.26 Sch-M Specify the arrangement for preparation of pure PSG was found provided for PSG was found not provided for NA NA steam & its use. preparation of pure steam preparation of pure steam 4.27 Sch-M Specify whether pure steam (condensate) used in Pure steam (condensate) used in No records were available production meets the microbiological specification production meets the microbiological of not more than 10 cfu/100ml and IP/BP/USP NA specification of not more than 10 NA specifications of WFI. cfu/100ml and IP/BP/USP specifications of WFI. 4.28 WHO TRS- Verify PQ of the PSG. PQ of PSG was found carried out 970 and records found maintained NA NA NA 4.29 Sch-M Specify the system in place for the compressed Compressed air generation system Compressed air is not filtered Unfiltered gases used gases / air used in the facility. was found in place with arrangement before use in coating operation NA during filling of injectable of filtration before use in coating and drying. or eye preparations operation and drying. 4.30 ISO/PICS Verify the qualification documents of compressed Qualification documents of air system specially where it comes in contact with compressed air system specially product or primary container. where it comes in contact with product or primary container was NA NA NA verified and founds satisfactory 6Quality Rating S.No Reference 2 1 0 X 14 .B3u1ildingW anHdO p rTeRmSis-es:S -pecify whether action and alert limits are Action and alert limits are found 970 followed based on qualification of water and followed based on qualification of NA NA NA compressed Air system. water and compressed Air system. 5 Disposal of waste(Ambient protection):- 5.1 Sch-M Specify the system of disposal of sewage, and Centralized dust extraction system AHU with localized dust extraction No such system was found in effluents (solid, liquid, and gas) from the along with AHU for air, Scrubber system and ETP along with NOC from place. manufacturing site.(Enclosed the copy of NOC system for gases / air, ETP for State Pollution Control Board. obtained from State Pollution control board in this effluents along with NOC from NA regard.) State Pollution Control Board. 5.2 Sch-M Mention the procedure for storage and disposal of Segregated lock and key storage and No such SOP was found in place rejected drugs and applicable SOP. NA disposal in compliance to written although segregated area is NA norms provided 5.3 Sch-M Whether adequate records are maintained for the Records maintained for the disposal of No record could be produced in disposal of waste. NA waste was found adequate. this regard. NA 5.4 Sch-M Whether provision for disposal of bio-medical It was observed that provision for No such provision was found in waste made as per the provisions of the Bio disposal of bio-medical waste made as place. Medical Waste (Management and Handling) Rules NA per the provisions of the Bio Medical NA 1996. Waste (Management and Handling) Rules 1996. 6 Health, clothing and sanitation of workers: - 6.1 Sch-M Whether all personnel prior to employment have Medical examination of all personal No records were available undergone medical examination including eye was found carried out prior to examination and are all free from Tuberculosis, employment and all records found skin and other communicable or contagious NA maintained NA diseases & thereafter at regular intervals. 6.2 Sch-M Whether investigational reports, e.g. of X rays etc. Records regarding all investigational No records were available preserved. reports are found maintained NA NA Whether records of such medical examination are maintained thereof 6.3 Sch-M Specify whether employees report their illness to It was observed that employees report No such system was found in the supervising authority before entering into the their illness to the supervising authority place NA NA production area. before entering into the production area. 6.4 Sch-M Specify whether person from infectious disease is It was observed that person from No such system was found in barred to enter into production area. NA infectious disease is barred to enter place NA into production area. 6.5 Sch-M Specify if any unhygienic practise is observed No unhygienic practise is observed Unhygienic practise is observed in within the manufacturing areas. NA within the manufacturing areas during a manufacturing area during NA inspection inspection 6.6 Sch-M Whether all personnel are trained to ensure high All personnel were found trained to Neither any training record nor any level of personal hygiene. Mention the SOP no. ensure high level of personal hygiene SOP was found in place. NA NA followed in this regard. and respective SOP is followed 7Quality Rating S.No Reference 2 1 0 X 16 .B7uildingS acnhd- Mpremises:S -pecify whether cross over bench is in place in Cross over bench was found in place Although cross over bench was the change room and if so whether it rules out the in the change room and it rules out the found in place in the change room NA NA possibility of dust particle entering the clean side. possibility of dust particle entering the but can not prevent dust particle clean side. entering the clean side 6.8 Sch-M Whether arrangements provided for cleaning of Arrangement was found provided for No such arrangement was found outside dust and dirt from foot. NA cleaning of outside dust and dirt from provided NA foot. 7 Training:- 7.1 Sch-M Specify whether basic training on GMP is provided Basic training on GMP was found No such record could be produced to all personnel attached to production and quality provided to all personnel attached to during inspection control activity at the time of induction. NA production and quality control activity NA at the time of induction and records found maintained 7.2 Sch-M Specify whether specific training related to the job Training need are identified all Specific training related to the job duty No such record could be produced duty are provided to all personnel at the time of personnel and training calendar is was found provided to all personnel at during inspection induction. in place. The training imparted is the time of induction and records found NA assessed for its effectiveness. maintained 7.3 WHO TRS- Specify whether continuous training is provided. It was observed that whenever 986 there is a change in SOP, complete training was found provided to the concerned person NA NA NA before implementing the new SOP 7.4 WHO TRS- Specify whether concept of QA and its importance Concept of QA and its importance 986 is part of training session. was found a part of training NA NA NA session. 7.5 WHO TRS- Are all the persons associated with various Yes all the persons associated with 986 production activities properly trained as per various production activities guidelines provided in WHO working document. properly trained as per guidelines Verify the assessment records of the training of provided in WHO working few selected people who are associated with document. The training records of NA NA NA critical operations and procedure some of the persons working in critical areas/operation were Verified 8 Warehousing Area:- 8.1 WHO TRS- Is access to the area restricted to authorised Biometric system for access in NA NA NA 986 personnel only. place 8.2 Sch-M Whether adequate areas have been allocated for It was observed that adequate areas Due to inadequacy of the storage warehousing of Raw Materials, intermediates, with respect to stock volume have area materials was found stored in Packaging Material, products in quarantine, finish been allocated for warehousing of Raw manufacturing and other ancillary products, rejected or returned products. How are Materials, intermediates, Packaging area not meant for the storage. these areas marked or segregated. Material, products in quarantine, finish NA NA Please specify the total area provided for products, rejected or returned warehousing. products. These areas were found properly marked and segregated. 8Quality Rating S.No Reference 2 1 0 X 18 .B3uildingS acnhd- Mpremises:H -ow the warehousing areas being maintained to The warehousing areas are The storage area is clean and Storage condition was have good storage conditions. Are they clean and maintained to have good storage having required temperature for found unhygienic with dry and maintained within specified temperature conditions. The cleaning schedule and storage however records are not in accumulation of dust, limits? records are found maintained. The placed. dirt, pest manifestation, NA humidity and temperature are as per fungal growth, water the storage requirements and there stagnation and materials records are maintained. dumped without any identification labels. 8.4 WHO TRS- Is there any SOP defining maximum exposure maximum exposure time at room 986 time at room temperature for thermo labile temperature for thermo labile NA NA NA materials i.e. prior to storage in a refrigerator. materials was found followed as per the written document 8.5 Sch-M Specify the storage arrangement provided for It was observed that all sensitive No such arrangement was found NA materials which are sensitive to temperature, materials are stored in cold room or provided humidity and light and how the parameters are deep freezers and monitored at regular monitored. NA interval and records maintained Is cold room or deep freezers required for storage of goods? 8.6 WHO TRS- Verify the Thermal mapping of the cold rooms or Thermal mapping of the cold 986 deep freezers rooms and deep freezers were verified and found that probes for NA NA NA monitoring are placed at all strategic points including hotspots 8.7 Sch-M Whether receiving and dispatch bays are Receiving and dispatch bays were Receiving and dispatch bays were maintained to protect in coming and out going NA found covered. found not covered. NA materials. 8.8 Sch-M How incoming materials are treated and cleaned Tunnel was found provided to Vacuum cleaner was found used to No such arrangement was found before entry into the plant. clean the outer surface of the clean the outer surface of the provided Please specify the cleaning system for the outer container of incoming materials. container of incoming materials. NA surface of the container. 8.9 Sch-M How quarantined materials are segregated from Location of the materials is guided Quarantined materials are kept in the The quarantined material is other materials. through SAP or ERP System with separate rooms before sampling and segregated by labelling only and How access to quarantined area is restricted. records. The access to then shifted to the room for under test there is no control on access to quarantined area is allowed to materials and access to these areas these areas NA identified person by access cards. are controlled. 8.10 Sch-M Specify the system followed for storing passed All containers of passed raw materials The passed raw material are raw materials. NA are properly labelled and identified. stored batch wise but not NA identified. 8.11 Sch-M Whether proper racks, bins and platforms have Proper racks, bins and platforms was Proper racks, bins and platforms been provided for the storage. NA found provided for the storage. was not found provided for the NA storage. 9Quality Rating S.No Reference 2 1 0 X 18 .B1u2ildingW anHdO p rTeRmSis-es:W -hat is the control on entry of material and men The sampling area has access 986 into the sampling area? Whether reverse LAF control with PAL and MAL have been provided for sampling. Whether log arrangements. book for sampling booth maintained. Reverse LAF has been provided NA NA NA for sampling and log book of sampling booth is maintained. 8.13 Sch-M Specify the storage arrangement provided for Proper racks and bin were found Primary packaging materials are primary packaging materials. provided with temperature and found stored with other secondary NA NA humidity control. packaging material or with raw materials. 8.14 Sch-M Specify the arrangements provided to sample the Primary packaging Materials are No specific arrangement was primary packaging materials foils, bottles, etc. NA sampled under LAF in a specified area found provided NA which are used as such. 8.15 WHO TRS- Specify sampling plan used. 100 % sampling for identification of 100 % sampling for API but √n + 1 for No sampling plan is used 986 API & Excipients and complete excipients analysis following sampling procedure prescribed in WHO TRS NA 929. Well defined SOP in this regard was found in place and followed meticulously. 8.16 WHO TRS- Which type of sampling tools are used and how Scoops, Spears, Dip tubes, 986 they are cleaned, dried and maintained. Thieves etc. made of SS-316 as prescribed in WHO TRS 929 are used. Used sampling tools are NA NA NA cleaned in a separate washing area following the specified SOP 8.17 WHO TRS- How containers are cleaned before and after Outer surface of each container 986 sampling. (Specify whether the sampling is carried was found mopped before and NA NA NA out as per the current SOP). after sampling following the specified SOP in this regard 8.18 Sch-M What provisions have been made for segregated It was observed that restricted & No segregated area is provided storage of rejected, recalled or returned materials segregated area is provided for or products. How is the access to these areas NA rejected material. The Area was found NA restricted? controlled with authorised access. 8.19 Sch-M How printed secondary packaging materials are Separate area is provided for No separate area was found stored in safe, separate and in secure manner. NA secondary packaging materials with provided NA authorised access 8.20 Sch-M How printed packaging materials, product leaflets Printed packaging materials, product Storage arrangement can rule out etc. are stored separately to avoid chances of mix- leaflets etc. are stored separately in the possibility the chances of mix- NA NA up? almirahs under lock to avoid chances up. of mix-up 8.21 Sch-M How labels, cartons, boxes, circulars, inserts and Proper stock register is maintained No SOP was found in this regard leaflets are controlled. ? NA along with issue records following NA specified SOP 10Quality Rating S.No Reference 2 1 0 X 18 .B2u2ildingS acnhd- Mpremises:H -ow records of receipt of all labelling and Proper stock register is maintained Neither any SOP nor any stock packaging materials are maintained. NA along with issue records following register was found NA specified SOP 8.23 Sch-M Whether unused packaging materials return to the Unused labels and cartons with batch No records were available store or destroyed. no printed is destroyed and without NA NA batch no is returned to the store after proper reconciliation. 8.24 Sch-M How returned/unused packaging material like foils Unused primary packaging materials Returned to the store without is controlled so as to prevent contamination and like Aluminium Foils etc. are properly proper packing and sealing cross- contamination. packed, sealed, labelled and kept in a NA separate intermediate store in secured NA condition. 8.25 Sch-M Specify the arrangement provided for dispensing Reverse LAF has been provided for Dispensing is carried out in the of starting materials. NA dispensing and log book of dispensing storage area without any control NA booth is maintained. 8.26 WHO TRS- What is the control on entry of material and men The dispensing area has access 986 into the dispensing area? Whether reverse LAF control with PAL and MAL have been provided for dispensing with back arrangements and reverse phase NA NA NA ground clean air supply. LAF provided in a class C background 8.27 WHO TRS- Whether pressure differential is maintained The dispensing area is observed 986 between the dispensing and adjacent areas. under negative pressure of 15 pa NA NA NA in comparison with the adjacent PAL & MAL 8.28 WHO TRS- Specify the pressure differential maintained. 10-15 pa pressure differential was NA NA NA 986 found maintained. 8.29 Sch-M Examine the record of the daily check of balances It was observed that balances in the in the dispensing area. NA dispensing area are checked daily and NA NA records are maintained. 8.30 WHO TRS- How containers are cleaned before and after Outer surface of each container 986 dispensing. Who carries out the dispensing? was found mopped before and after dispensing following the specified SOP in this regard. NA NA NA Designated qualified person is carry out the dispensing operation. 8.31 WHO TRS- Specify whether appropriate air velocity is Appropriate air velocity was found 986 maintained in sampling & dispensing areas which maintained in sampling & rule out any influence in the balance readings dispensing areas which rule out placed inside the RLAFs Benches. any influence in the balance NA NA NA readings placed inside the RLAFs Benches. 8.32 Sch-M Specify whether the dispensing is carried out as Dispensing was found carried out as No SOP was found in this regard per the current SOP. NA per the current SOP. NA 11Quality Rating S.No Reference 2 1 0 X 18 .B3u3ildingS acnhd- Mpremises:S -pecify whether dispensed material for each batch Dispensed material for each batch of Dispensed material for each batch of final product are kept together and final product was found kept together was found not conspicuously NA NA conspicuously labelled. and conspicuously labelled. labelled. 8.34 Sch-M What steps are taken against spillage, breakage SOP was found in place for handling of No SOP was found in this regard and leakage of containers? spillage, breakage and leakage of NA NA containers in the warehouse area. 8.35 Sch-M How highly hazardous, poisonous and explosive In segregated area with all safety No segregated area was found materials, narcotics, and psychotropic drugs are features provided handled and stored. How these areas are safe NA NA and secure. 9 Raw Materials: - 9.1 Sch-M Please specify the procedures followed for SOP was found in place for receiving No SOP was found in this regard receiving and processing of in-coming materials and processing of in-coming materials NA NA (Starting materials and packing material). Verify (Starting materials and packing the SOP. material) 9.2 Sch-M Whether first in / first out or first expiry principal First in first out (FIFO) / first expiry No such system was found in NA NA has been adopted. (FIFE) principal was found adopted. place 9.3 Sch-M How they are labelled and stored as per their Under Test, Approved and Rejected No such SOP was found in place status – Under Test, Approved and Rejected NA materials are labelled as per specified NA SOP . 9.4 Sch-M Whether incoming materials are purchased from Incoming materials were found Incoming materials are not always approved vendors. NA purchased from approved vendors. purchased from approved NA vendors. 9.5 Sch-M Whether list of approved vendors is available to Approved vendors' list is available in Approved vendors' list is not NA NA the user. the receiving area available in the receiving area 9.6 WHO TRS- Specify the norms of vendor qualification. A questionnaire is sent to the 986 vendor, after getting satisfactory response against questionnaire, the vendor for API is audited given approval if all the parameters NA NA NA found complied. SOP for vendor selection criteria was found followed. 9.7 Sch-M How damaged containers are identified recorded SOP for identification and segregation No SOP for identification and and segregated of damaged containers for starting segregation of damaged NA NA materials was found in place . containers for starting materials was found in place . 9.8 Sch-M Whether each batch of a consignment is It was observed that each batch of a No such system was found considered for sampling, testing and release. NA consignment is considered for followed NA sampling, testing and release. 9.9 WHO TRS- Whether all the containers of each batch of It was observed that identity test is 986 starting materials sampled for identification test. carried out by FTNIR for each NA NA NA container and pooled sample for other tests. 12Quality Rating S.No Reference 2 1 0 X 19 .B1u0ildingS acnhd- Mpremises:W -hether labels of raw material in the storage area All relevant information was found All relevant information was found have information like ; available on the labels. not available on the labels. (a) designated name of the product and the internal code reference, where applicable, and analytical reference number; (b) manufacturer’s name, address and batch NA NA number; (c) the status of the contents (e.g. quarantine, under test,released,approved, rejected); and (d) The manufacturing date, expiry date and re- test date. 9.11 Sch-M Whether separate areas are provided for under separate and segregated areas was No such segregation was found in test, approved and rejected materials. NA found provided for under test, place NA approved and rejected materials. 9.12 Sch-M How the containers from which samples have Containers from which samples was No such system was found in been drawn labelled. NA drawn found labelled as per specified place NA SOP. 9.13 Sch-M Please specify the procedures by which it is Electronically controlled system Bin card system No specific system was found ensured that the raw materials which has been followed released by the Quality Control Department and NA which are within their shelf life are going to be used in the product. 10 Production Area for Non Sterile preparation:- 10.1 WHO TRS- Verify whether access to production area is Access control was found in place 986 restricted to authorised personnel only. to enter production area. List of NA NA NA authorised personnel was found in place in place.. 10.2 WHO TRS- Whether the facility is provided with a well-sealed The facility was found provided 986 structure with no air leakage through ceilings, with a well-sealed structure with no NA NA NA cracks or service penetrations. air leakage through ceilings, cracks or service penetrations. 10.3 WHO TRS- Whether entry and exit doors, for materials and It was observed that entry and exit 986 personnel, have an interlock mechanism or other doors for all PAL & MAL have NA NA NA appropriate system to prevent the opening of interlock arrangement. more than one door at a time. 10.4 WHO TRS- Specify the procedures for entry of maintenance Specific SOP was found prepared 986 people into the production area. and followed for entry of NA NA NA maintenance people into the production area. 10.5 WHO TRS- Whether the change rooms have an arrangement Step-over/cross-over bench was 986 with step-over/cross-over bench. found provided in all the change NA NA NA room. 10.6 Sch-M Is there any cris cross flow of materials and men? NO cris cross flow of materials and Cris cross flow of materials and men was observed within the men was observed within the NA NA manufacturing areas during inspection manufacturing areas during inspection 13Quality Rating S.No Reference 2 1 0 X 11 0B.u7ildingS acnhd- Mpremises:W -hether the premises and equipment are The premises and equipment are Design of the premises and appropriately designed and installed to facilitate appropriately designed and installed to installation of equipment do not NA NA cleaning and decontamination. facilitate cleaning and facilitate cleaning and decontamination. decontamination. 10.8 WHO TRS- Specify the position of IPQC lab in the IPQC lab was found in a separate 986 manufacturing area. enclosed cubical in the NA NA NA manufacturing area. 10.9 Sch-M Specify whether non storage areas are used for No such observation was found Yes materials was found stored in NA NA storage of any material. non storage areas. 10.10 WHO TRS- Specify the provisions for storage of dirty, washed SOP was found in place which 986 and cleaned equipment in process areas. prescribes provisions of storage of NA NA NA dirty, washed and cleaned equipment in process areas. 10.11 Sch-M Specify how service lines are identified for nature Fixed Pipe work was found labelled service lines are not identified for NA of supply and direction of the flow. NA with colour code to indicate the nature of supply and direction of contents & direction of flow. the flow. 10.12 WHO TRS- Whether service lines in production areas are It was observed that Service lines 986 through service pendants. If not, how they are (purified water, compressed air placed so as to avoid accumulation of dust. and electrical wires) are concealed NA NA NA in a service pendant.. 11 Air Handling Systems (HVAC):- 11.1 WHO TRS- Please specify whether following parameters are Following parameters were found 986 qualified: (IQ,OQ,PQ) qualified and documents are — temperature maintained (IQ,OQ,PQ) — relative humidity — temperature — supply air quantities for all diffusers — relative humidity — return air or exhaust air quantities — supply air quantities for all — room air change rates diffusers — room pressures (pressure differentials) — return air or exhaust air — room airflow patterns quantities — unidirectional flow velocities — room air change rates —filter penetration tests (HEPA) — room pressures (pressure NA NA NA — room particle counts differentials) — room clean-up rates — room airflow patterns — microbiological air and surface counts where — unidirectional flow velocities appropriate —filter penetration tests (HEPA) — operation of de-dusting — room particle counts — warning/alarm systems — room clean-up rates — microbiological air and surface counts where appropriate — operation of de-dusting — warning/alarm systems 11.2 WHO TRS- Verify the SOPs for AHUs operation and cleaning. SOPs for AHUs operation and 986 cleaning was verified and found NA NA NA satisfactory. 14Quality Rating S.No Reference 2 1 0 X 11 1B.u3ildingW anHdO p rTeRmSis-es:S -pecify whether the facilities and premises have Following basic air-handling 986 following basic air-handling characteristics: characteristics were found in the a) The absence of direct venting of air to the system of the facilities. outside. a) The absence of direct venting of b) Whether the facility is maintained at a negative air to the outside. air pressure to the environment. b) Whether the facility is c) The precaution taken to prevent the infiltration maintained at a negative air into the core areas. pressure to the environment. d) Whether appropriate air pressure alarm c) The precaution taken to prevent systems as well as alert and action limit is the infiltration into the core areas. provided. d) Whether appropriate air NA NA NA e) The type of HEPA filters used in the HVAC pressure alarm systems as well as system alert and action limit is provided. f) Whether the change rooms are supplied with e) The type of HEPA filters used in same quality of air as supplied to the working the HVAC system area. f) Whether the change rooms are g) The measures taken to prevent air flow from supplied with same quality of air as the primary packing area to the secondary packing supplied to the working area. area. g) The measures taken to prevent air flow from the primary packing area to the secondary packing area. 11.4 WHO TRS- Whether HVAC system description includes: It was observed that the HVAC 986 1) Schematic drawings detailing the filters and system includes following their specifications description: 2) Number of air changes per hour 1) Schematic drawings detailing NA NA NA 3) pressure gradients the filters and their specifications 2) Number of air changes per hour 3) pressure gradients 11.5 WHO TRS- Specify the emergency power systems in case of Standby Generator with UPS NA NA NA 986 power failure. 11.6 WHO TRS- Specify whether recirculated air is used. If yes, 10-12 % of ambient air is used 986 specify the proportion of fresh air supplied. NA NA NA 11.7 WHO TRS- Whether risk assessment study has been carried It was observed that risk 986 out in case of return air/ recirculated air system. assessment was carried out in this NA NA NA Verify the records thereof. regard and records found maintained. 11.8 WHO TRS- Specify what precaution has been taken during Filters are taken in polythene bags 986 filter change of AHUs. and sealed before taking into cleaning area. Dedicated filter cleaning area was found provided. NA NA NA Bag-in-bag-out system is also followed. 15Quality Rating S.No Reference 2 1 0 X 11 1B.u9ildingW anHdO p rTeRmSis-es:W -hether all exhaust systems from the facility, All exhaust systems from the 986 including dust extraction systems, vacuum system facility, including dust extraction exhaust, fluid bed drier exhaust, coating pan systems, vacuum system exhaust, exhaust, etc., are passed through safe change fluid bed drier exhaust, coating pan filter housings and wet scrubber before being exhaust, etc., was found passed NA NA NA exhausted to the atmosphere. through safe change filter housings and wet scrubber before being exhausted to the atmosphere. 11.10 WHO TRS- Whether all exhaust points outside the building All exhaust points outside the 986 are located as far as possible from air entry points, building are located at distance exit points and at a high level, to minimize the and at a high level from air entry possibility of re-entrainment of exhaust air. points of air to minimize the NA NA NA possibility of re-contaminant of incoming air. 11.11 WHO TRS- Whether the return air ducts are checked Duct Cleaning system was found in NA NA NA 986 periodically for dust accumulation. place 11.11 Sch-M Whether the dust collectors are located in a room Dust collectors were found located in a No such system was found in maintained at a negative pressure. NA room maintained at a negative place. NA pressure. 11.12 WHO TRS- Whether the filters cleaning facility is maintained Filters cleaning facility was found 986 at negative pressure. maintained at negative pressure. NA NA NA 11.13 WHO TRS- Whether records for safe disposal of all Records for safe disposal of all 986 contaminated filters and dust are maintained. contaminated filters and dust was NA NA NA found maintained. 11.15 WHO TRS- Specify whether total No. of AHUs used to cover Total No of AHUs used to cover 986 the whole production Area is commensurate with the whole production Area is NA NA NA the requirements commensurate with the requirements. 11.16 WHO TRS- Specify the Terminal Air Filter of various core HEPA NA NA NA 986 areas. 11.17 WHO TRS- Specify the no. of Air Change maintained in NLT 20 ACPH NA NA NA 986 various core areas. 11.18 WHO TRS- Specify the pressure balancing to segregate Difference of 15 pa was found 986 different areas. maintained as pressure balancing NA NA NA to segregate different areas. 11.19 WHO TRS- Are the returns risers cleaned during Product Returns risers were found cleaned 986 Change Over? during Product Change Over as NA NA NA per the prescribed SOP 11.20 WHO TRS- Verify if the AHU's / HVAC systems have been Whenever there is shut down of 986 shut down. If yes the reasons there of such as AHUs for preventive maintenance cleaning & maintenance & the procedures for re- or break down, requalification was initiation / re-start of the systems found carried out before carrying NA NA NA out normal production. 12 Cleaning Validation:- 16Quality Rating S.No Reference 2 1 0 X 11 2B.u1ildingS acnhd- Mpremises:I s- a validation performed to confirm cleaning Validation was found performed to Validation was found not NA effectiveness? NA confirm cleaning effectiveness performed to confirm cleaning effectiveness 12.2 WHO TRS- Does the protocol define the selection criteria for Protocol prepared in this regard 986 products or groups of products subject to cleaning was found established the validation? selection criteria for products or NA NA NA groups of products subject to cleaning validation 12.3 WHO TRS- Is data produced supporting the conclusion that Documents produced during 986 residues were removed to an acceptable level? inspection concluded that residues were removed to an acceptable NA NA NA level 12.4 WHO TRS- Specify whether the validation is implemented to Validation protocol was found 986 verify cleaning of: mentioned descriptively to verify 1 )Surfaces in contact with the product cleaning of 2) After a change in product 1 )Surfaces in contact with the NA NA NA 3) Between shift batches. product 2) After a change in product 3) Between shift batches. 12.5 WHO TRS- Specify whether the Validation Strategy include It was observed that validation 986 contamination risks & equipment storage time. strategy include contamination NA NA NA risks & equipment storage time. 12.6 WHO TRS- Whether Quality Control responsible of the It was observed that QA/QC is 986 sampling for cleaning verification? responsible for sampling of NA NA NA cleaning verification 12.7 WHO TRS- Whether personnel engaged in cleaning, sampling The Personnel engaged in 986 etc. trained. cleaning, sampling etc. was found NA NA NA adequately trained. 12.8 WHO TRS- Specify whether acceptance limits been set for It was observed that following 986 cleaning verification and are based on following criteria has been set: criteria: 1) Visually clean criteria is followed 1) Visually clean. for manufacturing of same product 2) 10 ppm in another product. of different batch number 3) 0.1% of the therapeutic dose? 2) 10 ppm criteria is followed NA NA NA during product change over of similar dosage form 3) 0.1% of the therapeutic dose criteria is followed during product change over from smaller to larger dosage form 12.9 WHO TRS- Specify whether detergent residues and It was observed that detergent 986 degradation products are investigated during residues and degradation products NA NA NA validation. are investigated during validation. 17Quality Rating S.No Reference 2 1 0 X 11 2B.u1i0ldingW anHdO p rTeRmSis-es:W -hether validation records include : It was observed that validation 986 Recovery study data, records contain Recovery study Analytical method, data, Acceptance Criteria, Analytical method, Swab recovery test, Acceptance Criteria, Signatures of the Quality Assurance Manager, Swab recovery test, Signature of the employee in charge of cleaning Signatures of the Quality NA NA NA verification from Production and Quality Control. Assurance Manager, Signature of the employee in charge of cleaning verification from Production and Quality Control. 13 Manufacturing Operations and Controls:- 13.1 Sch-M Whether the contents of all vessels and containers It was observed that the contents of all It was observed that the contents used in manufacture and storage is conspicuously vessels and containers used in of all vessels and containers used labelled with the name of the products. Batch no, manufacture and storage is in manufacture and storage is not Batch Size, and stage of manufacture along with conspicuously labelled with the name conspicuously labelled with the signature of technical staff. NA of the products. Batch no, Batch Size, name of the products. Batch no, NA and stage of manufacture along with Batch Size, and stage of signature of technical staff. manufacture along with signature of technical staff. 13.2 Sch-M Whether the products not prepared under aseptic Products not prepared under aseptic Products not prepared under conditions are free from pathogens like conditions was found tested for aseptic conditions was found not Salmonella, Escherichia coli, Pyocyanea etc. absence of pathogens like Salmonella, tested for absence of pathogens NA Escherichia coli, Pyocyanea etc. like Salmonella, Escherichia coli, NA Pyocyanea etc. 13.3 Sch-M If yes, pls give brief account of measures taken to MLT was found carried out MLT was found not carried out NA NA assure freedom from pathogens. 13.4 WHO TRS- Verify whether handling of materials and products It was observed that handling of 986 are carried out in accordance with the relevant materials and products are carried NA NA NA SOP’S. out in accordance with the relevant SOP’S. 13.5 WHO TRS- Specify Whether any deviation is approved in It was observed that any deviation 986 writing by a designated person and recorded. during any stage of manufacturing operation is approved in writing by a designated person and recorded. NA NA NA 13.6 WHO TRS- Is there an approved SOP for In process check? Approved SOP for In process NA NA NA 986 check was found in place 13.7 WHO TRS- Is the personnel clothing clean, unstained & dust It was observed that the garments 986 free, including shoes? including shoes used by the NA NA NA employees are clean, unstained & dust free, 18Quality Rating S.No Reference 2 1 0 X 11 3B.u8ildingW anHdO p rTeRmSis-es:I s- there a cleaning SOP for slippers or shoes that Cleaning SOP for slippers or shoes 986 is being used in the manufacturing area? that is being used in the NA NA NA manufacturing area was found in place 13.9 WHO TRS- Whether process hold time studies has been Process hold time studies was 986 carried out for various stages of production found carried out for various NA NA NA stages of production 13.10 Sch-M Specify whether all critical activities of production NA and testing is carried out under the direct All critical activities of production and Some of the critical activities of The critical activities of supervision of competent technical staff. testing was found carried out under the production and testing was found production and testing is carried out under the direct carried out without direct direct supervision of competent supervision of competent technical supervision of competent technical staff. staff. technical staff. 14 Precautions against mix-up and cross-contaminations:- 14.1 Sch-M Whether proper AHU, pressure differential, AHU, pressure differential, AHU, pressure differential, segregation, status labelling have been provided segregation, status labelling were segregation, status labelling were to prevent mix-up and cross-contamination in found provided to prevent mix-up and found not provided to prevent mix- manufacturing area NA cross-contamination in manufacturing up and cross-contamination in NA area manufacturing area 14.2 Sch-M Pls specify the areas of dust generation and Dust collectors were found installed in Dust collectors were found not mechanism involved in controlling the dust granulation, coating, compression and installed in granulation, coating, powder filling area to control the dust compression and powder filling NA generated during manufacturing. area to control the dust generated NA during manufacturing. 14.3 Sch-M Do all the areas have their own independent air Independent air locks separately for Independent air locks separately locks separately for men and material entry. men and material entry was found for men and material entry was NA NA provided in all areas. found not provided in all areas. 14.4 Sch-M What criteria of pressure differential has been set Criteria of pressure differential was Criteria of pressure differential was for production v/s adjoining areas. NA found set for production v/s adjoining found not set for production v/s NA areas. adjoining areas. 14.5 Sch-M Whether processing of sensitive drugs like Beta Processing of sensitive drugs like Beta Processing of sensitive drugs like Processing of sensitive lactam Antibiotics and Sex Hormones is done in lactam Antibiotics and Sex Hormones Beta lactam Antibiotics and Sex drugs like Beta lactam segregated areas with independent AHU and was found carried out in separate Hormones was found carried out in Antibiotics and Sex proper pressure differentials along with dedicated areas with independent AHU segregated areas in the same Hormones was found demonstration of effective segregation of these and proper pressure differentials along facility with independent AHU and carried out in the same areas with records. NA with demonstration of effective proper pressure differentials along facility without segregation of these areas with with demonstration of effective independent AHU and records. segregation of these areas with proper pressure records. differentials 19Quality Rating S.No Reference 2 1 0 X 11 4B.u6ildingS acnhd- Mpremises:P -lease specify what measures has been taken to Beta Lactam Antibiotics, Sex Beta Lactam Antibiotics, Sex Beta Lactam Antibiotics, prevent contamination of products with Beta hormones and cyto toxic substances hormones and cyto toxic Sex hormones and cyto- Lactam Antibiotics, Sex hormones and cyto toxic were found manufactured in a substances were found toxic substances were substances. separate dedicated facility with manufactured in a s dedicated found manufactured in a dedicated arrangements for raw area with common arrangements same facility without any materials store, sampling & dispensing for raw materials store, sampling & dedicated area with NA operations. dispensing operations. common arrangements for raw materials store, sampling & dispensing operations. 14.7 Sch-M What measures has been taken to prevent mix- Line clearance was found obtained Line clearance was found not ups during various stages of production. before proceeding every stages of obtained before proceeding every NA manufacturing operations. stages of manufacturing NA operations 14.8 Sch-M Whether equipments use for production are Equipment use for production were No status label was found affixed labelled with their current status. NA found labelled with their current with the equipment use in NA status. manufacturing process 14.9 Sch-M Whether packaging lines are independent and Packaging lines were found Packaging lines were found adequately segregated. NA independent and adequately neither independent nor NA segregated. adequately segregated 14.10 Sch-M How line clearance is performed. Whether records Line clearance was found performed Records of line clearance could of line clearance is maintained according to according to the prescribed SOP and not produce during inspection appropriate checklist. records of line clearance was found NA maintained according to the NA appropriate checklist. 14.11 Sch-M Whether separate carton coding area has been Separate carton coding area / online Separate carton coding area was provided or online carton coding is performed carton coding was found provided. found not provided. How carton coding procedure is controlled. NA NA 14.12 Sch-M Please specify how temperature, humidity and air Temperature, humidity and air Temperature, humidity and air filtration are controlled in the areas where raw filtration are controlled through AHU in filtration are not controlled through material and/or products are exposed and handled NA the areas where raw material and/or AHU in the areas where raw NA products are exposed and handled material and/or products are exposed and handled 14.13 Sch-M How access of authorized persons to List of authorized persons to enter Access of authorized persons to manufacturing areas including packaging is manufacturing areas including manufacturing areas including controlled. NA packaging was found in place and packaging is found not controlled. NA records found maintained in this regard. 14.14 Sch-M Whether separate gowning provision is followed Secondary gowning procedure was Secondary gowning procedure before entering the core areas. NA found followed before entering the core was found not followed before NA areas entering the core areas 20Quality Rating S.No Reference 2 1 0 X 11 4B.u1i5ldingS acnhd- Mpremises:W -hether segregated secured areas for recall or Segregated secured areas for recall or Segregated secured areas for rejected materials or for such material which are to rejected materials or for such material recall or rejected materials or for be processed or recovered are provided. NA which are to be processed or such material which are to be NA recovered was found provided. processed or recovered was found not provided. 14.16 Sch-M Whether various operations are carried out in Various operations were found carried Various operations were found not segregated areas. NA out in segregated areas carried out in segregated areas NA 14.17 Sch-M Are doors of all core areas closed at all times with Doors of all core areas were found Doors of all core areas were found interlock arrangements? NA closed at all times with interlock not closed at all times with NA arrangements interlock arrangements 14.18 Sch-M Specify whether any SOP is followed to verify the Specific SOP was found in place and No specific SOP was found in effectiveness for prevention of cross followed to verify the effectiveness for place to verify the effectiveness NA NA contamination. prevention of cross contamination. for prevention of cross contamination. 14.19 WHO TRS- Specify whether critical operations are carried out It was observed that all critical 986 in closed system. operations are carried out in closed NA NA NA system. 14.20 WHO TRS- Specify the methods followed for product change- Specific SOP was found prepared 986 over. and followed for product change NA NA NA over. 15 Sanitation in the Manufacturing areas:- 15.1 Sch-M Specify the cleaning procedure of the Specified SOP for cleaning procedure Neither any SOP nor any records manufacturing areas and verify with the SOP in of the manufacturing areas was found for cleaning procedure of the this regard. NA in place and followed. Records found manufacturing areas was found in NA maintained in this regard. place. 15.2 Sch-M Whether cleaning procedure is validated. Cleaning procedure was found Cleaning procedure was found not NA NA validated. validated. 15.3 Sch-M Whether a routine sanitation program is in place. Routine sanitation program was found Routine sanitation program was NA in place found not in place 15.4 Sch-M Verify the SOP & the records in this regard. SOP & records regarding sanitation Neither any SOP nor any records NA program was verified and found regarding sanitation program was NA satisfactory. found in place. 15.5 Sch-M Does the location facilitate cleaning of equipment Equipment was found installed in such Location of equipment installation as well as the cleaning of the areas in which they location which facilitate cleaning of the do not facilitate cleaning of the NA NA are installed? areas as well as the equipment. areas as well as the equipment. 15.6 Sch-M Whether production area is adequately lit. Production area was found adequately Lux level in the production area NA NA lit. was found adequate. 15.7 Sch-M Mention lux levels observed in production, visual Production Area - 400 to 500 Lux, No specific Lux level was found inspection and other areas. NA visual inspection area- 500 to 600 Lux maintained NA and other areas 200 to 400 Lux 15.8 Sch-M Specify in detail the procedure followed during Specific SOP was found in place and No specific SOP was found in NA NA product changeover. followed. place in this regard 16 Equipment: - 21Quality Rating S.No Reference 2 1 0 X 11 6B.u1ildingS acnhd- Mpremises:W -hether the equipment are designed aiming to It was observed that the equipment are No such measures was found minimize risk of error and permit effective cleaning designed aiming to minimize risk of taken. and maintenance in order to avoid cross error and permit effective cleaning and contamination & build up of dust. NA maintenance in order to avoid cross NA contamination & build up of dust. 16.2 Sch-M Whether all equipment are provided with log book. All equipment was found provided with Log book was found not NA log book. maintained for each equipment NA 16.3 Sch-M Please specify the procedures to clean the Specific SOP was found in place and No SOP was found in place and equipment after each batch production. NA followed to clean the equipment after followed to clean the equipment NA each batch production after each batch production 16.4 Sch-M Whether validity period for use after the cleaning Validity period for use after the Validity period for use after the of equipment is specified. NA cleaning of equipment was found cleaning of equipment was found NA specified. not specified. 16.5 Sch-M Whether separate area is provided for storage of Separate area was found provided for No separate area is provided for machine parts etc. NA storage of machine parts etc. storage of machine parts etc. NA 16.6 Sch-M Whether balances and other measuring Balances and other measuring Balances and other measuring equipments with appropriate range are available equipment with appropriate range equipments with appropriate range in the Raw Material stores & production areas and were available in the Raw Material are available in the Raw Material they are calibrated in accordance with SOP stores & production areas and they stores & production areas but they maintained. Specify the calibration schedule of were found calibrated in accordance are not found calibrated and no the balances. NA with SOP maintained. Calibration SOP was found in place in this NA schedule of the balances was found regard. mentioned in the SOP. Record of calibration was found maintained. 16.7 Sch-M Specify material of construction of contact parts of MOC of contact parts of all the MOC of contact parts of all the the production equipments. manufacturing equipment was found manufacturing equipment was The material of made up of SS-316 found not made up of SS-316 construction of the NA equipment is not suitable. e.g., found rusted, cracked, leaking etc. 16.8 Sch-M Which types of lubricants are used in the Food grade lubricants was found in Food grade lubricants was found equipment. Specify the quality and control NA use. not in use. NA reference No. of these lubricants 16.9 Sch-M Specify the procedures to remove defective Specific SOP was found in place in this No specific SOP was found in NA NA equipments from production areas. regard. place in this regard. 16.10 WHO TRS- Verify whether washing and cleaning of equipment Washing and cleaning of 986 are not a source of contamination. equipment was found not a source NA NA NA of contamination. 16.11 Sch-M Whether all equipment is provided with an ID NO. All equipment was found provided All equipment was found not NA NA with an ID No. provided with an ID No. 16.12 WHO TRS- Specify the procedures to clean the equipment Specific SOP was found in place in 986 after each batch production and verify with the this regard NA NA NA SOP. 22Quality Rating S.No Reference 2 1 0 X 11 6B.u1i3ldingW anHdO p rTeRmSis-es:S -pecify whether CIP or SIP is in place. CIP/SIP was found in place NA NA NA 986 16.14 WHO TRS- Specify whether the CIP / SIP system is qualified CIP/SIP system was found NA NA NA 986 qualified. 16.15 WHO TRS- Are there cleaning agent labelled with a catalogue Cleaning agent was found labelled 986 no. indicating that they were received through the with a catalogue no. indicating that warehouse. they were received through the NA NA NA warehouse. 16.16 WHO TRS- Are there records for preparation of cleaning Records for preparation of cleaning 986 agent? agent was found in place. NA NA NA 17 Production Area for Sterile Preparation 17.1 Building and Facilities:- 17.2 Sch-M Specify the building is devoid of cracks especially Building was found devoid of cracks Cracks are observed in non critical Wide cracks on in the Critical solutions preparation rooms, Filling especially in the Critical solutions areas. walls/floor/ceiling or rooms, Sealing rooms. preparation rooms, Filling rooms, fungal growth or Sealing rooms. cobwebs, or insects NA infestations seen in filling areas of parenteral or eye drop preparations 17.3 Sch-M Are the location of services like water, steam, Location of services like water, steam, Location of services like water, gases etc. Such that the servicing or repairs can gases etc. Such that the servicing or steam, gases etc. can not rule out be carried out without any threat to the integrity of NA repairs can be carried out without any the threat to the integrity of the NA the facility threat to the integrity of the facility facility during servicing or repairs. 17.4 Sch-M Specify water lines pose any threat of leakage to Water lines do not pose any threat of Threat of leakage to the critical the critical area NA leakage to the critical area area can not ruled out from water NA lines. 17.5 Sch-M Specify the manufacturing areas clearly separated Manufacturing area was found clearly Following support areas was found into following Support Areas: separated into following Support not clearly separated. 1) Washing of containers & closures Areas: 1) Washing of containers & 2) Storage of washed containers & closures 1) Washing of containers & closures closures 3) Sterilization of containers & closures 2) Storage of washed containers & 2) Storage of washed containers 4) Preparation of bulk solution ( critical/non critical) NA closures & closures NA 5) Change room 3) Sterilization of containers & closures 3) Sterilization of containers & 4) Preparation of bulk solution ( closures critical/non critical) 4) Preparation of bulk solution ( 5) Change room critical/non critical) 5) Change room 17.6 Sch-M Specify de-cartoning areas to remove outer De-cartoning areas to remove outer De-cartoning areas to remove cardboard wrappings of primary packaging cardboard wrappings of primary outer cardboard wrappings of materials segregated from the washing areas. NA packaging materials was found primary packaging materials was NA segregated from the washing areas. found not segregated from the washing areas. 23Quality Rating S.No Reference 2 1 0 X 11 7B.u7ildingS acnhd- Mpremises:S -pecify whether particle shedding materials like No particle shedding materials like Particle shedding materials like wooden pallets, fibre board drums, cardboards wooden pallets, fibre board drums, wooden pallets, fibre board drums, NA NA etc. are taken into the preparation areas. cardboards etc. are taken into the cardboards etc. was found in the preparation areas. preparation areas. 17.8 Sch-M Specify in the classified areas: In the classified area following In the classified area some of the 1) Walls are flat, smooth and devoid of recesses. observations were noted : following points were found not 2) Surface joints like electric sockets, gas points 1) Walls are flat, smooth and devoid of complied with : flushed with walls. recesses. 1) Walls are flat, smooth and 3) Joints in the ceiling are properly sealed 2) Surface joints like electric sockets, devoid of recesses. 4) Air grills and lights flushed with the ceiling. gas points flushed with walls. 2) Surface joints like electric 5) Grade A & B areas devoid of sinks and drains. 3) Joints in the ceiling are properly sockets, gas points flushed with 6) Doors and windows made up of non shedding sealed walls. materials. 4) Air grills and lights flushed with the 3) Joints in the ceiling are properly 7) Doors open towards higher pressure areas and NA ceiling. sealed NA close automatically due to air pressure. 5) Grade A & B areas devoid of sinks 4) Air grills and lights flushed with and drains. the ceiling. 6) Doors and windows made up of non 5) Grade A & B areas devoid of shedding materials. sinks and drains. 7) Doors open towards higher pressure 6) Doors and windows made up of areas and close automatically due to non shedding materials. air pressure. 7) Doors open towards higher pressure areas and close automatically due to air pressure. 17.16 WHO TRS- Is there a glass panel between critical area & Glass panel between critical area 961 support area so that all operations in Grade A & B & support area was found so that ANNEXE-06 areas can be supervised from support areas? all operations in Grade A & B NA NA NA areas can be supervised from support areas 17.17 WHO TRS- Fire extinguishers are suitably fastened to the Fire extinguishers were found 961 walls without gaps. suitably fastened to the walls NA NA NA ANNEXE-06 without gaps. 17.18 Sch-M Quality of the furniture used is smooth & washable Quality of the furniture used was found Quality of the furniture used was and made of SS316. NA smooth & washable and made of found not smooth & washable NA SS316. 17.19 Sch-M Change rooms entrance provided with air locks Three change rooms were found Three change rooms were found before entry to the sterile product manufacturing provided with air locks before entry to not provided with air locks before NA NA areas. the sterile product manufacturing entry to the sterile product areas. manufacturing areas 17.20 Sch-M How many change rooms are provided to enter Three Less than three NA NA into the critical areas? 17.21 WHO TRS- Specify an appropriate inter- locking system with Appropriate inter- locking system 961 visual and/or audible warning system installed to with visual and/or audible warning ANNEXE-06 prevent the opening of more than one door at a system was found installed to Na NA NA time. prevent the opening of more than one door at a time 24Quality Rating S.No Reference 2 1 0 X 11 7B.u2i2ldingS acnhd- Mpremises:A -re the critical and support areas provided with Critical and support areas were found Critical and support areas was intercom telephones or speak phones for provided with intercom telephones or found not provided with intercom communication purposes. NA speak phones for communication telephones or speak phones for NA purposes. communication purposes. 17.23 Sch-M Specify the critical areas and support areas Critical areas and support areas were Critical areas and support areas provided with suitable air- locks or pass boxes found provided with suitable air- locks were found not provided with with proper interlocking arrangements for material or pass boxes with proper interlocking suitable air- locks or pass boxes transfer. NA arrangements for material transfer. with proper interlocking NA arrangements for material transfer. 17.24 WHO TRS- Specify whether dynamic pass box is used for Dynamic pass box was found 961 material transfer between two different air class. used for material transfer between NA NA NA ANNEXE-06 two different air class 17.25 Sch-M Specify the method of transfer of sterile rubber Specific SOP was found in place and No specific SOP was found in bungs & aluminium caps to the aseptic area. followed for transfer of sterile rubber place and followed for transfer of NA bungs & aluminium caps to the aseptic sterile rubber bungs & aluminium NA area. caps to the aseptic area. 17.26 Sch-M Specify whether grade A/B area is devoid of sinks Grade A/B area was found devoid of Sinks and drains was found NA NA and drains. sinks and drains provided in grade A/B area. 18 Air Handling System (Central Air Conditioning):- 18.1 Sch-M Specify whether the Air Handling Units for sterile Air Handling Units for sterile product Air Handling Units for sterile product manufacturing area are separated from manufacturing area was found product manufacturing area was NA NA those for other areas separated from those for other areas found not separated from those for other areas 18.2 Sch-M Give the Background Grade of air for following Background grade of air for following Background grade of air for critical areas: critical areas were found as given following critical areas were found 1) Aseptic filling area below: not complied with the 2) Sterilized components unloading area for 1) Aseptic filling area- Grade B requirements prescribed in aseptic filling. 2) Sterilized components unloading Schedule M. 3) Batch manufacturing area for aseptic filling area for aseptic filling-Grade B preparations. NA 3) Batch manufacturing area for NA 4) Component washing and preparation area. aseptic filling preparations-Grade B 5) Change rooms to enter into Critical area. 4) Component washing and preparation area-Grade C 5) Change rooms to enter into Critical area-Grade B 25Quality Rating S.No Reference 2 1 0 X 11 8B.u3ildingW anHdO p rTeRmSis-es:S -pecify the steps taken in air handling system to As per the qualification records 961 achieve the Grade A, B, C and D of air as per submitted it was observed that ANNEXE-06 designated classified areas. following steps were taken to achieve the Grade A, B, C and D of air as per designated classified areas: Grade-A - Vertical LAF NA NA NA Grade-B - 60 % ceiling is covered under HEPA and keeping ACPH more than 60 Grade C & D - Keeping appropriate ACPH 18.4 Sch-M Specify the recovery time of B & C zone from the Recovery time of B & C zone from Recovery time of B & C zone from the No records regarding recovery NA time of personnel leaving the room after the time of personnel leaving the time of personnel leaving the room time of B & C zone from the time completion of operations and verify the records in room after completion of after completion of operations was of personnel leaving the room after this regard. operations was found less than 20 found less than 30 minutes from the completion of operations could be minutes from the available records. available records. produced. 18.5 Sch-M Specify whether filling operations are challenged Filling operations were found Filling operations were found Media fill studies are not initially and there after periodically by simulation challenged initially and there after challenged initially but not there performed for aseptic trials including sterile media fill. NA periodically by simulation trials after periodically by simulation products in simulated including sterile media fill trials including sterile media fill conditions as per Rules. 18.6 WHO TRS- Specify the procedure followed for medial fill and Specific SOP was found prepared 961 the acceptance criteria. & followed as prescribed in WHO NA NA NA ANNEXE-06 TRS-961, Annex-06 18.7 WHO TRS- Whether the medial fill trial is based on worst case Medial fill trial was found based on 961 situation taking into consideration all interventions, worst case situation taking into ANNEXE-06 activities occurring during normal activity as well consideration all interventions, as worst case. activities occurring during normal NA NA NA activity as well as worst case. 18.8 WHO TRS- Whether simulation tests are repeated at defined Simulation tests was repeated at 961 intervals and after any significant modification to defined intervals and after any ANNEXE-06 HVAC system, equipment or process. significant modification to HVAC NA NA NA system, equipment or process. 18.9 Sch-M Specify the number of air changes in Grade A/B Number of air changes in Grade A/B No records could be produced in and Grade C areas. NA and Grade C areas was found NLT 20 this regard NA 18.10 Sch-M Specify the air velocity maintained in Grade A Air velocity was found maintained 100 No records could be produced in Laminar Air Flow stations NA + 10 feet per minute in Grade A this regard NA Laminar Air Flow stations 18.11 Sch-M Specify the differential pressure between areas of 15 pa was found maintained as No records could be produced in different environmental standards. NA differential pressure between areas of this regard NA different environmental standards 26Quality Rating S.No Reference 2 1 0 X 11 8B.u1i2ldingS acnhd- Mpremises:S -pecify type of manometer installed for Magneheilic Manometer was found Manometer installed for measurement and verification of Air Pressure installed for measurement and measurement and verification of NA NA Differential. verification of Air Pressure Differential. Air Pressure Differential was found faulty. 18.13 WHO TRS- Specify the air classification in final change room 961 to enter A/B area. Grade-B NA NA NA ANNEXE-06 19 Environmental Monitoring:- 19.1 Sch-M Specify the temperature and humidity maintained Temperature and humidity is Temperature and humidity is Temperature and humidity is not 1. Suitable arrangements in the critical areas. maintained through automated maintained and periodically monitored maintained consistently as per are not made for building management system or with suitably calibrated instruments specified limits. Temperature and maintaining temperature any other suitable system and is and recorded with predefined intervals humidity not always recorded and humidity in critical recorded continuously as as per SOP. periodically as evidence. areas. retrievable and printable data. 2. The viable counts are not performed as per rules. The microbial counts were found well above the limits however reported within limits. 3. The HEPA filter integrity test (smoke testing), particulate monitoring in air, air change rates tests are not performed as per Rules. 19.2 WHO TRS- Verify the area qualification records and specify Area Qualification performed with 961 whether the following were taken into predefined protocols taking into ANNEXE-06 consideration : account following parameters 1) 1) No. of Persons No. of Persons 2) ACPH (Air Changes per hours) 2) ACPH (Air Changes per hours) 3) Particle count (Static & Dynamic) 3) Particle count (Static & 4) Viable count (Static & Dynamic) Dynamic) 5) Temperature & Humidity 4) Viable count (Static & Dynamic) 6) Air Sampling location and interpretation of 5) Temperature & Humidity results (Both viable and non-viable) 6) Air Sampling location and NA NA NA 7) Whether the above method is in compliance interpretation of results (Both with ISO 14644-1 viable and non-viable) 8) Action and Alert limits for all the above 7) Whether the above method is in parameters compliance with ISO 14644-1 8) Action and Alert limits for all the above parameters 27Quality Rating S.No Reference 2 1 0 X 11 9B.u3ildingS acnhd- Mpremises:M -ention the periodic monitoring frequencies of the Periodic monitoring frequencies of the 1) Frequency of monitoring not 1.The monitoring not followings: following parameters were observed followed as required done as per the pre- 1) Particulate counts as detailed below: 2) Air change rate calculations not specified SOPs 2) HEPA filters integrity testing 1) Particulate counts-6 Monthly proper 2.The monitoring data is 3) Air Change rates 2) HEPA filters integrity testing-Yearly 3) No immediate actions taken on manipulated/falsified 4) Air pressure differentials 3) Air Change rates-6 Monthly adverse results 3.There is gross 5) Temperature and Humidity 4) Air pressure differentials-Daily 4) The monitoring results are not in deviation from the pre- 6) Microbiological monitoring by settle plates and/ 5) Temperature and Humidity-Daily desired limits. specified limits or swabs in Critical areas & Other areas 6) Microbiological monitoring by settle 4. The corrective actions NA plates and/ or swabs in Critical areas & are inadequate and Other areas-Daily deviations from the limits are not justified/explained. 5.The production activity is performed under non- compliant conditions 19.4 Sch-M Does a written Environmental Monitoring Program SOP for environmental monitoring Witten environmental monitoring exist? programme was found available for programme was available but not clean areas " In operation" adequate in compliance with NA NA Schedule M. 19.5 Sch-M How long the settle plates are exposed in Grade A Individual settle plates are exposed for Settle plates exposed for less time and other areas. not less than two hrs. in Grade B,C than specified. NA and D areas and not less than 30 mins NA in Grade A area. 19.6 Sch-M Verify the records of microbiological results also Trend analysis for microbiological SOP was found specified alert and Records proves that the alert and specify whether alert and actions limits are monitoring is performed with action limits and within the limits actions limits are not followed. NA followed or not. respect to predefined alert and specified in Sch.M. The limits are action limits/ monitored and followed. 19.7 Sch-M What action is taken in case particulate and SOP for corrective action is available Corrective and preventive actions microbiological monitoring counts exceed the in case particulate and microbiological not taken adequately for the limits? monitoring count exceeds the limits. incidences where particulate, For the incidences of exceeding limits microbial monitoring values NA NA appropriate corrective and preventive exceed the limits. action is taken so which may not impact product quality. 19.8 WHO TRS- Specify what parameters are reassessed and Specific SOP was found prepared 961 approved before starting production and in case of and followed in this regard. ANNEXE-06 major engineering modifications being carried out to the HVAC system of any area. NA NA NA 20 Garments: 28Quality Rating S.No Reference 2 1 0 X 12 0B.u1ildingS acnhd- Mpremises:S -pecify type of garments used in critical areas? Garments used are made of non- Garments are not made of non- shredding and tight wave material. The shredding and tight wave material. NA garments not are not shedding fibres The garments are shedding NA or particulate matter. fibres or particulate matter. 20.2 Sch-M Specify type of Zips used in garments Zips are made up from plastic material Zips are not made from plastic NA NA and not damaged. material and some garments in 20.3 Sch-M Whether garments used in critical areas are The garments sued in critical areas are uGsaer mhaesn tdsa imn uasgee da rzeip n.ot properly NA NA sterile. clean and sterilized. cleaned and sterilized 20.4 Sch-M Specify the process of sterilization of the garments Validated load pattern with Garments were found sterilized after Garments were found sterilized by & the practise followed to carry the sterilised pressure -vacuum cycle, Bowie dipping in 70% IPA solution followed moist autoclaving but no garments to the final change room. dick test is performed periodically. by air- drying & moist autoclaving. The precaution is taken to avoid further NA sterilized garments was found taken to contamination during carry over the final change room in sealed the same to final change room. condition. 20.5 Sch-M Are garments,masks,gloves are changed at every Garments,masks,gloves were found No such system was found work session? NA changed at every work session. followed. NA 20.6 Sch-M Are the gloves used made of latex or other Gloves used in clean rooms are made Gloves used in clean rooms are suitable plastic material NA of latex or plastic material. made not of latex or plastic NA material. 20.7 Sch-M Are powder free gloves used in clean rooms Powder free gloves used in clean powder free gloves are not used in NA NA rooms clean rooms 20.8 Sch-M Are the gloves long enough to cover the wrists The gloves are long enough to cover The gloves are not long enough to completely and allow the over-all cuff to be tucked NA the wrists completely and over-all cuff cover the wrists completely and NA in is tucked in. over-all cuff is tucked in. 20.9 Sch-M Are the foot-wear used made of plastic or rubber Foot-wear used are made from plastic Foot-wear used are not made from material NA or rubber material which is not plastic or rubber material and NA shredding and easy for cleaning does not permit easy cleaning. 20.10 Sch-M Are the foot-wear daily cleaned with a bactericide Foot-wears are cleaned and Foot-wears are cleaned and Foot-wears are not cleaned and 1. Sterile garments are sterilized before use. disinfected with suitable disinfectants. disinfected with suitable not used in aseptic area. disinfectants daily. 2. Unclean foot wears are used in critical areas. 20.11 Sch-M Are the safety goggles / numbered glasses worn Safety goggles with side extensions Safety goggles does not have inside the critical areas and have side extensions NA are used. side extensions. NA 20.12 Sch-M Are safety goggles sanitized by a suitable method Safety goggles are sanitized with Safety goggles are not sanitized NA suitable disinfectant . before use. NA 20.13 Sch-M Specify the garment changing procedure and SOP for garment changing is available. Procedure for garment changing SOPs NA not documented as followed NA practically. 20.14 Sch-M Specify whether operators are trained in garment Personnel are adequately trained for Personnel are not properly trained changing procedure. NA garment change procedure. for garment change procedure. NA 29Quality Rating S.No Reference 2 1 0 X 12 0B.u1i5ldingS acnhd- Mpremises:i f- full size mirror has been provided in the final The full size mirror is provided in the The full size mirror is provided in change room to ascertain that the operator has final change room. the final change room. Mirror is appropriately attired in the garments. NA provided but it is cracked. NA 20.16 WHO TRS- Specify how the garments used in clean areas are Specific SOP was found in place 961 cleaned and sterilized. for cleaning of Garments used in ANNEXE-06 clean areas. In in-house laundry NA NA NA facility and sterilization was found with validated cycle. 21 Sanitation: 21.1 Sch-M Specify the SOP followed for sanitisation of sterile Detailed SOP/SOPs is available with SOP for sanitizing procedure is not processing facilities and mention the SOP nos. the procedure for sanitization, adequate with respect to frequency of sanitization, concentration procedure for sanitization, of sanitizing agent, rotation policy of frequency of of sanitizing agent, NA sanitizing agent, preparation of rotation policy of sanitizing agent, NA sanitizing agent and maintenance of preparation of sanitizing agent and sanitization record. maintenance of sanitization record. 21.2 Sch-M Specify whether employees carrying out the The sanitization activity is performed Not all the personnel including sanitation of critical areas are specially trained for by trained personnel( including contractual staff is trained to carry this purpose. NA contractual staff) .The periodic training out the sanitization activity. NA is imparted to personnel on change/modification of the 21.3 Sch-M Verify the training records. pPreorcioeddiuc rtera/sinainnigtiz riencgo ardgse natr ee tc. Training records not maintained for maintained including the assessment the all concern staff including and further retraining if required. contractual staff. Training not Instructions for cleaning and imparted on the procedure change NA NA sanitization available in a language or disinfectant change or that is understood by the user and introduction of new equipment for concern staff trained in same sanitization. language. 21.4 Sch-M Specify the sanitizing agent/s used. Sanitization agents used in Sanitation agent not used in accordance with SOP and is used in rotation as defined in SOP. The rotation and concentration of it same concentration of sanitizing agent as recommended by manufacturer of not complying as recommended by NA sanitizing agent and the dilution is manufacturer and the dilution is NA validated with its efficacy test. Records not validated with its efficacy test of rotational of use of sanitization is maintained. 21.5 Sch-M Specify the quality of water used for preparation of Distilled water freshly collected from Disinfectants are diluted with sanitising solution. NA distilled water plant or water distilled water which is not NA maintained above 70 degree collected freshly or with water that 21.6 Sch-M Specify the disinfectant used for hand sprays? c7e0n %tig Irsaod ep rforopmyl athlceo rheocli rocru alalctioohno llo wopa s iIss on optr ompayiln atalcionheodl aobr oavlceo 7h0o ld ies gnroete NA found used for hand disinfectant used for hand spray ( disinfection) NA 30Quality Rating S.No Reference 2 1 0 X 12 1B.u7ildingS acnhd- Mpremises:S -pecify whether disinfectant solutions are filtered Disinfectants and detergents are Disinfectant solutions are sterilized by Sterilized disinfectants are not through membrane into suitable sterile containers monitored for microbial membrane filtration or any other stored in sterile containers. The or sterilized before use? contamination; dilutions are in suitable method( if available) and is sterilization procedure is not previously cleaned containers and stored in the sterile containers. properly followed ( i.e. selection of are only be stored for defined suitable sterilization grade filter or NA periods unless sterilized. any other ineffective sterilization Disinfectants and detergents used procedure is adopted). The in Grade A and B areas are sterilization records not effectively sterilized before use. maintained etc. 21.8 Sch-M Specify whether the diluted disinfectants bear ‘use Use before period for the diluted Containers of the diluted before’ labels based on microbiological disinfectant is established based on disinfectants does not bear 'USE establishment of their germicidal properties & the efficacy test of diluted disinfectant BEFORE" Label based on the verify the records (i.e. Disinfectant validation by microbial microbial efficacy test (validation). NA challenge). Based on the validation Use before date is not established NA used before date is mentioned in the for the concentration actually used. documents and label of the containers. Use before date for all disinfectants is not established. 21.9 Sch-M Specify whether fumigation is carried out in critical Fumigation( with Formaldehyde or SOP for fumigation not followed. areas. If yes, specify fumigating agent and its other equally effective fumigant) is Fumigation is routinely done in conc. used. NA performed in case of major civil place of routine sanitization NA modification or as per conditions procedure. Fumigant used not mentioned in SOP. mentioned SOP. 21.10 Sch-M Specify whether any SOP exists for the purpose of Detailed SOP for fumigation is SOP of fumigation is deficient with fumigation if so mention the SOP nos. available with procedure of fumigation respect to procedure of fumigation & defumigation, concentration/quantity & defumigation, of fumigant viz viz area of the clean concentration/quantity of fumigant NA room, precautions to be taken during viz area of the clean room, NA fumigation etc. precautions to be taken during fumigation etc. 21.11 Sch-M Specify the cleaning procedure of critical areas. Detailed SOP with procedure of No SOP was found followed in this cleaning of critical area, dilution and regard. quantity of diinfectant, type of NA disinfectants & rotation schedule is NA available and record of that is maintained. 21.12 WHO TRS- Specify whether particle monitoring in Grade A Continuous particle monitoring 961 zones is undertaken for the full duration of critical system is installed in Grade A at ANNEXE-06 processing including equipment assembly. appropriate location as per risk based assessment NA NA NA 21.13 WHO TRS- Specify whether particle monitoring in Grade B Continuous particle monitoring 961 zones is undertaken for the full duration of critical system is installed in Grade B at ANNEXE-06 processing. appropriate location as per risk NA NA NA based assessment 31Quality Rating S.No Reference 2 1 0 X 12 1B.u1i4ldingS acnhd- Mpremises:W -hether more than one sanitizing agent is used in Sanitizing agent/class of agent used Sanitization agents not used in rotation. If yes list the sanitizing agents their on rotational basis. rotation and same agent/or class concentration and frequency. of agent used. NA NA 22 Equipment: 22.1 Sch-M Specify whether the unit- sterilizers are double Double door sterilizer are installed with Sterilizers do not have door ended with suitable inter-locking between the effective interlocking system between interlocking system. Unloading doors. both the doors. Unloading side is in the side is not opening in clean room. NA clean room where the sterilized NA material will be used or conveyed to other clean rooms for use. 22.2 Sch-M Specify the initial effectiveness of sterilization Suitable microbial spores are used to 1) Suitable microbial indicator as 1) Effectiveness of process established by using microbial spore establish effectiveness of sterilization per the type of sterilization sterilization process not indicators. process, ( as mentioned in IP) e.g. procedure not used for established by using 1) For Moist heat-Bacillus Stereo establishment of effectiveness of microbial spore thermophillus sterilization process. indicators. 2) For Dry heat sterilization: Bacillus 2) The population of spores are 2) The spore indicators Substilis var-niger not adequate. used have inadequate 3) For Eto-Basillus Substilis var-niger. 3) The appropriate no of microbial population or no spore spore indicators are not distributed population. 6 log reduction observed after throughout the load. 3) Post sterilization NA sterilization procedure. The appropriate 4) After sterilization cycle the testing of the spore strips no of microbial spore indicator units spores indicators are not tested is not performed to are distributed through out the adequately to establish 6log establish 10 log sterilizer. reduction. reduction. 5) Before use The microbial spore indicators are not stored as per manufacturer's recommendations. 22.3 Sch-M Specify whether thermal Mapping of heat Thermal mapping of the sterilizers are 1) Thermal mapping of the sterilizers is carried out on regular basis. Check performed at least once a year by sterilizers are not performed at records. adequate number of calibrated least once a year. independent probes for all type loads. 2) No. of external probes used are The sterilization parameters like not adequate temperature, duration, pressure( where 3) The external probes used for NA ever applicable) are established during validation are not calibrated NA thermal mapping are followed during 4) The sterilization cycle is not routine sterilization( as per established controlled by coolest spot prob. SOP). The sterilization cycle is 5) The established parameters controlled by temperature probe which during validation are not used in is place at coolest spot which routine sterilization process. established during thermal mapping. 32Quality Rating S.No Reference 2 1 0 X 12 2B.u4ildingS acnhd- Mpremises:S -pecify if suitable vent filters and recording Autoclave is installed with Suitable sterilizing grade hydrophobic 1) Vent filters are installed are not thermographs are provided for autoclaves & dry continuous temperature recording vent filters are installed on autoclave suitable to sterilize air. heat sterilizers. data logger and the data is on the unloading i.e. Clean roll side. 2) Vent filters not installed at retrievable and non editable. Each cycle temperature is recorded unloading site. with continuously through thermograph 3) The vent filters not periodically or printout. changed. 4) The vent filter periodic integrity NA test not performed. 5) Continuous temperature recording system or thermograph not installed 6) The thermographs are not legible 7) Thermograph not recording temperature of control 22.5 Sch-M Specify whether cool air is passed through HEPA DHS/Tunnel is installed with 1) Suitable HEPA filters are installed p1r)o HbE.PA filters not installed filter and recording thermographs provided in continuous temperature recording for cooling air and tested for integrity appropriately DHS/Tunnel. data logger and the data is periodically. 2) Periodic integrity test of HEPA retrievable and non editable. 2) Each cycle temperature is recorded filter not performed with continuously through thermograph 3) The thermograph is not NA or printout. recording temperature properly( Not legible) 4) Thermograph not recording temperature of control prob. 22.6 WHO TRS- Specify whether provisions of CIP or SIP are Provision for Cleaning in place or 961 available. sterilization in place is available for ANNEXE-06 the non moving equipment, tanks etc.( cleaning and sterilization NA NA NA procedure adopted is validated) 22.7 Sch-M Specify whether pure steam is in use. Clean steam or pure steam is used to Pure steam is not used to sterilize sterilize the product contact the product contact parts/accessories. They steam used is parts/accessories. NA NA sterile and pyrogen free. It does not contains additives. 22.8 Sch-M Specify if filter integrity test is carried out before Integrity test of Membrane filters ( 0.22 1) Integrity test either before or and after the sterile filtration process. micron or 0.45 micron) is carried out after use not carried out. before use and after use by suitable 2) Parameters of integrity testing method like bubble point, diffusive flow not same as recommended by NA or pressure hold test with the values Manufacturer. NA recommended by filter manufacture. 3) The records of integrity test not preserved 4) Procedure followed for integrity test not in line with SOP. 33Quality Rating S.No Reference 2 1 0 X 12 2B.u9ildingS acnhd- Mpremises:S -pecify the material of construction of the The construction material used for the The MOC of the parts which are in equipment & type of glass containers parts which are in direct contact with product contact is SS but not products and the manufacturing vessel SS316. The glass containers are NA are of SS 316 which washable and not made from Borosilicate glass. NA sterilizable. Glass containers is of Borosilicate. 22.10 Sch-M Specify the tubing used in critical areas Tubing used are of capable of being Tubing used is washable but not washed and sterilized. Made up of sterilizable. NA NA inert material. 22.11 Sch-M Specify the qualifications of critical equipment. Equipments are qualified with Critical equipments are identified. Qualifications are not adequately predefined protocols. Installation qualification been done of performed. all the equipments by the engineers (with the support of production and quality assurance personnel). NA Equipments performance qualification is performed by validation. 22.12 WHO TRS- Verify the qualification, protocol and reports for the Details qualification protocol with 961 critical equipment. reports available NA NA NA ANNEXE-06 22.13 Sch-M Specify SOPs available for each equipment for its Each equipment is operated as per SOP for equipment operation and operation and cleaning. standard operating procedure made in cleaning not adequate. The actual NA accordance with equipment manual. operations carried out does not NA The Cleaning of equipment is reflect in SOP. performed as per the SOP. 22.14 Sch-M Specify whether the measuring devices attached Measuring devices attached to Calibration schedule not followed, to equipment calibrated at suitable intervals. equipments are calibrated at intervals not strictly adhered predefined intervals. NA NA 22.15 Sch-M Specify whether a written calibration program is Calibration schedule is in place with 1) Instruments are calibrated but available frequency of calibration. The schedule written calibration programme not is followed and calibration tag available available. . on the equipment/instrument 2) The calibration tags are not in NA NA displaying calibration status of it. legible condition. 3) Calibration not performed adequately. 34Quality Rating S.No Reference 2 1 0 X 12 2B.u1i6ldingS acnhd- Mpremises:S -pecify whether calibration status documented Each instrument has calibration status As per documents instrument is 1) Calibration data for the and displayed on the equipment and the gauges tag. Calibration documents are calibrated but no calibration tag on instruments/ equipment matching with the calibration label on the instrument. The calibration is falsified. the instrument. SOP is deviated NA 2) The calibration status label and calibration document are not matching 23 Manufacturing Process 23.1 Sch-M Specify whether the bulk raw materials and bulk Bio burden of bulk raw material is No SOP was found prepared and solutions monitored for bio-burden periodically periodically monitored with predefined followed in this regard. (solutions not to contain more than 100 cfu/ml). frequency. Bio-burden of bulk solutions NA before filtration is monitored NA periodically (limit : 100 cfu/ml) 23.2 Sch-M Specify the minimum possible time between the Maximum time from preparation of The sterilization by filtration of preparation of the solution and its sterilization or bulk batch to filtration through bulk through the microorganism filtration through microorganism retaining filters microorganism retaining filter is retaining membrane filter is NA NA followed. defined. The allowed time gap is performed beyond the predefined based on the master manufacturing time. formula. 23.3 Sch-M Specify the porosity of the filters when any The external gases which are coming 1) The external gases not filtered external gases are coming into contact with the in contact with the sterile product are through two 0.22 micron filters in sterile product. NA filtered through two 0.22 micron series. NA hydrophobic filters connected in series. 2) Integrity test of gas filters not This filters are tested for integrity. performed. 23.4 Sch-M Specify whether gas cylinders are kept out side of Gas cylinders are kept out side of the Gas cylinders are not kept out the critical areas. NA critical areas and gases are carried at side of the critical areas and gases NA the point of use by suitable pipes. are not carried at the point of use by suitable pipes. 23.5 Sch-M Specify the procedure of sterilization of washed The washed containers are sterilized The procedure adopted for containers. with suitably validated procedure sterilization is not adequately (documented in operation SOP) and validated, all load pattern are not NA NA validated load patterns are followed in defined. Established parameters routine. during validation are violated. 23.6 Sch-M Specify whether the sterilized containers not used Hold time before use of sterilised 1) The sterilized containers used within an established time, rinsed with WFI and re- containers are defined based on the beyond the established hold time. sterilized. validation. If within specified time the 2) The containers/load does not sterilised containers are not used, they bear use before date after are again rinsed with WFI and re- sterilization. NA NA sterilized as per SOP. 3) The containers are re-sterilized after established hold time without rinsing with WFI. 4) The seal/packing of the containers is not intact up established hold time. 35Quality Rating S.No Reference 2 1 0 X 12 3B.u7ildingS acnhd- Mpremises:I s- each lot of the finished product filled in one Finished product is filled in in one Finished product is not filled in continuation operation? continuous operation. In case where continuous operation. The lots not one batch is filled using more than segregated. The sterility test NA operation , each lot is tested performed as whole batch. NA separately for sterility and held separately till sterility test results are known. 23.8 Sch-M Specify whether all critical process is validated. The critical process parameters are 1) Critical process validated but all Verify the records. identified, the testing procedure to the critical parameters are not establish the quality by maintaining validated or Verified. NA critical parameters is defined and 2) The established critical NA Process validation is performed with parameters are not followed during predefined protocol. routine process. 23.9 WHO TRS- Verify the process validation protocol and reports Process validation protocol and 961 for the critical operation. reports for some critical operations ANNEXE-06 was verified during inspection and found comply with the norms NA NA NA specified in WHO TRS. 23.10 WHO TRS- Specify whether critical operations are carried out All critical operations were found 961 in closed system. carried out in closed system. NA NA NA ANNEXE-06 24. Aseptic processing and sterilization by filtration: 24.1 Sch-M Specify whether the filling area is of Grade A Ascetic Filling and preparation is done 1) Critical individual activities environment with Grade B background. in Grade A with grade B background . during filling process e.g. rubber Grade of area is established by area closer addition in to hopper, validation taking into account viable conveying sterilized and non viable particle count, ACPH, vials/accessories to filling station NA Air velocity and differential pressures. etc. are not carried out in Grade A. NA 2) The grade of area is not appropriately established by validation and certified area layout with classification not available. 24.2 Sch-M Specify the room classification of solutions Preparation of solution which are to be The grade of area is not preparation area which is sterilized by filtration. sterilized by filtration was found carried appropriately established by out in Grade C environment, and for validation and certified area layout NA aseptic filling the operation was found with classification not available. NA carried out in Grade A environment with Grade B background. 24.3 Sch-M Specify the filter used for sterilization of solution by Solution was found sterilized by Solution filtered through fibre filtration. filtration through a non-fibre releasing, releasing filter and pore size of sterilizing grade cartridge/membrane filter is not defined or no evidence NA filter of nominal pore size of 0.22 for pore size available. NA micron for aseptic filling whereas 0.45 micron porosity is used for terminally sterilized products. 36Quality Rating S.No Reference 2 1 0 X 12 4B.u4ildingW anHdO p rTeRmSis-es:S -pecify the maximum possible time used for It was observed that the maximum 961 filtration process. possible time used for filtration was ANNEXE-06 established through validation. NA NA NA 24.5 Sch-M Specify whether integrity of the sterilizing filters is Integrity test of sterilizing filters is 1) Integrity test either before or verified before and after use. If so, by which carried out before use and after use after use not carried out. method. by suitable method like bubble point, 2) Parameters of integrity testing diffusive flow or pressure hold test with not same as recommended by the values recommended by filter Manufacturer. NA NA manufacture. 3) The records of integrity test not preserved 4) Procedure followed for integrity test not in line with SOP. 24.6 WHO TRS- Specify whether the personal working in the It was observed that the personal 961 aseptic area are qualified for clean room working in the aseptic area are ANNEXE-06 procedure or not. If so verify the training records. qualified for clean room procedure through appropriate training and NA NA NA the training record was found maintained. 25 Product Containers & Closures:- 25.1 Sch-M Specify whether the containers and closures used Container/closure was found suitable Containers and closures use do Recycled /second hand comply with pharmacopoeia or other specific for the product filled (specific not comply with pharmacopoeia containers and closures NA requirements. requirements) and in accordance with requirements are used for primary pharmacopoeia packaging. 25.2 Sch-M Specify whether Specifications, Test methods, Specifications , test methods are 1) Specification are not available Cleaning procedures, Sterilizing procedures etc. available in compliance with for containers and closures. are available of the containers/ closures and other pharmacopoeia. Validated cleaning 2) All lots of container and closures component parts of drug packages. and sterilization procedure area are not tested before use for available for containers and closures. production 3) Cleaning/sterilization of NA containers are not appropriately NA performed. 4) Containers and closured which are out of specification used for production. 5) Second hand containers and closures are used. 25.3 Sch-M Specify whether the container & closures are The containers and closures are The container & closures are not compatible with the product without affecting its compatible with the product without compatible with the product and quality and purity. Verify the records. affecting quality and purity which is affecting its quality and purity. NA established through validation and e.g.absorbtion of preservative by NA product stability testing. the closures. 25.4 Sch-M Specify whether containers and the closures are WFI is used for final washing/rinsing of The containers and closures not finally washed with WFI before sterilization. the containers and closures before washed with WFI NA NA sterilization. 37Quality Rating S.No Reference 2 1 0 X 12 5B.u5ildingS acnhd- Mpremises:S -pecify whether a written procedure exist for SOP is available for washing of glass No SOP for washing. The quality washing of glass ampoules/vials. vials and ampoules. Parameters of of water used is not as per SOP NA washing are established through vial e.g. PW used in place of WFI NA washing procedure validation. 25.6 Sch-M Specify whether the material quality of the Biological and physico chemical testing Material used for stoppers /closure stoppers and closures ensures that it does not is performed on the closures before is not as per pharmacopeia. The affect the quality of the product and avoids the risk use. The effect on quality is material is not inert. of toxicity. NA established through validation and NA stability testing. 26 Sterilization 26.1 Sch-M Whether the sterilizing processes have been Sterilization process validated by Validation not performed. validated (Dry heat, Moist heat, filtration, ETO, thermal mapping, biological indicators, ionizations whichever applicable. endotoxin challenge(as applicable) and NA parameters for sterilization are NA established for day to day operations. 26.2 Sch-M Whether the validity of the process verified at It was observed that sterilization Validation not performed. regular intervals (at least annually) process is validated as per predefined NA protocol at least once a year. NA 26.3 Sch-M Whether the terminal sterilizer’s capacity is It was observed that the terminal The maximum capacity of the sufficient to sterilize one batch completely at one sterilizer’s capacity is sufficient to sterilizer is not defined based on time. If not specify controls and measures taken sterilize one batch completely at one loading pattern and type of in lot sterilizations. time. If sterilization is performed in packaging. Each sterilized lot was different lot,tracebility was found well found not tested for sterility . NA NA maintained by documentation and Sterility testing was found each lot was found tested separately performed on combined lots only for all parameters including sterility and and not on the individual lots the lots kept separately. sterilized. 26.4 Sch-M Whether biological indicators used in monitoring of Suitable biological indicators was Biological indicators not used for sterilization. NA found used for monitoring of the the monitoring of sterilization cycle. NA sterilization cycle. 26.5 WHO TRS- Verify that the probe is placed at the coolest point The probes were found placed at 961 on the basis of validation studies the coolest point on the basis of NA NA NA ANNEXE-06 validation studies. 26.6 WHO TRS- Verify the qualification, protocol and reports for the Protocols for qualification of 961 sterilisers sterilizers was found well defined NA NA NA ANNEXE-06 and reports available 38Quality Rating S.No Reference 2 1 0 X 12 6B.u7ildingS acnhd- Mpremises:W -hether the biological indicators stored and used The BI's are stored as per Biological indicators not stored as as per manufacturers instructions. Whether manufacturer's instruction. The quality per manufacturers quality of BI’s checked by positive controls. of BI's ascertained by positive control recommendations. The media during microbial analysis. used for verification BI with NA positive control is not same as NA recommended by manufacturer. 26.8 Sch-M Whether a clear means of differentiating ‘sterilized’ The sterilized and unsterilized products Sterilized and unsterilized product from ‘unsterilized‘ products is in place. Specify. were found stored in well segregated stored haphazardly without proper area where possibility of accidental mix-segregation . Status labels are ups is complete avoided. The status is ambiguous . There are chances of properly indicated on label. There is mix-up due to the practices NA uniflow of material movement from followed. NA unsterilized product storage area to sterilized product storage area after process of sterilization only. 26.9 Sch-M Whether the label on the basket / tray or other The carrier/basket /tray has clear-cut The carrier/basket /tray do not carrier of product / component clearly states: identification with name of material, have status label indicating • Name of the material Batch no.,sterilization states. sterilization status, name of • Its batch number Appropriate sterilization indicator is material, Its batch/lot number. • Its sterilization status NA used for each load and it is preserved Indicator not placed during NA Indicator (in case it has passed through as evidence of sterilization. sterilization. Indicator not sterilization process) preserved. 26.10 Sch-M Whether sterilization records including Thermographs and Sterilization Manual temperature recording thermographs and sterilization monitoring slips indicators are preserve and are part of available but thermographs are not attached with the Batch Production Record Batch processing record. These preserved. Sterilization monitoring records are reviewed for batch release. slips not attached with Batch NA records and not preserved. The NA thermographs and sterilization monitoring slips not reviewed for batch release. (No signatures) 27 Sterilization (By Dry Heat) 27.1 Sch-M Whether the sterilization cycle recording device of DHS./ Tunnel was found provided with DHS./ Tunnel was found not suitable size and precision provided in DHS./ recording device of suitable size and provided with recording device of NA NA Tunnel precision for sterilization cycle suitable size and precision for recording. sterilization cycle recording. 39Quality Rating S.No Reference 2 1 0 X 12 7B.u2ildingS acnhd- Mpremises:W -hether the position of temperature probes used The temperature probe( RTD or The control probe was found not for controlling and / or recording determined thermocouple) was found placed at at exactly same position of coolest during validation and (where applicable) been coolest spot determined during point. The temperature recording checked against a second independent validation by independent calibrated was found not continuous. The temperature probe located in the same position prob. The temperature of same probe validation was found not NA NA was found recorded and the recording performed by independent probe is continuous through the cycle/ at the same position/suitable position that of control probe 27.3 Sch-M Whether the chart forms a part of the batch Temperature Chart/ Thermograph was Temperature Chart/ Thermograph record. NA found part of batch record. was found not part of batch record. NA Thermograph not preserved. 27.4 Sch-M Whether sterilization cycle validated only by Sterilization cycle validated physically Physical verification by thermal The sterilizers are not biological indicator and chemical indicators or by thermal mapping along with mapping for heat distribution and studied for heat physical validation is also carried out biological and chemical indicators. heat penetration was found not distribution / penetration. During validation sterilization carried out. Effectiveness of parameters are established e.g. 1) For sterilization process not NA DHS Temperature, duration, positive established by using pressure microbial spore 2) For tunnel , indicators. temperature,duration,speed of conveyor etc. 27.5 Sch-M Whether the time allowed reaching the required Lag time was found determined for all The sterilization time is measured temperature before commencing the load types. The lag rimes was found without considered established lag measurement of sterilizing time, separately NA specified in SOP for routine time. NA determined for each type of load. sterilization 27.6 Sch-M Are adequate precautions taken to protect the Adequate precaution was found taken No adequate precaution was found load during cooling after it has gone through the to protect the load during cooling after taken to protect the load during high temperature phase of a heat sterilization it has gone through the high cooling after it has gone through NA NA cycle temperature phase of a heat the high temperature phase of a sterilization cycle. heat sterilization cycle. 27.7 Sch-M In case the cooling is affected with any fluid or gas Cooling air was found filtered through Cooling air was found not filtered in contact with the product , is it sterilized. HEPA filters through HEPA filters NA NA 27.8 Sch-M Whether the equipment air inlet and outlets been Inlet and outlet was found provided Inlet and outlet was found not provided with bacteria retaining filters NA with HEPA filters. provided with HEPA filters. NA 40Quality Rating S.No Reference 2 1 0 X 12 7B.u9ildingS acnhd- Mpremises:I n- the process of sterilization by dry heat, does the 1) Efficient blowers/fans was found 1) Air circulation is not effective equipment have: provided for air circulation in sterilizer. due to faulty or inefficient blower 1 Air circulation facility within the chambers 2) Positive pressure was found system 2) The positive pressure 2 Positive pressure to prevent entry of non-sterile maintained in the chamber which is not monitored through out the air NA monitored by magnahelic gauges with sterilization cycle. NA established differential pressure limits. 3) The limits for differential pressure not adequately established. 4) No records of positive pressure 27.10 WHO TRS- Verify the sterilizer loading pattern & whether is Validated load pattern with 961 complied with the validated loading pattern. pressure -vacuum cycle, was ANNEXE-06 found established. Bowie dick test NA NA NA was found performed periodically. 27.11 Sch-M Whether the process of dry heat sterilization Endotoxin challenge test was found Endotoxin challenge test was intended to remove the pyrogens performed to ensure three log found not performed to ensure If so, has the validation been done with challenge reduction. three log reduction. tests using endo-toxins NA NA 28.Sterilization (By Moist Heat) 28.1 Sch-M Whether recording of both temperature and Temperature and pressure was found Temperature and pressure was pressure carried out to monitor the process monitored as per specified SOP found not monitored as per NA NA specified SOP 28.2 Sch-M Whether the control instrumentation independent There are multiple probes inside No monitoring done in routine of the monitoring instrumentation and recording chamber. Probe at coolest point is sterilization except with controlling charts. NA controlling probe and other probes are prob. Recording throughout the NA monitoring prob. Recording is done chamber not performed for uniform with the controlling probe values sterilization in routine. 28.3 Sch-M Whether the equipment has automated control Equipment have automated control 1) Automated control and and monitoring system, if so, have these been system and monitoring . Which monitoring system is not properly validated to ensure that critical process ensures sterilization temperature, functioning and manual requirements are met. duration and pressure as per the interventions required. NA established parameters. Effective 2) Validation does not included NA alarm system is installed to notice the alarm testing discrepancies during sterilization process. The automated system is validation for performance. 28.4 Sch-M Whether the system and cycle faults are recorded System and cycle faults were found System and cycle faults are not inbuilt and also observed by the operator and recorded in-built. recorded. record maintained. System and cycle faults are noticed and alarmed to operator. NA The suitable alarm record system NA available. With critical faults the cycle is aborted or appropriate action is taken by system. 41Quality Rating S.No Reference 2 1 0 X 12 8B.u5ildingS acnhd- Mpremises:W -hether the readings of the thermograph during Operator was found recording the Operator was found not recorded sterilization cycling are routinely checked by the temperature in checklist or BMR during temperature / or missed the entries operator against the reading shown by the dial the sterilization cycle after defined time in checklist or BMR during the thermometer fitted with autoclave. NA interval. sterilization cycle. NA 28.6 Sch-M Whether the sterilizer fitted with a drain at the The sterilizer was found fitted with The drain temperature was found bottom of the chamber If so, does the record of drain and the drain temperature is not recorded through out the temperature at this position is recorded through NA recorded through the sterilizing period. sterilization cycle. NA out the sterilizing period 28.7 Sch-M Are frequent leak tests conducted on the chamber Leak test with prespecified limits as Leak test with prespecified limits of the autoclave on each day of operation. per SOP was found performed daily. as per SOP was found not NA performed daily. NA 28.8 Sch-M Whether all items to be sterilized (other than All items were found wrapped in Items to be sterilized are not sealed containers) are wrapped for sterilization. suitable steam penetrable wrappers. wrapped during sterilization. NA NA The wrapping paper does not withstand stem sterilization 28.9 Sch-M Whether the wrapping material allows removal of The items to be sterilized, other than Wrapping paper does not allow the air and penetration of steam ensuring contact with products in sealed containers, was penetration of steam adequately. the sterilizing agent at the required temperature found wrapped in a material that for required time allows the removal of air and the penetration of steam but prevents recontamination after sterilization. NA Specially designed autoclavable NA stainless steel containers, that allow steam to enter and air to leave are used. All parts of the load are in contact with saturated steam at the required temperature for the specified time. 28.10 Sch-M Whether the wrapping prevent contamination after It was observed that the wrapping It was observed that the wrapping sterilization NA prevent contamination after may not prevent contamination NA sterilization after sterilization 42Quality Rating S.No Reference 2 1 0 X 12 8B.u1i1ldingS acnhd- Mpremises:W -hether the steam used for sterilization is of The steam generating boilers and The quality of steam used for suitable quality and doesn’t contain additives at a distribution systems is validated and sterilization that comes in direct level which could cause contamination of the the monitoring is done by suitable contact with the product to be product or equipment laboratory analysis of the steam and sterilized was found not verified. feed water samples; There is periodic There is no testing performed to maintenance of the steam generating check the quality of steam. equipment and the distribution pipe- lines until point of use. Steam used for NA STERILIZATION is tested for NA (chemical, microbiological and endotoxin analysis of condensate and physical examination of steam (such as dryness, superheat, and non- condensable gases) and does not contain additives at a level that could cause contamination of the product or equipment. Steam used for sterilization is tested regularly. 29. Others 29.1 Sch-M Specify whether products released only after Products were found released only Products were found released complete filling and testing. NA after complete filling and testing. before complete filling and testing. NA 29.2 Sch-M Specify whether result of the tests relating to Result of the tests relating to sterility, Result of the tests relating to Batches failing initial sterility, bacterial endo-toxins are maintained in bacterial endo-toxins was found sterility, bacterial endo-toxins was sterility test are released the analytical records maintained in the analytical records not available but products were for sale on the basis of a NA found released second test without proper investigation. 29.3 WHO TRS- Whether process hold time studies has been Process hold time studies was 961 carried out for various stages of production found carried out for various NA NA NA ANNEXE-06 stages of production 30. Documentation and Records 30.1 Sch-M Whether all daily documents are filled correctly Daily documents was found filled Daily documents was found not and timely. NA correctly and timely. filled correctly and timely. NA 30.2 Sch-M How the documents are designed, prepared, Specific SOP was found prepared and No specific SOP was found reviewed and controlled to provide an audit trail. NA followed in this regard. prepared and followed in this NA regard. 30.3 Sch-M Whether documents are approved signed and Documents was found approved, Documents was found not dated by appropriate and authorized person. signed and dated by appropriate and approved, signed and dated by NA NA authorized person. appropriate and authorized person. 30.4 Sch-M Whether documents specify title, nature and NA Yes No NA purpose. 30.5 Sch-M Whether documents are regularly reviewed and Documents was found regularly Documents was found not kept up to date. reviewed and kept up to date as per regularly reviewed and kept up to NA NA the specified SOP. date as per the specified SOP. 43Quality Rating S.No Reference 2 1 0 X 13 0B.u6ildingS acnhd- Mpremises:W -hether the records are made at the time of each Records was found made at the time Records was found not made at operation in such a way that all significant of each operation in such a way that all the time of each operation. activities concerning to the production are NA significant activities concerning to the NA traceable. production are traceable. 30.7 Sch-M Whether data is recorded by electronic data Data was found properly recorded Data was found not properly processing system or by other means. If by through electronic system with proper recorded. electronic data processing system then how NA access control. NA access is controlled to enter, modify etc. the data. 30.8 Sch-M Whether master formula and detailed operating Master formula and detailed operating Master formula and detailed No written Master procedures for each product are available? NA procedures for each product was operating procedures for each Formula Records. available. product was not available. 30.9 Sch-M Specify the duration of retaining the documents 1 year after expiry of the product and No records could be produced in after the expiry of the respective product and who QA is responsible for its maintenance. this regard NA NA is responsible for its maintenance. Do the manufacturing records pertaining to manufacture of Sterile & Non- Sterile products indicate the following details: Serial number of Batch Manufacturing ,Record ,Name of the product, Reference to Master Formula Record, Batch/ Lot number, Batch/ Lot size, Date of commencement and completion of manufacture, Date of manufacture and assigned date of expiry, Date of each step in manufacturing, Names of all ingredients with reference number given by the quality control department ,Quantity of all ingredients, Time and duration of blending, mixing etc. where ever applicable, PH of solutions All relevant records as specified under whenever applicable, Filter integrity testing records, All relevant records as specified Sch.M was found maintained. Temperature and humidity records whenever applicable, NA under Sch.M was found not NA Some of the records verified during Records of plate-counts whenever applicable, Results of maintained. inspection and found satisfactory. bacterial endo-toxin and toxicity, Records of weight or volume of drug filled in containers, Bio burden records before sterilisation, Leak test records, Inspection records, Sterilization records including load details, date, duration, temperature, pressure etc. Container washing & testing records, Total number of containers filled, Total number of containers rejected at each stage, Theoretical yield, permissible yield, actual yield and variation there of, Clarification for variation in yield ,beyond permissible yield, Reference number of relevant analytical reports, Details of re-processing, if any, Names of all operators 31 Labels and Other Printed Materials:- 31.1 Sch-M Whether the printing is in bright colour and legible Printing on labels and other printing Printing on labels and other on labels and other printed materials? materials was found bright in colour printing materials was found not NA NA and legible bright in colour and legible 31.2 Sch-M How printed labels (art work) are approved. Verify Specified SOP was found in place in No specified SOP was found in the SOP. NA this regard. place in this regard. NA 44Quality Rating S.No Reference 2 1 0 X 13 1B.u3ildingW anHdO p rTeRmSis-es:S -pecify whether cut labels or rolled labels are Rolled labels were found used NA NA NA 986 used. 31.4 Sch-M Whether the labels comply with requirements of Labels were found comply with Labels were found not comply with Rule 96 & 97 & other relevant provisions requirements of Rule 96 & 97 & other requirements of Rule 96 & 97 & NA NA relevant provisions in all respects other relevant provisions in all respects 32 Master Formula Records: - 32.1 Sch-M How master formula records for each product are Master formula records for each Master formula records for each prepared, authorized and controlled. product was found prepared, product was found not prepared, NA authorized and controlled as authorized and controlled as NA prescribed in Sch.M prescribed in Sch.M 32.2 Sch-M Whether master formula is batch size specific. Master formula was found batch size Master formula was found not NA NA specific batch size specific 32.3 Sch-M Whether master formula record covers all the Master formula record was found Master formula record was found points as prescribed in Schedule ‘M’. covers all the points as prescribed in not covers all the points as No written Master NA Schedule ‘M’. prescribed in Schedule ‘M’. Formula Records. 32.4 WHO TRS- Whether master formula record covered all the Master formula record was found 986 points as prescribed in WHO-TRS 986 & PIC/S covered all the points as guidelines prescribed in WHO-TRS 986 & NA NA NA PIC/S guidelines 33 Batch Processing / Manufacturing Records:- 33.1 Sch-M Whether the BPR/BMR for each product is BPR/BMR for each product was found BPR/BMR for each product was prepared on the basis of currently approved prepared on the basis of currently found not prepared on the basis of NA NA master formula. approved master formula. currently approved master formula. 33.2 Sch-M Whether BPR / BMR covered all the points as BPR / BMR was found covered all the BPR / BMR was found not covered prescribed in Schedule ‘M’ NA points as prescribed in Schedule ‘M’ all the points as prescribed in NA Schedule ‘M’ 33.3 WHO TRS- Whether BPR / BMR covered all the points as BPR / BMR was found covered all 986 prescribed in WHO-TRS 986 & PIC/S the points as prescribed in WHO- NA NA NA TRS 986 & PIC/S 33.4 Sch-M Whether all the documents generated during All the documents generated during All the documents generated Batch production are attached with the BPR /BMR Batch production was found attached during Batch production was found NA NA with the BPR /BMR not attached with the BPR /BMR 34 Batch Packaging Records: - 34.1 Sch-M Whether authorized packaging instructions for Authorized packaging instructions for Authorized packaging instructions each product of various pack size and type are each product of various pack size and for each product of various pack maintained and complied with. NA type were found maintained and size and type were found not NA complied with. maintained and complied with. 45Quality Rating S.No Reference 2 1 0 X 13 4B.u2ildingS acnhd- Mpremises:S -pecify whether all material, equipment, rooms All material, equipment, rooms and All material, equipment, rooms and and packaging lines are labelled with an indication packaging lines were found labelled packaging lines were found not of product being processed with batch no. with an indication of product being labelled with an indication of NA processed with batch no. product being processed with NA batch no. 34.3 Sch-M Whether packaging lines are independent and Packaging lines were found Packaging lines were found not adequately segregated. independent and adequately independent and adequately NA NA segregated. segregated. 34.4 Sch-M How line clearance is performed. Whether records Specific SOP was found in place in this NO Specific SOP was found in of line clearance is maintained according to NA regard and records found maintained. place in this regard and records NA appropriate checklist. found not maintained. 34.5 Sch-M Do the packaging materials arrive on a covered Packaging materials was found arrive Packaging materials was found trolley? NA on a covered trolley not arrive on a covered trolley NA 34.6 Sch-M Are packaging materials verified against a master Packaging materials were found Packaging materials were found set to ensure that they are the most recent edition verified against a master set to ensure not verified against a master set and the correct materials for the batch? that they are the most recent edition to ensure that they are the most NA and the correct materials for the batch. recent edition and the correct NA materials for the batch. 34.7 Sch-M Are the quantities of packaging materials verified Quantities of packaging materials was Quantities of packaging materials against the amounts stated as dispensed from the found verified against the amounts was found not verified against the warehouse? stated as dispensed from the amounts stated as dispensed from NA warehouse the warehouse NA 34.8 WHO TRS- Specify the monitoring code (bar code, pinholes Monitoring code (bar code, 986 etc.) for final packing materials. pinholes etc.) for final packing materials was found followed as NA NA NA per prescribed SOP. 34.9 Sch-M Is the batch yield calculated immediately upon Batch yield was found calculated Batch yield was found not completion of packaging operation & prior to the immediately upon completion of calculated immediately upon introduction of a new batch into the area? packaging operation & prior to the completion of packaging operation NA introduction of a new batch into the & prior to the introduction of a new NA area batch into the area 34.10 Sch-M Is the yield calculation independently verified by Yield calculation was found Yield calculation was found not second individual and whether any significant independently verified by second independently verified by second deviation from accepted yield is recorded and individual and any significant deviation individual and any significant NA NA investigated? from accepted yield is recorded and deviation from accepted yield is investigated. not recorded and investigated. 34.11 Sch-M Is any excess printed packaging material Excess printed packaging material was No records could be produced in destroyed on completion of the batch? found destroyed on completion of the this regard NA NA batch 46Quality Rating S.No Reference 2 1 0 X 13 4B.u1i2ldingS acnhd- Mpremises:I s- there a provision in the department for the Specific SOP was found in place in this No specific SOP was found in separation of printed packaging material for regard. place in this regard. destruction & rejected product? NA NA 34.13 Sch-M Whether Batch packaging record covered all the Batch packaging record was found Batch packaging record was found points as prescribed in Schedule ‘M’ NA covered all the points as prescribed in not covered all the points as NA Schedule ‘M’ prescribed in Schedule ‘M’ 34.14 WHO TRS- Whether Batch packaging record covered all the Batch packaging record was found 986 points as prescribed in WHO-TRS 986 & PIC/S covered all the points as prescribed in WHO-TRS 986 & NA NA NA PIC/S 34.15 Sch-M Whether all the documents generated during All the documents generated during All the documents generated packaging are attached with the Batch packaging packaging was found attached with the during packaging was found not record. NA Batch packaging record. attached with the Batch packaging NA record. 34.16 Sch-M Whether BPR are based on current master BPR was found based on current BPR was found not based on formula record. NA master formula record. current master formula record. NA 35 Standard Operating Procedure and Records: - 35.1 Sch-M Verify the List of SOPs and mention total number All relevant SOPs were found in place. More SOPs are required to be NA NA of SOPs followed by the firm. prepared. 35.2 Sch-M Has all the SOPs been displayed. NA All SOPs found displayed. All SOPs found not displayed. NA 35.3 Sch-M The formats, logs & SOPs are current Formats, logs & SOPs were found Formats, logs & SOPs were found NA NA current and updated. not current and updated. 35.4 Sch-M Is any obsolete copy seen in the Area? No obsolete copy was seen in the Area Some obsolete copy was seen in NA NA the Area 36 Reprocessing and Recoveries:- 36.1 Sch-M Verify the SOP for reprocessing. Specific SOP was found in place for No specific SOP was found in NA NA reprocessing. place for reprocessing. 36.2 WHO TRS- Whether reprocessed batch is subjected to Reprocessed batch was found 986 stability evaluation. subjected to stability evaluation. NA NA NA 36.3 Sch-M Whether the recoveries are added into the Specific SOP was found in place to No specific SOP was found in subsequent batches. If yes specify the NA add recoveries into subsequent place to add recoveries into NA procedures. batches. subsequent batches. 37 Finished Product:- 37.1 Sch-M Specify whether finished products are held in Finished products were found held in Finished products were found not quarantine until their final release. quarantine until their final release. held in quarantine until their final NA NA release. 37.2 Sch-M Specify the storage arrangement of finished Adequate storage arrangement was Storage arrangement was found products after final release by QA found provided for finished products inadequate for finished products. NA NA after final release by QA. 38 Quality Control Area: - 47Quality Rating S.No Reference 2 1 0 X 13 8B.u1ildingS acnhd- Mpremises:S -pecify whether QC area is independent of QC area was found independent of QC area was found adjacent to production area. NA production area. production area. NA 38.2 Sch-M Specify the working space provided for QC: Adequate working space was found Working space provided for QC NA provided for QC. was found inadequate. NA 38.3 Sch-M Specify the procedure followed for Specific SOP was found in place in this No specific SOP was found in approval/rejection of raw materials, packaging regard and records found maintained. place in this regard. materials, intermediate products and finished NA NA products. Verify the SOP and record. 38.4 Sch-L1 Specify the arrangement provided to protect Temperature and humidity control Temperature and humidity control sensitive electronic balances from vibrations, room was found provided to protect room was found not provided to electrical interference, humidity etc. sensitive electronic balances from protect sensitive electronic NA vibrations, electrical interference, balances from vibrations, electrical NA humidity etc. interference, humidity etc. 38.5 Sch-L1 Specify the safety measures taken to avoid any Proper safety measures like Air No safety measures like Air accidental hazards in the QC department. showers etc. was found provided to showers etc. was found provided NA NA avoid any accidental hazards in the QC to avoid any accidental hazards in department. the QC department. 38.6 Sch-M Specify whether separate washing and drying Separate washing and drying area was No separate washing and drying area is provided for glassware NA found provided for glassware area was found provided for NA glassware 38.7 Sch-L1 Specify which grade of glassware is used in assay Certified and calibrated glassware was Certified and calibrated glassware procedures and whether they are found provided. was found not provided. certified/calibrated. Verify the certificates and NA NA calibration records. 38.8 Sch-M Specify whether any particular test is outsourced. Outsource laboratory was found Outsource laboratory was found If so mention the name of laboratory and verify the mentioned in the licence. not mentioned in the licence. contract made in this regard. NA NA 39 Microbiology Lab 39.1 Sch-M Whether separate AHU's are provided for Separate AHU's was found provided Separate AHU's was found not microbiological testing areas. for microbiological testing areas. provided for microbiological testing NA NA areas. 39.2 Sch-M Whether support areas are under same AHU Support areas were found under Support areas were found under which is used for sterile area. NA different AHU. same AHU which is used for sterile NA area. 39.3 Sch-M Briefly describe layout of the microbiology lab Layout of the microbiology lab was Layout of the microbiology lab was (attach copy of the layout if available) found satisfactory. found not satisfactory. NA NA 48Quality Rating S.No Reference 2 1 0 X 13 9B.u4ildingS acnhd- Mpremises:W -hether entry to the sterile area is through three Entry to the sterile area was found Entry to the sterile area was not air lock systems with separate exit through three air lock systems with found through three air lock NA NA separate exit systems with separate exit 39.5 WHO TRS- Specify whether access in sterile area is Access in sterile area was found 986 controlled, and if so the system followed in this controlled through access control NA NA NA regard (Biometric) system. 39.6 Sch-M Verify the list of equipment used in the Equipment used in the microbiological Equipment used in the microbiological lab and also specify whether these laboratory was found adequate and microbiological laboratory was are placed logically and function accurately comply with the requirements. found not adequate and comply NA with the requirements. NA 39.7 Sch-M Specify whether operators are trained in gowning Operators were found trained in Operators were found not trained procedures. Verify the training records. gowning procedures. Training records in gowning procedures. NA NA found maintained. 39.8 Sch-L1 Specify the gowning procedure to enter the sterile Specific SOP for gowning procedure to No specific SOP for gowning area. Verify the entry and exit records. enter the sterile area was found in procedure to enter the sterile area NA place and records found maintained. was found in place. NA 39.9 Sch-L1 Specify the air class of sterile areas and whether Pressure differential was found Pressure differential was found not pressure difference is maintained. Verify the maintained in the sterile areas. maintained in the sterile areas. records. NA NA 39.10 WHO TRS- Specify whether an environmental monitoring Environmental monitoring 986 programme is followed with alert and action limit. programme was found followed NA NA NA with alert and action limit. 39.11 Sch-M Specify whether a documented cleaning and Documented cleaning and disinfection No documented cleaning and disinfection programme is in place. programme was found in place. disinfection programme was found NA NA in place. 39.12 WHO TRS- Specify whether a procedure for dealing with Procedure for dealing with 986 spillages in sterile area is in place. spillages in sterile area was found NA NA NA in place. 39.13 WHO TRS- Whether separate areas provided for sterility Separate areas was found 986 testing, assay of antibiotics & vitamins and MLT in provided for sterility testing, assay sterile area. of antibiotics & vitamins and MLT NA NA NA in sterile area. 39.14 Sch-M Specify the type of workstations (LAF) provided in Vertical LAF was found provided. Vertical LAF was found not the sterile area. NA provided. NA 49Quality Rating S.No Reference 2 1 0 X 13 9B.u1i5ldingS acnhd- Mpremises:W -hether double door autoclave is provided for Double door autoclave was found Double door autoclave was found transferring of materials from unclassified area to provided for transferring of materials not provided for transferring of sterile area. NA from unclassified area to sterile area. materials from unclassified area to NA sterile area. 39.16 WHO TRS- Verify the area qualification document for sterile Qualification documents for sterile 986 area. area including IQ.OQ.& PQ was NA NA NA found in place. 39.17 WHO TRS- Verify the procedure for selection of sampling The procedure presently followed 986 location and interpretation of results for was found in compliance with ISO environmental monitoring of sterile area along with 14644-1 the SOP and documents. (Specify whether the NA NA NA method is in compliance with ISO 14644-1). 39.18 Sch-L1 Specify whether qualification of all equipment and Qualification of all equipment and Qualification of all equipment and instruments used in this department is covered instruments used in this department instruments used in this under VMP. NA was found covered under VMP. department was found not covered NA under VMP. 39.19 Sch-L1 Verify the qualification document of major Qualification document of major No document could be produced in equipment like autoclave/incubator, hot air oven, equipment like autoclave/incubator, this regard. refrigerator, LAF etc. NA hot air oven, refrigerator, LAF etc. NA were verified and found satisfactory. 39.20 Sch-L1 Specify the Calibration procedure of temperature Calibration procedure of temperature No such procedure was found measurement devices used in autoclave and measurement devices used in followed. incubator. Verify whether it is traceable to autoclave and incubator was found NA NA standard temperature. elaborately specified in a SOP and it is traceable to standard temperature. 39.21 Sch-M Verify the procedure for the handling and disposal Specific SOP was found in place for No SOP was found in this regard of chemical and microbial waste. the handling and disposal of chemical NA and microbial waste. NA 39.22 WHO TRS- Specify the procedure followed to verify the validity Judicial limits of error was found 986 of the test in case of antibiotic potency testing. calculated as per standard statistical analysis. NA NA NA 39.23 WHO TRS- Specify whether there is separate autoclave for Separate autoclave for 986 decontamination. decontamination was found NA NA NA provided. 39.24 WHO TRS- Specify whether the Vendors for dehydrated Vendors for dehydrated media was 986 media is approved and qualified. found approved and qualified. NA NA NA 50Quality Rating S.No Reference 2 1 0 X 13 9B.u2i5ldingW anHdO p rTeRmSis-es:S -pecify whether GPT is carried out for dehydrated GPT was found carried out for 986 / IP media. dehydrated media NA NA NA 39.26 Sch-L1 Specify whether performance of culture media Performance of culture media Performance of culture media (recovery or survival maintenance) is carried out (recovery or survival maintenance) (recovery or survival maintenance) and the results meet acceptance criteria. NA was found carried out and the results was found not carried out. NA meet acceptance criteria. 39.27 Sch-L1 Specify the source of procurement of reference Reference culture was found procured No procurement records could be culture and its maintenance. from Microbial Institute of Technology, produced. NA Chandigarh (MIT) NA 39.28 Sch-L1 Specify the Air Grades for following areas: Sterility testing room-Grade A No documents could be produces —Sterility testing room Microbiological Assay room-Grade A regarding air grades in the —Microbiological Assay room MLT room-Grade A following classified area : —MLT room Airlocks (entry and exit both)-Grade —Sterility testing room —Airlocks (entry and exit both) NA B,C & D —Microbiological Assay room NA —MLT room —Airlocks (entry and exit both) 39.29 Sch-M Verify the following records: Following records were checked and Records regarding the following —Log book for the entry/exit in the sterile area found satisfactory and updated. were found not updated —media preparation record —Log book for the entry/exit in the —Log book for the entry/exit in the —records for water testing (micro) sterile area sterile area —records for MLT NA —media preparation record —media preparation record NA —records for water testing (micro) —records for water testing (micro) —records for MLT —records for MLT 39.30 IP Verify how the concentration of the inoculums is Concentration of the inoculums was Concentration of the inoculums determined. found determined as prescribed in IP. was found not determined as NA NA prescribed in IP. 39.31 Sch-M Whether firm has provided microbiology lab for The firm was found carry out MLT in Neither any microbiology MLT test for nonsterile dosage form. If no how this their on testing lab for which laboratory has been set up nor the test is complied. NA Microbiology lab has been set up. test for MLT is outsourced NA 40 Quality Control System: - 40.1 Sch-L1 Specify the source of procurement of various IPC, Ghaziabad Could not produce any document reference standards NA BP in this regards. NA USP 40.2 Sch-L1 How the reference standards are stored, Specific SOP was found in place in this No specific SOP was found in evaluated and maintained. NA regard. place in this regard. NA 40.3 WHO TRS- Specify whether authorized access system is Authorized access system was 986 followed for reference standards. found followed for reference NA NA NA standards. 51Quality Rating S.No Reference 2 1 0 X 14 0B.u4ildingS acnhd- Lpr1emises:V -erify the SOP and records for preparation of Specific SOP was found in place in this No specific SOP was found in working standard from the reference standard. regard. place in this regard. NA NA 40.5 Sch-L1 Verify the SOP and records for destruction of Specific SOP was found in place in this No specific SOP was found in unused working standard NA regard. place in this regard. NA 40.6 Sch-M Verify the sampling SOPs and records for: All the relevant SOPs and related No specific SOP was found in —starting materials records were found in place. place in this regard. —primary packaging materials —secondary packaging materials —in process materials —finished products NA NA —water analysis —wash water analysis —swab analysis —wash water analysis of cleaned garments 40.7 Sch-M Specify whether approved specifications are All the relevant approved specification Approved specification and related available for all: and related records were found in records were found in place. —starting materials place. —primary packaging materials —secondary packaging materials —in process materials NA NA —finished products —water analysis —wash water analysis —swab analysis —wash water analysis of cleaned garments 40.8 Sch-L1 Verify whether all approved specifications are All approved specifications were found All approved specifications were NA NA based on validation. based on validation. found not based on validation. 40.9 WHO TRS- Is there any SOP for handling of OOS product (out SOP for handling of OOS product 986 of specification)? (out of specification) was found in place. NA NA NA 40.10 WHO TRS- Specify the procedure for review of test data & Specific SOP was found in place 986 calculations. for review of test data & NA NA NA calculations. 40.11 Sch-L1 Specify whether a designated person is Designated person was found No designated person was found responsible for receipt of samples for testing. responsible for receipt of samples for responsible for receipt of samples NA NA testing. for testing. 40.12 Sch-L1 Specify the procedure followed for receiving and Specific SOP was found in place in this No specific SOP was found in recording (logging in). Verify the SOP and records NA regard. place in this regard. NA 52Quality Rating S.No Reference 2 1 0 X 14 0B.u1i3ldingS acnhd- Lpr1emises:S -pecify the procedure for storage and distribution Specific SOP was found in place for No specific SOP was found in of received samples to different analyst. NA storage and distribution of received place in this regard. NA samples to different analyst. 40.14 Sch-L1 Is there a maximum time limit for retention of Maximum time limit for retention of No specific SOP was found in sample in the laboratory prior to testing? sample in the laboratory prior to testing place in this regard. NA was found mentioned in the relevant NA SOP. 40.15 Sch-L1 Specify the procedure followed for preparation, Specific SOP was found in place for No specific SOP was found in consumption & destruction of volumetric solution. preparation, consumption & place in this regard. Verify the SOP and records. NA destruction of volumetric solution. NA Verify the SOP and records. 40.16 Sch-L1 Specify whether there is a log book for the Log book for the preparations of the No log book was found in place. preparations of the reagent including name of the reagent including name of the analyst, analyst, name of the reagent, Calculations, Date name of the reagent, Calculations, of preparation & expiration. NA Date of preparation & expiration log NA books was found in place. 40.17 Sch-L1 Specify the procedure followed for using GR, LR Specific SOP was found in place for No specific SOP was found in and AR grade of chemicals / solvents used for using GR, LR and AR grade of place in this regard. calibration & sample testing. NA chemicals / solvents used for NA calibration & sample testing. 40.18 Sch-L1 Specify whether respective STP is followed by the Respective STP was found followed by No STP was found followed. NA NA analyst for analysis. the analyst for analysis. 40.19 Sch-L1 Specify the procedure of reporting the result of Specific SOP was found followed for No specific SOP was found in analysis by the analyst to QC Head. reporting the result of analysis by the place in this regard. NA NA analyst to QC Head. 40.20 Sch-L1 Specify the procedure followed for storage of Specific SOP was found followed for No specific SOP was found in samples after testing. storage of samples after testing. place in this regard. NA NA 40.21 Sch-L1 Specify the procedure for retention of samples Specific SOP was found followed for No specific SOP was found in after testing is completed. NA retention of samples after testing is place in this regard. NA completed. 40.22 Sch-L1 Specify the procedure followed for issuance of Specific SOP was found followed for No specific SOP was found in COA. NA issuance of COA. place in this regard. NA 40.23 Sch-L1 Specify procedures for safe removal of waste from Specific SOP was found followed for No specific SOP was found in the laboratory. NA safe removal of waste from the place in this regard. NA laboratory. 40.24 Specify whether raw materials, intermediates and Raw materials, intermediates and Raw materials, intermediates and 1) Raw material testing, finished product testing is carried out as per finished product testing was found finished product testing was found intermediate testing or specifications and raw data is maintained. carried out as per specifications and carried out partially and raw data finished product testing raw data was found maintained. not maintained. NA was found not carried out. 2) Raw data was found falsified 53Quality Rating S.No Reference 2 1 0 X 14 1B uAinldainlygt iacnadl pMreemthisoeds :V -alidation (AMV):- 41.1 IP Specify whether following Characteristics are Following Characteristics were found Following Characteristics were considered during validation of analytical methods: considered during validation of found not considered during — Specificity analytical methods: validation of analytical methods: — Linearity — Specificity — Specificity — Range — Linearity — Linearity — Accuracy — Range — Range — Precision — Accuracy — Accuracy — Detection Limit — Precision — Precision — Quantification Limit NA — Detection Limit — Detection Limit NA — Robustness. — Quantification Limit — Quantification Limit —Solution Stability/Filter Study — Robustness. — Robustness. —Solution Stability/Filter Study —Solution Stability/Filter Study 42 HPLC Calibration 42.1 IP Verify the records of calibration of following Records of calibration of following Records of calibration of following parameters: parameters were verified and found parameters were verified and — Calibration of pump. complied with IP: found not complied with IP: — Calibration of Gradient proportionate valve — Calibration of pump. — Calibration of pump. (GPV). — Calibration of Gradient — Calibration of Gradient — Calibration of Auto injector. proportionate valve (GPV). proportionate valve (GPV). — Calibration of Detector. — Calibration of Auto injector. — Calibration of Auto injector. — Temperature calibration for Column oven and — Calibration of Detector. — Calibration of Detector. — Sample Trays compartment. — Temperature calibration for Column — Temperature calibration for — Auto Sampler Carry over. NA oven and Column oven and NA — Manual injector calibration — Sample Trays compartment. — Sample Trays compartment. — System suitability — Auto Sampler Carry over. — Auto Sampler Carry over. — Manual injector calibration — Manual injector calibration — System suitability — System suitability 43 Dissolution Apparatus Calibration 54Quality Rating S.No Reference 2 1 0 X 14 3B.u1ildingI aPnd premises:V -erify the records of calibration of following Records of calibration of following Records of calibration of following parameters: parameters verified and found parameters verified and found not —Checking of RPM complied with IP : complied with IP : —Checking of Temperature —Checking of RPM —Checking of RPM —Checking of distance between inside bottom of —Checking of Temperature —Checking of Temperature the vessel & paddle —Checking of distance between inside —Checking of distance between —Checking of distance between inside bottom of bottom of the vessel & paddle inside bottom of the vessel & the vessel & Basket —Checking of distance between paddle —Checking Wobbling of paddle inside bottom of the vessel & Basket —Checking of distance between —Checking of Wobbling of Basket —Checking Wobbling of paddle inside bottom of the vessel & —Checking of Timer: Calibrate against standard NA —Checking of Wobbling of Basket Basket NA stop watch —Checking of Timer: Calibrate against —Checking Wobbling of paddle —Performance verification test standard stop watch —Checking of Wobbling of Basket [Verify whether dissolution is calibrated —Performance verification test —Checking of Timer: Calibrate against standard prednisolone tablets] against standard stop watch Dissolution was found calibrated —Performance verification test against standard prednisolone tablets Dissolution was found not calibrated against standard prednisolone tablets 44 UV-VIS 44.1 IP Verify the records of calibration of following Records of calibration of following Records of calibration of following parameters: parameters verified and found parameters verified and found not —Control of wavelengths (Wavelength accuracy) complied with IP : complied with IP : —Control of absorbance (Photometric accuracy) —Control of wavelengths (Wavelength —Control of wavelengths —Limit Of Stray Light accuracy) (Wavelength accuracy) —Resolution Power —Control of absorbance (Photometric —Control of absorbance —Resolution (second order derivative spectrum) accuracy) (Photometric accuracy) —CELLS Verification —Limit Of Stray Light —Limit Of Stray Light —I0 flatness —Resolution Power —Resolution Power —Calibration of Visible Wavelength —Resolution (second order derivative —Resolution (second order —Calibration of absorbance reproducibility for NA spectrum) derivative spectrum) NA visible wavelength —CELLS Verification —CELLS Verification —Photometric linearity at 430nm —I0 flatness —I0 flatness —Calibration of Visible Wavelength —Calibration of Visible —Calibration of absorbance Wavelength reproducibility for visible wavelength —Calibration of absorbance —Photometric linearity at 430nm reproducibility for visible wavelength —Photometric linearity at 430nm 46 FTIR 55Quality Rating S.No Reference 2 1 0 X 14 6B.u1ildingI aPnd premises:V -erify the records of calibration of following Records of calibration of following Records of calibration of following parameters: parameters verified and found parameters verified and found not —Verification of the wave number scale complied with IP complied with IP —Control of resolution performance NA —Verification of the wave number —Verification of the wave number NA scale scale —Control of resolution performance —Control of resolution performance 47 TOC Analyser+ 47.1 USP Verify the records of calibration of following Records of calibration of following Records of calibration of following parameters: parameters verified and found parameters verified and found not —System suitability: complied with USP : complied with USP : —Calibration (Four point calibration) NA —System suitability: —System suitability: NA —Calibration (Four point calibration) —Calibration (Four point calibration) 48 Stability Studies 48.1 Sch-M Specify whether stability study is carried out in the Separate stability area with 02 or 02 or more than 02 Vertical stability 1) No stability chambers or No stability studies are QC and if so, is there separate area for Stability more than 02 walk-in or vertical chambers with all required temperature one/both stability chambers are performed either in- Chamber for stability studies. How many Stability stability chambers are provided for and RH conditions are provided under out of order. house or by way of Chambers have been provided? accelerated, real time studies the control of QC. The Chart/records of 2) No temperature and RH records outsourcing to assess the under the control of QC. The temperature and RH are maintained. are maintained for stability shelf life of the products Specify whether shelf life of the product is fixed on additional chambers are provided Shelf life of the product was found chambers. before marketing and the the basis of stability studies. for stability studies at intermediate assigned on the basis of accelerated 3) Records of the stability studies expiry date of the product conditions. The stability chambers and/or real-time stability data. was found not maintained for is fixed arbitrarily are provided with all required assigning shelf life of the product. temperature and RH monitoring and control devices and records of such monitoring is maintained centrally by software. Shelf life of the product was found assigned on the basis of accelerated as well as real-time stability data. 48.2 WHO TRS- Verify the qualification documents of all the All the stability chambers are 986 stability chambers. qualified by following written validation protocol and reports. Further the routine temperature and RH is monitored and recorded NA NA NA through centralized software with Alarm system in case of excursions. 48.3 WHO TRS- Specify whether a written programme for ongoing SOP for stability studies including 986 stability determination is in place. details of accelerated, real-time, and ongoing stability study is maintained. The criteria for NA NA NA carrying out stability study of every product per year is included. 56Quality Rating S.No Reference 2 1 0 X 14 8B.u4ildingW anHdO p rTeRmSis-es:S -pecify whether a complete description of stability The complete description of 986 study is available. stability studies describing study NA NA NA type, protocols, reporting formats etc. are well defined. 48.5 WHO TRS- Verify the stability calendar along with stability Product specific Stability study 986 protocol and documents. Attach the copy of protocol and calendar are NA NA NA stability calendar maintained 48.6 WHO TRS- Specify whether the stability protocol indicates The stability protocol indicates 986 complete set of testing parameters and methods. complete set of testing parameters and methods as applicable to the products. The method for testing NA NA NA used is stability indicating method. 48.7 WHO TRS- Specify whether summary of all generated data Stability summary report with 986 from the study are retained. Comparative results of all stations NA NA NA with conclusion is preserved. 48.8 WHO TRS- Specify the testing schedule for each product 0,1,2,3,6, for accelerated 986 0,3,6,12,18,24,36,48,60 for real NA NA NA time 48.9 WHO TRS- Specify whether stability study is performed after stability study is performed after 986 any significant changes in process equipment, any significant changes in process packaging materials etc. equipment, packaging materials etc. and found defined in VMP as well in SOP for stability studies and NA NA NA records were maintained. Additional comparative stability study report is also maintained. 48.10 WHO TRS- Specify the validation method for stability stability chambers are validated by 986 chambers following written protocol and NA NA NA reports. IQ, OQ,PQ reports are available. 48.11 WHO TRS- Specify the Temperature and humidity for real 40ºC +75% for accelerated stability 986 times studies carried out for fixing shelf life of drug study and 30ºC +70% for real time for in the country. products to be stored around 30ºC. For product to be stored in cold conditions the real time long term NA NA NA stability study is carried out at 2-8ºC and accelerated study is carried out at /25ºc+65% to determine shelf life of product 49 Quality assurance:- 57Quality Rating S.No Reference 2 1 0 X 14 9B.u1ildingS acnhd- Mpremises:M -ention the documents prepared and maintained QA function is elaborate and has SMF, VMP, Validation , SOPs, BMRs, SOPs Product release etc. 1) No separate QA by QA department role in document preparation, Protocols, BMRs, Product No other documents related to in- Department. control, monitoring, etc. pertaining specification, In-process controls, Self process control, validation, product to all aspects having impact on inspection, Product release , etc. complaint and recall etc. quality and compliance. The QA is invariably involved in documents like SMF, VMP, Validation , SOPs, Protocols, MFRs, BMRs, Vendor approval, Product specification, In- process controls, Self inspection, Product release , product complaints, recall, APQR, QRM, Change and Deviation control, Technology transfer, Management review, Training, etc. prepared and maintained by QA. 49.2 Sch-M Specify the responsibility of the QA Head. The QA head is responsible for The QA head is responsible for relapse No QA head is appointed. No QA function and QA release of Finished Product after of FP after verification of all relevant head is not independent. verification of all relevant documents from production, QC, and documents from production, QC, other related department. T and other related department. The responsibility of QA head is well defined and approved by the management. 49.3 Sch-M Specify the procedure followed by QA department The document control is function of Training of SOPs and Self inspection No formal training and self to ensure the implementation of all SOPs in the QA. Well defined procedure for and quality audits are performed for inspection records are not plant. training to the respective personnel verification of compliance of SOPs, maintained. for each SOP is imparted and only GMP, GLP etc. and records/reports are after assessment the personnel is not maintained authorize to work in accordance with that SOP. Self inspection and NA quality audits are performed for verification of compliance of SOPs, GMP, GLP etc. and records/reports are maintained. 49.4 Sch-M Verify the total list of SOPs maintained by QA and Total list of SOP is maintained. Index of SOPs are maintained. Current Both obsolete and current version how QA ensure that no obsolete SOP is in New version of sops are issued version of SOP are available at of SOP found at working place. circulation. only after retrieval of old version of respective place. No records for SOP. The issuance & retrieval issuance and retrieval of controlled NA records are maintained for each copy of SOP are maintained. controlled copy of SOP by QA. 58Quality Rating S.No Reference 2 1 0 X 14 9B.u5ildingW anHdO p rTeRmSis-es:S -pecify whether any procedure is followed for SOP for SOP defines procedure 986 preparation of SOPs and its circulation to all for preparation of SOPs and its concerned. How master, controlled and circulation to all concerned and uncontrolled copy of SOPs are processed. maintenance of master, controlled and uncontrolled copy of SOPs NA NA NA with format of SOP, type of identification for master, controlled and obsolete version. 49.6 WHO TRS- Mention the change control procedures & examine Well defined procedure for 986 three recent change control forms. recording of changes, evaluation, impact assessment and implementation of change controls NA NA NA are maintained. Change control log and detailed documents are maintained. 49.7 WHO TRS- Specify the procedures followed to ensure CAPA The well defined written procedure 986 process. Verify the SOP and three recent records are in place for reporting of in this regard. incidences or deviations and its follow up (CAPA process). The NA NA NA records of outcome are maintained. 49.8 WHO TRS- How deviation are controlled. Verify SOP and The well defined written procedure 986 three recent deviations. Specify whether all in place for handling/investigation deviations are reported and records maintained. of deviation. Records are maintained with respect to NA NA NA reported deviations. 49.9 Sch-M Is the production batch record and release test The production batch record and The production batch record and test The production batch record and No QA procedure for results reviewed for accuracy and completeness test results are reviewed by QA for results are reviewed by QA for test results are not reviewed by reviewing of production before a batch/lot of finished product is released? accuracy and completeness along accuracy and completeness before QA for accuracy and batch record and test with deviation monitoring, product is released in the market but completeness before product is results before product is records are not maintained released in the market and record released in the market are not maintained 49.10 Sch-M Verify the checklist and SOP in this regard. SOP for product release found SOP for product release not found NA NA followed. followed. 49.11 Sch-M Whether QA is involved in control of starting QA is actively involved and review all SOP has provision of QA for materials, intermediate products, bulk products, in control of starting materials, involvement and review however process controls, calibrations, validation and intermediate products, bulk products, for several functions records of release of finish goods. process controls, calibrations, review are not maintained. No validation activity NA validation and release of finish goods performed by QA as per the written procedure and records are maintained. 59Quality Rating S.No Reference 2 1 0 X 14 9B.u1i2ldingS acnhd- Mpremises:S -pecify whether QA is responsible for review of QA Procedures are established for No specific SOP was found production batch record and test results before review of production batch record and followed in this regard. No QA procedure for product is released in the market test results before product is released reviewing of production NA in the market batch record and test results before product is released in the market 50 Annual Product Quality Review (APQR):- 50.1 WHO TRS- Specify Whether Annual Product Quality review is SOP and protocol for APQR are 986 carried out for each product prepared, APQR of each product are reviewed as per well defend NA NA NA procedure, and reports are maintained 50.2 WHO TRS- Specify whether following criteria are considered all specified criteria are considered 987 for review: for review of APQR of each —Starting materials and packaging materials product: —Starting materials and —Critical in-process controls and finished product packaging materials results; —Critical in-process controls and — All significant deviations or non-conformance finished product results; —All changes made to the processes or analytical — All significant deviations or non- methods; conformance — Results of the stability monitoring programme —All changes made to the and any adverse trends processes or analytical methods; —All quality-related returns, complaints and — Results of the stability NA NA NA recalls and the investigations performed at the monitoring programme and any time adverse trends —Adequacy of any other previous corrective —All quality-related returns, actions on product process or equipment complaints and recalls and the —The qualification status of relevant equipment investigations performed at the and utilities e.g. HVAC, water, or compressed time gases —Adequacy of any other previous corrective actions on product process or equipment —The qualification status of relevant equipment and utilities 50.3 WHO TRS- Verify whether Cp and CpK values are calculated The system of measuring how 988 and what is the acceptance criteria fixed. close a process is running to its specification limits is based on process capabilities and process NA NA NA capability index. The values of Cp and CpK are maintained more than 1. 51 Product Recalls:- 51.1 Sch-M Specify the product recall system. Well defined SOP on defective Procedure of effective product recall is SOP on product recall is either product recall is maintained. defined in SOP. No mock recall are deficient or not prepared. No Additionally mock recalls are performed. effective recall system from each performed every year for level of distribution. NA verification of effectiveness of recall procedure and records are maintained. 60Quality Rating S.No Reference 2 1 0 X 15 1B.u2ildingS acnhd- Mpremises:V -erify the procedure followed to handle the Recalled product are stored separately No separate & secured area for NA NA recalled products in a secured area. recalled product 51.3 Sch-M Are distribution records available for a prompt Distribution records are promptly Distribution details are not shared recall of products from the market? NA available for product recall up to each with QA/QC or designated person NA distribution level for recall of product. 51.4 Sch-M Verify the SOP for recall of products clearly QA head is designated for product Recall decision are communicated defining responsibility, procedure reporting, recall, distribution details up to each to each distributor to retail level reconciliation etc. level are promptly available to QA. with plenty of time and not recalled Fax, Email and Emails are used for any quantity. The product are sold fast communication and recall is even after product recall NA performed in shortest possible time. communications. NA The communication on recall decision, response from each distributor, recalled qty and reconciliation are maintained. 52 Complaints and Adverse Reactions:- 52.1 Sch-M Are complaints, whether received in oral or written Handling of complaint including SOP for product complaint handling is Procedure for handling of 1) No procedure for form, documented in writing, and retained in a product complaints are defined in available. complaint is available. Complaints complaint handling designated file? SOP. Each compliant is logged in are not handled as per SOP 2) Complaints are not logbook. addressed. 52.2 WHO TRS- Are complaints reviewed on a timely basis by the time bound review is performed by NA NA NA 988 Quality Assurance unit? QA 52.3 WHO TRS- Is CAPA process followed in response to each CAPA is followed for each NA NA NA 988 complaint documented? complaints 52.4 WHO TRS- Specify whether system of route cause analysis is Technical and scientific evaluation 988 followed by the firm on the complaint of adverse is performed on complaint of drug reaction. adverse drug reaction to established the root cause. The reports on adverse events with NA NA NA comments and documents are reported to the licensing authority. 52.5 Sch-M Specify the review system for complaints The QA head is responsible for The QA head is responsible for review SOP is available however not concerning the quality of products. review of product complaints. The of complaint. The complaint are being followed. QA further investigate the investigated by QA team. complaint with the help of other NA section to take CAPA in time bound manner 52.6 Sch-M How records of complaint and adverse reactions NA And records are maintained as per No records of complaints are maintained. SOP. maintained. Usually nil complaint NA are reported. 52.7 Draft Rules Whether the firm has provided Pharmacovigilance The firm has well defined department for analysing complaints of adverse pharmocovigilance section to drugs reactions resulting from the use of a drug. generate the data of adverse NA NA NA reaction and product complaints. 61Quality Rating S.No Reference 2 1 0 X 15 2B.u8ildingS acnhd- Mpremises:A -re there any criteria for action to be taken on the The criteria describing action to be No criteria for recall of product is basis of nature of complaint / adverse reaction? taken , recall to be made w.r.t. nature defined NA NA of product complaint are well defined in SOP 53 Site Master File:- 53.1 Sch-M Whether all the relevant information has been Yes with annexures as required. Yes without annexures. SMF is not factual. NA included in the site master file. 53.2 Sch-M Whether quality policy has been included in the Quality policy and quality system are Quality policy is defined NA NA site master file. well defined 53.3 Sch-M Verify whether all information as per schedule M All informations provided in SMF was All informations provided in SMF NA found complied with the Sch-M was found not complied with the NA requirement. Sch-M requirement. 53.4 WHO TRS- Verify whether all information as per WHO TRS All informations provided in SMF 988 986 and PIC/S document. was found complied with WHO NA NA NA TRS 986 54 Validation 54.1 WHO TRS- Specify the validation policy of the company Validation policy is well defined 988 and covers all aspects like system, NA NA NA processes and facility. 54.2 WHO TRS- Whether a Validation Master Plan has been Validation Master Plan is as per NA NA NA 988 prepared. the policy. 54.3 Sch-M Verify resources and those responsible for its In-house QA capacity with specialized No in-house capacity or deficient NA implementation. assistance from out side technical system of validation. NA resources the validations are completed. 54.4 WHO TRS- Identify the systems and processes to be validated All critical quality attributes or 988 as per VMP critical system and process identified doing product NA NA NA development are validated as per latest available practices. 54.5 WHO TRS- Verify whether documentation, standard operating Standard operating procedures 988 procedures (SOPs), Work Instructions and (SOPs), Work Instructions and Standards (applicable for national and Standards are incorporated in VMP NA NA NA international) are incorporated in VMP 54.6 WHO TRS- Validation list for facilities/equipment, processes / Yes available NA NA NA 988 procedure and products. 54.7 WHO TRS- Specify whether key approval criteria are Key approval criteria are 988 mentioned in the VMP & how record and mentioned in the VMP & recording NA NA NA conclusion of such validation studies are prepared system with conclusion found and maintained. followed. 54.8 WHO TRS- Verify Protocol format for each validation activity, Yes worst case scenario taken into 988 including re-validation and reasonable unforeseen consideration as per the written NA NA NA events (power failures, system crash and protocols. recovery, filter integrity failure. 54.9 WHO TRS- Whether validation calendar is specified in VMP. Validation schedule is maintained NA NA NA 988 in a calendar 62Quality Rating S.No Reference 2 1 0 X 15 4B.u1i0ldingS acnhd- Mpremises:S -pecify whether the critical processes validated Prospective or concurrent validation Retrospective validation. Prospectively, retrospectively or concurrently. NA NA 54.11 WHO TRS- In case electronic data processing systems are Yes the computer system 988 used, are these validated? validation is in place including Excel sheets. The system NA NA NA included both testing as well as manufacturing equipments 54.12 WHO TRS- Please specify whether periodical challenge tests 988 performed on the system to verify reliability. Yes NA NA NA 54.13 Sch-M Are the validation studies performed according to The validation studies performed Yes however protocols are not based Yes however format is deficient pre-defined protocols? according to pre-defined protocols on any recognized guidelines. NA 54.14 Sch-M Is a written report summarized, results and Yes however protocols are not based Yes however format is deficient conclusions prepared and maintained? NA on any recognized guidelines. NA 54.15 WHO TRS- Is the validity of the critical processes and The validity of the critical 988 procedures established based on a validation processes and procedures NA No NA study? established based on a validation study 54.16 WHO TRS- Are criteria established to assess the changes Revalidation policy is well defined NA No NA 988 originating a revalidation? covering changes. 54.17 WHO TRS- Are trend analyses performed to assess the need Trend analysis is performed and is 988 to re-validate in order to assure the processes and followed for signals and NA No NA procedures continue to obtain the desired results? corrections. 55 Internal Quality / GMP Audit Programme 55.1 Sch-M Does a formal auditing function exist in the Quality Yes, as per the written policy and Checklist for self audit and gap SOP and Checklist for self audit NA Assurance department? schedule. The criteria for self audit analysis is used for gap analysis. Well available however the outcomes with follow up actions are very well written criteria for follow up actions is are not effective. established. not specified. 55.2 Sch-M Does a written SOP specify who shall conduct audits and qualifications (education, training, and experience) for those who conduct audits? Yes NA NA NA 55.3 Sch-M Does a written SOP specify the scope and frequency of audits and how such audits are to be Yes NA NA NA documented? 55.4 WHO TRS- Specify whether record is maintained for CAPA on CAPA record was found 988 the basis of self quality audit / inspection and maintained on the basis of self whether same is reviewed by the management quality audit / inspection and the same is reviewed by the NA NA NA management 63Quality Rating S.No Reference 2 1 0 X 15 6B uPihldainrmg aancde uprteicmails Dese: v-elopment 56.1 ICH/Q-8- Whether there is Research and Development R&D Facility for in house PICS facility available. characterization of API, formulation NA NA NA etc. 56.2 ICH/Q-8- Whether formulation development facility up to Formulation development facility PICS development of exhibit batches available. was found up to development of NA NA NA exhibit batches. 56.3 ICH/Q-8- Whether firm hires consultants for technology The development of product and PICS transfer. If so details thereof. process is based on design of NA NA NA Experiment 56.4 ICH/Q-8- Whether firm has adopted latest tools (quality by The development of product and PICS design) to develop new products. process is based on design of NA NA NA Experiment 57 Quality Risk Assessment System:- 57.1 ICH/Q-9- Whether the firm has adopted QRM principle to Yes ICH guidelines PICS mitigate risk involved in pharmaceutical development, manufacturing and distribution. If NA NA NA yes specify which guidelines are followed in this regard. 57.2 ICH/Q-9- Whether firm has policy document on QRM. Written policy describing QRM PICS Specify document number and its effective date. approach at the time of implementation of any activity is specified. The RPN numbering NA NA NA based controls are put in SOP's and documents for monitoring and control 57.3 ICH/Q-9- Which known principles have been adopted to FMEA, HAZOP, HACCP, FTA PICS analyse risks e.g. FMEA, HAZOP, HACCP, FTA used and outcome is linked to NA NA NA etc. monitoring and control 57.4 ICH/Q-9- Whether risk priority number (RPN) is calculated yes PICS based on severity, probability and detectability. If so, what is the criteria of acceptance. NA NA NA 57.5 ICH/Q-9- How many products, process etc. have been All as per policy PICS analysed for risk. Give brief. NA NA NA 58 Data Integrity 64Quality Rating S.No Reference 2 1 0 X 15 8B.u1ildingS acnhd- Mpremises:W -hether the records are completed at the time of Records in paper as well as Records in paper as well as software Records in paper are maintained 1) Data is not recorded the operation and are legible maintained with raw software based system are based system are maintained contemporaneously. No system on a contemporary data if applicable. maintained contemporaneously. contemporaneously. Software for maintain Software based data. basis/Records are not Software supported audit trail as supported audit trail is not available. made at the time of per the written policy is in place.. actual activity. 2) Records are completed later on arbitrarily. 3) Falsification of data is observed. 58.2 Sch-L1 Whether the firm has software based yes for both manufacturing and Only for testing facility. Not even for testing. NA manufacturing and testing equipment testing facility. 58.3 Sch-L1 Whether the individuals are provided log in IDs for access. All login and logout information should be Yes NA NA NA available. 58.4 Sch-L1 Whether rights to work, amend, modify, delete are Yes NA NA NA specified in written document. 58.5 Sch-L1 Whether right to access and modify are with two Critical modification are verified by different individuals. If yes how QA is involved in the QA and is a part of audit trail NA NA NA modification of data. and batch release criteria. 58.6 Sch-L1 Whether audit trails related to project creation Yes (study creation), project (study) modification, NA NA NA deletion etc. are available. 58.7 Sch-L1 Whether the data is backed up at regular intervals. Yes server based. Yes but not server based (data in hard No data back up. If yes what is the written back up policy. The data discs) NA backup must be server based. 58.8 Sch-L1 How Excel sheets are validated if calculation are Yes validated NA NA NA done in Excel sheet. 58.9 Sch-L1 Whether the firm has QA SOP for review of data Yes, the rights are well defined and Yes however no QA SOP integrity or audit trail. If yes how the modification found as per written SOP NA NA and deletions are reviewed. 59 Pharmaceutical Quality Management System (PQS) 59.1 WHO TRS- Specify the management responsibility defined as Corporate or Top management 986 per the quality manual responsibilities are defined and NA NA NA specified in the quality manual. 59.2 WHO TRS- Specify the Procedures followed for continual The management review meetings 986 improvement of process performance and product are held at regular intervals. Key quality performance indicators impacting NA NA NA quality are reviewed. 65Quality Rating S.No Reference 2 1 0 X 15 9B.u3ildingW anHdO p rTeRmSis-es:S -pecify the performance indicators presently The effectiveness of the quality 986 followed by the firm to monitor the effectiveness of system is assesses by the top PQS like product quality monitoring, CAPA, management by reviewing key change management and management review performance indicators includes NA NA NA product quality, monitoring, CAPA, change management etc. 59.4 WHO TRS- whether purchases are also included under PQS Yes as per the written policy NA NA NA 987 59.5 WHO TRS- Specify whether life cycle approach is followed The system of monitoring and 986 controlling quality from production NA NA NA development to marketing is in place. 59.6 WHO TRS- Give synopsis of last to management review The Management review and 986 meeting held by the firm CAPA shared. Top management found providing necessary NA NA NA resources to meet any quality related compliance. REMARKS & RECOMMENDATIONS: 66Quality Rating System Rating Meaning Interpretation 2 Good Item/area/system/knowledge is superior. 1 Adequate Item/area/system/knowledge meets basic minimum requirements 0 Deficient Item/area/system/knowledge is weak and not up to acceptable standards. X Critical Item/area/system/knowledge is missing or of such Deficiencies nature to warrant serious quality/compliance concerns. NA Not Question is not applicable to type of operation or item Applicable was unable to be addressed during the audit. Comment: - 1. All deficiencies under critical category will be marked as “X” and one critical finding will make the manufacturing site unsuitable for acceptance till rectified irrespective of scores in other points. 2. Some users of the checklist find responses to some questions are difficult to quantify on a 0-2 scale and prefer to use a simple “Yes” or “No” approach. In such cases, a “Yes” should be assigned a “1” value and a “No” should be assigned as “0” value.