See Full Document Text
Draft Guidance document
Post Approval Changes in
Biological Products:
Quality Safety and Efficacy
Documents
Document No - PAC/ 2024
Version – 1.2
Published by
Central Drugs Standard Control Organization
Ministry of Health, Government of India
Date Revised
Date Adopted
Date ImplementationGuidance for Industry
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Table of Contents
Abbreviations ......................................................................................................................................................... 4
1. INTRODUCTION....................................................................................................................................... 5
1.1 Objectives .................................................................................................................................................. 5
1.2 Scope and Application ............................................................................................................................ 5
1.3 Background ................................................................................................................................................ 5
2. GUIDANCE FOR IMPLEMENTATION ................................................................................................ 6
2.1 Reporting Categories for Quality Changes .......................................................................................... 6
2.1.1 Level I – Supplements (Major Quality Changes) ............................................................................. 6
2.1.2 LeveI II – Notifiable Changes (Moderate Quality Changes) .......................................................... 6
2.1.3 Level III – Annual Notification (Minor Quality Changes) ................................................................ 7
2.1.4 Level IV – Changes (Record of Changes) ............................................................................................ 7
2.2 Documentation – Quality Changes ........................................................................................................ 7
2.2.1 General Information .................................................................................................................................. 7
2.2.2 Supporting Data – Level I and Level II Changes: ................................................................................ 8
2.2.3 Supporting Data – Level III Changes ................................................................................................... 9
2.2.4 Supporting Data – Level IV Changes .................................................................................................... 9
2.3 Reporting Categories for Safety, Efficacy Changes ............................................................................ 9
2.3.1 Level I – Supplements (Safety and Efficacy) ...................................................................................... 10
2.3.2 Level II – Notifiable Change (Safety and Efficacy) that are risk/harm management changes .... 12
2.3.3 Level II – Notifiable Change (Safety and Efficacy) that are not risk/harm management changes
13
2.3.4 Level III (Safety and Efficacy) Changes – Annual Notification ......................................................... 14
2.3.5 Documentation – Safety and Efficacy Changes: ................................................................................ 14
3. SPECIAL CONSIDERATIONS ............................................................................................................. 16
3.1 Comparative Studies .............................................................................................................................. 16
3.2 Bridging Clinical Studies ........................................................................................................................ 16
3.3 Stability Testing ....................................................................................................................................... 17
3.4 Pharmaceutical Development and Quality by Design ....................................................................... 18
3.5 Multiple Changes .................................................................................................................................... 19
3.6 Post-Approval Change Management Protocol-PACMP ................................................................... 20
3.7 Production Documents ........................................................................................................................... 20Guidance for Industry
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3.8 Expedited Review Procedure (Reliance Pathway) ............................................................................ 21
3.9 Similar Biotherapeutic Products (SBP) / Similar Biologics ............................................................... 21
4. POST APPROVAL CHANGES (BIOLOGICALS) ............................................................................... 22
3.2.S DRUG SUBSTANCE ................................................................................................................. 23
3.2.S.1 General Information ................................................................................................................ 23
3.2.S.2 Manufacture ............................................................................................................................. 23
3.2.S.3 Characterization ...................................................................................................................... 42
3.2.S.4 Control of the Drug Substance ............................................................................................. 42
3.2.S.5 Reference Standards or Materials ....................................................................................... 49
3.2.S.6 Container Closure System ..................................................................................................... 51
3.2.S.7 Stability ..................................................................................................................................... 53
3.2.P DRUG PRODUCT....................................................................................................................... 58
3.2.P.1 Description and Composition of the Drug Product ........................................................ 58
3.2.P.2 Pharmaceutical Development ........................................................................................... 65
3.2.P.3 Manufacture ......................................................................................................................... 66
3.2.P.4 Control of Excipients ........................................................................................................... 75
3.2.P.5 Control of Drug Product ..................................................................................................... 82
3.2.P.6 Reference Standards or Materials.................................................................................... 89
3.2.P.7 Container Closure System ................................................................................................. 90
3.2.P.8 Stability ................................................................................................................................. 95
5. POST-APPROVAL CHANGE MANAGEMENT PROTOCOL-PACMP ........................................... 99
6. EFFICACY POST APPROVAL CHANGES ........................................................................................ 99
7. ADMINISTRATIVE CHANGES ........................................................................................................... 103
8. PRODUCT LABELLING INFORMATION CHANGES ..................................................................... 105
9. APPENDICES ....................................................................................................................................... 106
Appendix 1: Examples of Level IV Changes but not limited to .......................................................... 106
Appendix 2: ANNUAL REPORT FORM (Minor Changes) ................................................................. 107
Appendix 3: Glossary ............................................................................................................................... 108
10. REFERENCES ...................................................................................................................................... 119Guidance for Industry
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Abbreviations
AEFI : Adverse Event Following Immunization
BAN : British Approved Names
BSE : Bovine Spongiform Encephalopathy
CDSCO : Central Drugs Standard Control Organisation
CMC : Chemistry, Manufacturing and Control
CQA : Critical Quality Attribute
CTD : Common Technical Document
EDQM : European Directorate for the Quality of Medicines & HealthCare
GMP : Good Manufacturing Practices
HA : Haemagglutinin
HVAC : Heating, Ventilation, Air Conditioning
ICH : International Council for Harmonisation
INN : International Non‐proprietary Name
MA : Marketing Authorization
MCB : Master Cell Bank
NA : Neuraminidase
NC : Notifiable Change
NCL : National Control Laboratory
NIBSC : National Institute for Biological Standards and Control
NRA : National Regulatory Authority
PAC : Post Approval Change
PACMP : Post-approval change management protocol
PI : Package Insert
PK/PD : Pharmacokinetic/pharmacodynamic
PPD : Product Permission Document
PSUR : Periodic Safety Update Report
QC : Quality Control
SBP : Similar Biotherapeutic Products
SPC : Summary of Product Characteristics
TAG : Technical Advisory Group
TSE : Transmissible Spongiform Encephalopathy
USAN : United States Adopted Name
WCB : Working Cell Bank
WFI : Water for Injection
WHO : World Health OrganizationGuidance for Industry
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1. INTRODUCTION
Biological products contain substances that have been produced by using living cells or
organisms. Examples of biological products include but not limited to:
Vaccines
Recombinant DNA products
Similar Biotherapeutic Products (SBP)/ Similar Biologics
Cell and Gene therapy products
Blood and blood products
MA holder (refer Glossary) is required to apply all Post Approval Changes (PAC’s) mentioned
in this document through online portal of CDSCO as per the checklist in the module.
1.1 Objectives
a) To assist with the classification of changes made to biological products approved by
CDSCO for import / manufacturing and marketing in India.
b) To provide Marketing Authorization Holders (MA holders) with recommendations on
the data to support a change which would be considered sufficient to allow a
determination of the impact of the change on the quality of the approved products as it
relates to safety, efficacy and/or effective use of the products.
1.2 Scope and Application
This guidance document applies to MA holders intending to make changes to biological
products that have received an approval to market the products.
1.3 Background
This would include an emphasis on applying a science-based and risk-based approach to the
quality, safety and efficacy assessment of the biological products. As such, the guidance
documents were needed to outline the information needed to support quality, safety and
efficacy changes to biological products which apply a modernized, science-based, and risk-
based approach to this area.Guidance for Industry
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2. GUIDANCE FOR IMPLEMENTATION
2.1 Reporting Categories for Quality Changes
The following criteria are meant to provide guidance with respect to the classification of a
change. Specific change examples based on the application of these criteria are provided in
this guidance. For assistance in classifying a change, MA holders are advised to contact
CDSCO.
2.1.1 Level I – Supplements (Major Quality Changes)
Level I - Supplements (Major Quality Changes) are changes that have a substantial
potential to have an adverse effect on the identity, strength, quality, purity, or potency of
a biological product as these factors may relate to the safety and/or efficacy of the product.
In general, a change that is supported by extensive documentation and/or requiring extensive
assessment of the supporting documentation would be considered a Level I - Supplement
(Major Quality Change) (e.g., a change supported by in-vivo studies). This is to allow CDSCO
the opportunity to apply the principles of risk management by having the necessary time for
an appropriate assessment of the documentation. This assessment will take into
consideration any potential impact upon market availability as well as the adverse effects on
the identity, strength, quality, purity, or potency of the biological product.
The changes included in this reporting category shall not be implemented for commercial
purpose without prior approval from CDSCO.
The changes included in this reporting category shall be submitted along with the
recommended supporting data, to CDSCO. Appropriate fee, as applicable and in accordance
with rules shall be paid along with submission.
2.1.2 LeveI II – Notifiable Changes (Moderate Quality Changes)
Level II - Notifiable Changes (Moderate Quality Changes) are changes that have a
moderate potential to have an adverse effect on the identity, strength, quality, purity, or
potency of the biological product as these factors may relate to the safety and/or efficacy of
the product.Guidance for Industry
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The changes included in this reporting category shall not be implemented for commercial
purpose without prior approval from CDSCO.
The changes included in this reporting category should be submitted along with the
recommended supporting data, to CDSCO as a Notifiable Change (NC).
2.1.3 Level III – Annual Notification (Minor Quality Changes)
Level III -Annual Notification (Minor Quality Changes) are changes that have minimal
potential to have an adverse effect on the identity, strength, quality, purity, or potency of the
biological product as these factors may relate to the safety and/or efficacy of the product. The
changes included in this reporting category may be implemented by the MA holder without
the prior review by CDSCO of the data supporting such a change (except for cases of
change in shelf life).
2.1.4 Level IV – Changes (Record of Changes)
Level IV (Quality only) changes are changes to a biological product that are not Level I, Level
II or Level III and are not expected to have an adverse effect on the identity, strength, quality,
purity, or potency of the drug product as these factors may relate to the safety and/or efficacy
of the drug product. The changes included in this reporting category may be implemented by
the MA holders without prior review by CDSCO. The changes should be retained as part of
the drug product’s record by MA holders and should comply with the requirements of ‘Good
Manufacturing Practices’.
A list of examples of Level IV changes is provided in Appendix 1.
2.2 Documentation – Quality Changes
2.2.1 General Information
The examples presented in Post Approval Changes (Biologics) are intended to assist with the
classification of changes made to the Quality, Safety, Efficacy and Administrative information.
The information summarized in the tables provides recommendations for:
a) The conditions to be fulfilled for a given change are classified as a Level I, II, III or IV
change. If the conditions outlined for a given change are not fulfilled, the particular
change is automatically considered the next higher level of change.; For example, ifGuidance for Industry
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any of the conditions recommended for a Level II ‐ Notifiable Change are not fulfilled,
the change is considered a Level I ‐ Supplement. Similarly, if any of the conditions
recommended for a Level I ‐ Supplement are not fulfilled, the change would warrant
the filing of a New Drug.
b) The supporting data for a given change is either to be submitted to CDSCO and/or
maintained by the MA holders. Wherever applicable, the corresponding sections of the
application for the supporting data have been identified; if any supporting data is not
provided / not applicable, then a justification should be provided.
c) The reporting categories (e.g., Supplement, Notifiable Change, Annual Notification
and Record of Changes).
2.2.2 Supporting Data – Level I and Level II Changes:
All data recommended to support the change should be provided with the submission.
Where applicable, these data should be provided in the format defined by CDSCO or in
the format of Common Technical Documents (CTD).
Supporting Data Common to Level I and Level II Changes:
The following should be included, where applicable, in the submission package for Level I
and Level II Quality changes:
a) a covering letter (including a list of changes describing each in sufficient detail to allow
for a quick assessment as to whether the appropriate reporting category has been
used);
b) where relevant, a side-by-side comparison of the previously approved and the
changed information;
In addition to the above common information, recommendations are included in Post
Approval Change (Biologics) categories outlining the specific information to support the
various changes of Quality, Safety, Efficacy and Administrative. It should be noted that the
common information is not repeated for the various changes outlined in the sections.
When cross-references are made to previously submitted information, details on the
cross-referenced information should be indicated in the covering letter (e.g., brand name
/ generic name of the drug product, MA holders name, submission type, File number, dateGuidance for Industry
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approved).
2.2.3 Supporting Data – Level III Changes
Annual notifications shall be submitted to CDSCO by 1st quarter of every calendar year. Any
data for calendar year (January to December) that may have been generated by the MA
holders in support of a Level III change should not be submitted with annual notification,
however, should be available to CDSCO within thirty (30) calendar days, if requested. For
submission of each minor change, Appendix 2: Annual Report Form (Minor Changes) of this
guidance shall be referred by MA holder.
Note: For extension of shelf life that is categorized as Level III as per this guidance, MA
holder should submit the PAC application along with applicable supporting documents and
should implement the change only after approval from CDSCO.
2.2.4 Supporting Data – Level IV Changes
The Quality changes included in this category should be retained as part of the drug
product’s record by MA holder and comply with the requirements of ‘Good Manufacturing
Practices’. These changes should be annotated / updated in the affected documents (e.g.,
Package Insert, SPC or PPD) with the filing of the next submission to CDSCO.
2.3 Reporting Categories for Safety, Efficacy Changes
After assessing the effect of a change related to clinical use or to product labelling
information on the safe and effective use of a biological product, MA holders should classify
this change in one of the following categories:
Level I – Supplements (Safety and Efficacy);
Level II – Notifiable Changes (Safety and Efficacy) i.e. risk/harm management change
Level II – Notifiable Changes (Safety and Efficacy) that are not risk/harm management
changes
Level III – Annual Notifications (Safety and Efficacy)
Further information on each category is provided below.
Safety and efficacy changes are changes that have an impact on the clinical use of the
biological product in relation to safety, efficacy, dosage and administration and that require
data from clinical studies to support the change. Safety and efficacy changes requireGuidance for Industry
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approval prior to implementation of the change.
The type and scope of the required supporting non-clinical and/or clinical safety and efficacy
data are determined case-by-case on the basis of risk-benefit considerations related to the
impact of the changes. Additionally, non-clinical and/or clinical data generated in other
countries may be used for such risk benefit consideration.
Other considerations which may applicable for vaccines, only:
robustness of the immune response elicited by the vaccine and availability of a
correlate of protection (i.e. data establishing a threshold level of antibody needed to
protect against the development of disease following exposure);
availability of animal models; and
vaccine attributes (e.g. live vaccines as opposed to inactivated ones).
MA holders are encouraged to consult CDSCO on the adequacy of the clinical data needed
to support a safety and efficacy change if deemed necessary. Additionally, some changes
such as dosage form, content of excipients or residual components, or delivery device may
require clinical data as well as revision of the product labelling information. CDSCO may also
be consulted on the data required to support such changes.
If the conditions / supporting data outlined for a given change are not fulfilled, then
appropriate scientific justification shall be provided by the MA holders.
2.3.1 Level I – Supplements (Safety and Efficacy)
A Level I change is defined as a change to the label of a drug that has the potential to
change the exposure levels of the drug, either by expanding the population that is exposed
(i.e. related to market expansion), or by increasing individual exposure. Label changes that
can result in increased exposure levels of the drug include:
addition or expansion of a safety claim or efficacy claim, whether explicit or implied;
change in the strength, route of administration, recommended dose/dosing range,
dosage form, dosing schedule, including the addition of a booster dose;
co-administration with other vaccines or biological products; or
deletion or reduction of existing risk management measures (e.g. contraindications,
adverse events, warnings or cautionary text/statements, in the product labelling
information).Guidance for Industry
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The changes included in this reporting category shall not be implemented for commercial
purpose without prior approval from CDSCO.
Examples: Examples of Level I changes include but are not limited to the following:
The addition of a new contraindication, a change in an existing contraindication, the
addition of a serious warning or precaution or the tightening of clinical monitoring
requiring a change to the labels of sections of the Package Insert
Changes to the existing text of the label that refers to any potential benefits of the drug
(implied or explicit), including claims regarding the safety profile or efficacy. This
includes changes in text with reference to sub-populations and any reference to
possible claims regarding side effects.
Addition of a new indication or the revision to existing text of a current indication.
Addition of a new route of administration, dosage form, or strength.
A change regarding the mechanism of action of the product as detailed in the Action
and Clinical Pharmacology section of the Product labelling that results in an explicit or
implicit claim.
A change to the Clinical Trial section of the Product labelling which results in a new
claim, explicit or implied (e.g., listing of additional outcome measures, or revision to
the description of study design such that a new benefit is implied for a specific
subpopulation).
Data has been added from an efficacy or safety (tolerability) study in a special
population
A change in condition of use from prescription to non-prescription status.
An existing contraindication, warning or cautionary text anywhere in the Product
Labelling, has been deleted in its entirety, has been modified to reflect a reduction or
diminishment in risk/harm management measure. These may result from a range of
supporting data (e.g., post-marketing data, safety studies, pharmacokinetic data etc.).
Existing text regarding an adverse event or set of events has been modified to reflect,
in any way, an apparent reduction in risk/harm. This includes changes related only to
animal data.
Note: The changes that are considered as “New Drugs” as per “The New Drugs and Clinical
Trials Rules, 2019, MA holder should submit the MA application in Form CT-21/Form CT-18Guidance for Industry
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in SUGAM with applicable fee along with supporting documentation as described for the
respective post approval change category, followed by amendment / endorsement of current
Form 28 D license, as applicable .
Note: A declaration to state that no change to other remaining section/s of the MA dossier,
including impact on safety/efficacy, shall be submitted, as applicable.
2.3.2 Level II – Notifiable Change (Safety and Efficacy) that are risk/harm management
changes
A Level II - Notifiable (Safety and Efficacy) change (i.e. risk/harm management change) is
defined as a change to the label that has the potential to improve the management of
risk/harm to the population currently indicated for use of the drug, or in any other way
exposed to the drug by:
the identification or characterization of any adverse event following immunization (AEFI)
resulting in the addition or strengthening of risk management measures for an adverse
event which was identified to be consistent with a causal association to immunization
with the vaccine concerned;
the addition or strengthening of risk management measures, including instructions on
dosing or any other conditions of use.
the identification of subgroups, or conditions of use, for which the benefit/risk profile of
biological product has the potential to be less favorable; and
The changes included in this reporting category shall not be implemented for commercial
purpose without prior approval from CDSCO.
Examples:
Examples of Level II – Notifiable (Safety and Efficacy) that are risk/harm management
changes include but are not limited to the following:
An addition to, strengthening or clarification of text anywhere in these sections:
Contraindications, Warnings and Precautions and Adverse Events. These changes may
include the provision of recommended risk/harm management actions (e.g., required
testing prior to initiation of the drug, specific monitoring during product use, ensuring
patient awareness of certain risks, etc.), or the identification of a specific sub-populationGuidance for Industry
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as being at greater risk such as those with a concomitant condition, those taking
concomitant medicine, or a specific age group.
The instructions for use including dosage and administration, in the Product labelling
have been reworded and/or otherwise altered with respect to risk/harm management to
optimize the safe use of the drug.
A new drug interaction has been added, or an existing drug interaction has been better
characterized that identifies a risk/harm.
A change to the toxicology data, explicitly or implied, stating an increase in risk/harm to
the target population (other changes to the toxicology data, in general, are submitted as
Level II - Supplements (Safety and Efficacy) that are not risk/harm management
changes.
An existing indication has been withdrawn in its entirety or the indication has been
modified for the purpose of risk/harm management including a reduction in scope.
A change to improve the clarity of the message to patients in Part III of the Product
labelling.
Revisions to the existing text of the labels to add clarity to the safe use of the drug, but
without expanding, explicitly or implied, the claims of the drug.
2.3.3 Level II – Notifiable Change (Safety and Efficacy) that are not risk/harm
management changes
There are some Level II - Notifiable (Safety and Efficacy) changes that do not meet the
criteria of a Level I - Supplement or a risk/harm management change of a Level II - Notifiable
(Safety and Efficacy), but for which prior approval by CDSCO is required.
Examples include but are not limited to the following:
Changes to the text related to the Overdose section (e.g., additional overdose
symptoms or treatments).
Changes made to the text of the Pharmacology, Microbiology, Toxicology sections of
the Package Insert, except where criteria for Level II – Notifiable (Safety and Efficacy)
risk/harm management changes are met.
A new drug interaction or pharmacokinetic study has been added, or has been better
characterized with no risk/harm identified and does not expand the claim of the drug,
explicitly or implied.Guidance for Industry
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The addition of data or modification of text, other than Level I - Supplements, Level II –
Notifiable (Safety and Efficacy) that are risk/harm management changes or Level III
changes, that does not result in any other changes to the information provided to the
Health Care Professional or patient/consumer. For these changes, the applicant is not
seeking a statement that may be interpreted as a new claim.
2.3.4 Level III (Safety and Efficacy) Changes – Annual Notification
A Level III change is defined as any change to the label that is not expected to impact the
safety, efficacy, and/or effective use of the drug. The changes included in this reporting
category may be implemented by the applicant without prior review by CDSCO of the data
supporting such a change. Any data that may have been generated by the MA holder in
support of a Level III change should be submitted to DCGI within 30 calendar days, upon
request.
Examples of Level III related changes include but are not limited to the following:
The existing text of the labels have been revised to add clarity and maintain consistency
with common label phrase standards (e.g., change from "Product labelling information
available on request" to "Product labelling information available to health care
professional on request",
change from "Not recommended for children" to "Not for use in children".
Revisions to Product labelling to standardize text in each of the following sections:
Overdose, Missed Dose, How to Store It or Reporting Suspected Side Effects.
Any change in spelling of the text of the label (e.g.,"adition" is replaced by "addition").
Updating bar codes and technical codes,
Removing graphics,
Removing non-regulatory label information,
Changing colour of graphics where there is no text overlay or changing colour of
company logo,
Updating contact information (e.g., customer service number, website addresses, etc.).
2.3.5 Documentation – Safety and Efficacy Changes:
For a change under these categories (Safety and Efficacy), the MA holder should submit an
application to CDSCO that may include but is not limited to;Guidance for Industry
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a detailed description and rationale of the proposed change;
a summary of the methods used and studies performed to evaluate the effect of the
change on the biological products safety or efficacy;
amended product labelling information;
clinical studies (protocol, statistical analysis plan, clinical study report and Periodic
Safety Update Report (PSUR) data or bioequivalence trials, pharmacokinetic studies,
pharmacodynamic studies, epidemiological data, pharmacovigilance studies, review
reports/analysis of specific safety concerns, if applicable);
the risk management plan/pharmacovigilance plan or patient registry data.
Other data that may be relevant to the submission. Real world information regarding
drug use, declarations/attestations, opinion papers, conference presentations,
publications in peer-reviewed scientific journals and drug utilization information.
Pre-submission meeting minutes or other written feedback, if applicable.
2.4 Administrative Product Labelling Information Changes
Administrative product labelling information changes are changes that are not expected to
affect the safe and efficacious use of the biological product. In some cases, these changes
may require reporting to the CDSCO and receipt of approval prior to implementation, while in
other cases reporting may not be required, as follows:
Examples of product labelling information changes that require approval by the CDSCO
prior to implementation are changes in the name of the MA holder that are due to a
merger or changes in the proper name or trade name of the biological product. The
changes in this category are considered important for reasons of liability and monitoring.
o Product labelling changes submitted along with the MA transfer or license
amendment application, to the CDSCO, may not require separate reporting.
Examples of product labelling information changes that do not require approval by the
CDSCO prior to implementation are changes to a distributor’s address or minor changes
in format. These changes should be reported to the CDSCO as part of subsequent safety
and efficacy changes or product labelling information changes when updated product
labelling information is included.Guidance for Industry
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For an administrative product labelling information change that requires approval prior to
implementation, the MA holder should submit an application containing background
information on the change and annotated and clean drafts of the product labelling
information. The review and approval timeline for an administrative product labelling
information change shall be around 30 days from the date of submission.
3. SPECIAL CONSIDERATIONS
3.1 Comparative Studies
The need for – and extent of – a comparability exercise depends upon the potential impact of
the change(s) on the quality, safety and efficacy of the product. Comparability exercises can
range from analytical testing alone (for example, where process changes have no impact on
any quality attribute) to a comprehensive exercise requiring nonclinical and clinical bridging
studies. For example, a change in the culture conditions or in the purification process may
cause the alteration of the glycosylation profile of the product, including site directed
glycosylation. Alteration of glycosylation profiles may cause a change in the pharmacokinetic/
pharmacodynamic (PK/PD) profile of the product (see also section 3.2 on Bridging Clinical
Studies). If comparability can be demonstrated through analytical studies alone, then,
nonclinical or clinical studies with the post change product are not necessary. However,
where the relationship between specific quality attributes and safety and efficacy has not
been established, and/ or differences are observed between some critical quality attributes of
the pre-change and post-change product, it may be necessary to include a combination of
quality, nonclinical and/or clinical studies in the comparability exercise.
3.2 Bridging Clinical Studies
A number of changes outlined in this guidance document include recommendations for
supporting by bridging clinical studies.
Clinical bridging studies are trials in which a parameter of interest (e.g. manufacturing
process, formulation, dosing schedule) is directly compared with a changed version of that
parameter with respect to the effect of the change on the product’s clinical performance.
Comparison of immune responses and safety outcomes (e.g. rates of common and serious
AEFIs) are often the primary objectives. If the immune response and safety profiles are
similar, the safety and efficacy of the vaccine can be inferred.Guidance for Industry
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If the physicochemical properties, biological activity, purity and/or level of impurities of the
pre-change and post change product are comparable, the safety and efficacy of the
biotherapeutics product can be inferred. However, nonclinical and/or clinical bridging studies
may be required when analytical data alone either do not establish comparability or are
insufficient to do so. The comparison of efficacy responses and safety outcomes (for
example, PK/PD profile, or rates of common adverse events and serious adverse events) is
often the primary objective.
a) For ethical reasons, it is desirable to apply the 3R principles (Replacement, Reduction,
Refinement) to the use of animals where scientifically appropriate. The following are
examples of changes that are likely to require nonclinical and/or clinical bridging
studies: generation of a new MCB derived from a different host cell line;
b) a new dosage form;
c) a new formulation (for example, a new excipient);
d) a new presentation (for example, addition of pre-filled pens to vials); (e) a new route of
administration; and
e) a new dosing schedule
For these and comparable changes, any proposed use of alternative approaches to a
bridging study must be justified and discussed with CDSCO
In some cases, safety and efficacy data comparing the approved vaccine to the vaccine
produced with the change (bridging studies) may be required. The following are examples of
manufacturing changes that may require clinical bridging studies:
use of a new or re-derived antigen (i.e. re-derived virus seed or bacterial cell bank) or
host cell line (i.e. re-derived master cell bank);
new agents used for inactivation or splitting of the antigen;
a new dosage form (e.g., lyophilized powder to liquid, Intramuscular to Subcutaneous,
oral to injectable).
a new formulation (e.g. amount of ingredients, adjuvants, preservatives, reactogenic
residual components from the manufacturing process).
MA holders should consult the applicable “The New Drugs and Clinical Trials Rules, 2019”,
ICH and WHO guidance documents when conducting clinical bridging studies.
3.3 Stability TestingGuidance for Industry
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If stability studies are recommended to support a change, these studies should be conducted
in accordance with applicable CDSCO, ICH and WHO guidance documents,
a. The New Drugs and Clinical Trials Rules, 2019
b. Stability Testing of New Drug Substances and Products (Q1A)
c. Stability Testing: Photostability Testing of New Drug Substances and Products (Q1B)
d. Stability Testing for New Dosage Forms (Q1C)
e. Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and
Products (Q1D)
f. Evaluation of Stability Data (Q1E)
g. Stability Testing of Biotechnological/Biological Products (Q5C)
h. Guidelines on stability evaluation of vaccines. In: WHO Expert Committee on
Biological Standardization: Fifty-Seventh report. Geneva: World Health Organization;
2011: Annex 3 (WHO Technical Report Series, No. 962).
3.4 Pharmaceutical Development and Quality by Design
The International Council for Harmonization (ICH) has developed two guidelines, Q11
Development and Manufacture of Drug Substances (Chemical Entities and
Biotechnological/Biological Entities) and Q8: Pharmaceutical Development and Q8 Annex
which describe respectively the suggested contents for the 3.2.S.2.2 to 3.2.S.2.6 sections
and for the 3.2.P.2 Pharmaceutical Development section of a regulatory submission in the
Common Technical Document (CTD) format.
The Pharmaceutical Development section is intended to provide a comprehensive
understanding of the product and manufacturing process for reviewers and inspectors.
The aim of pharmaceutical development is to design a quality product and its manufacturing
process to consistently deliver the intended performance of the product. The information and
knowledge gained from pharmaceutical development studies and manufacturing experience
provide scientific understanding to support the establishment of the design space,
specifications, and manufacturing controls.
Design space is proposed by the applicant, and is subject to regulatory assessment and
approval. Working within the design space is not considered as a change that would require
prior approval but should be documented with the requisite Change Controls where
necessary.Guidance for Industry
Central Drugs Standard Control Organization Page 19 of 119
Movement outside of the design space is considered to be a change and would normally
initiate a regulatory post approval change process.
For example, some of the Post Approval Changes that are listed in Post-Approval Changes
(Biologics) of this guidance document as Level I ‐ Supplements (Major Quality Changes) or
Level II ‐ Notifiable Changes (Moderate Quality Changes) may not require approval prior to
implementation if they are within the approved design space.
If desired, a MA holder may also establish a new design space for an existing product. This
would provide the advantage, once approved, of limiting the necessity to file future
submissions for changes within the ranges of the design space.
If proposed and approved, the details of the design space should be recorded in the PPD.
MA holders are encouraged to discuss with CDSCO when considering the establishment of a
design space.
3.5 Multiple Changes
Multiple related changes, involving various combinations of individual changes, may be
submitted in the same supplement. For example, a manufacturing site change may also
involve changes to the equipment and manufacturing process. For submissions that include
multiple changes, the marketing authorization holder should clearly specify which data
support each change. Multiple major or moderate quality changes for the same product may
be filed in a single submission provided that the changes are related and/or supported by the
same information. Minor quality changes that were implemented previously and that are
related and/or consequential to a moderate or major quality change should be described in
the Supplement change for the moderate or major quality change. If the proposed changes
are related, the marketing authorization holder should indicate the association between them.
The marketing authorization holder should also clearly specify which supporting data support
which change. Such changes could affect both the drug substance and the drug product. If
too many changes are filed within the same submission, or if major issues are identified with
a change and extensive time would be required to review them, the CDSCO may ask the
marketing authorization holder to divide the changes into separate submissions and to
resubmit the file. If the recommended reporting categories for the individual changes differ,
the submission should be in accordance with the most restrictive of the categories
recommended for the individual changes. In the case of numerous changes of the sameGuidance for Industry
Central Drugs Standard Control Organization Page 20 of 119
category, the CDSCO may reclassify the submission to the next higher level on the basis of
the potential impact of the totality of the changes on the quality, safety and efficacy of the
product. This reclassification should be communicated to the marketing authorization holder
at the start of the assessment.
In case where an identical change is applicable to multiple drugs, a single submission may
be submitted capturing the impacted products in the cover letter and supported with
appropriate data.
3.6 Post-Approval Change Management Protocol-PACMP
Post-approval change management protocol (PACMP) establishes a framework for a well-
defined plan for the future implementation of a quality change, including the tests to be done
and acceptable limits to be achieved to demonstrate the lack of negative effect of specific
manufacturing changes on the quality, safety or efficacy of a biological product. A
comparability protocol is a highly specific plan for the future implementation of a quality
change.
For some changes, the routine quality tests performed to release the drug substance or drug
product are not considered adequate for assessing the impact of the change, and additional
in-process tests and characterization tests may be needed (e.g. addition of bioburden and
endotoxin tests to support the removal of preservatives from the manufacturing process).
Comparability protocols are often used for routine replenishment of WCBs and reference
standards used in quality control tests when the remaining aliquots of reference standards
expire or diminish.
Comparability can be demonstrated for a particular step/stage of manufacture (eg. Upstream
manufacturing change could be evaluated within the drug substance manufacturing stage).
For such approach of comparability scientific justification should be provided without
generating drug product data for comparability.
The purpose of a comparability protocol is to allow for a more expedient distribution of a
product by permitting the MA holder to submit a protocol for a change which, if approved,
may justify a reduced reporting category for the change when the comparability data are
obtained and the change is implemented.
3.7 Production DocumentsGuidance for Industry
Central Drugs Standard Control Organization Page 21 of 119
Production documents (i.e. executed lot records) or topics related to GMP are in general not
required to support changes to the MA dossier or product license. However, such documents
may be requested and should be available during site GMP inspections.
3.8 Expedited Review Procedure (Reliance Pathway)
Expedited review/Reliance pathway can be considered in Biological products for priority
diseases to treat serious or life-threatening illness with unmet medical needs, in public health
emergencies or during shortages, and also for orphan products.
The CDSCO office could recognize the decision of recognized regulatory authorities
(Reference NRA) and may expedite the review of the change submission on case by case
basis, once the change is submitted through expedited review / reliance pathway procedure.
The CDSCO office performs an assessment of the decision of the recognized regulatory
authority to determine if recognition of that recognized regulatory authority decision is
appropriate. The submission consists of:
the cover letter from the MA holder informing the procuring NRA about the change;
a copy of the approval letter and assessment report issued by recognized reference
country;
a detailed description of the change along with supporting data.
If accepted, the review and approval timeline shall be expedited.
3.9 Similar Biotherapeutic Products (SBP) / Similar Biologics
Following approval, an SBP is considered to be independent from the reference product and
has its own life-cycle. The manufacturer is not required to re‐establish similarity to the
reference product when comparability exercises are conducted.
A major change in clinical use for an SBP that relies on the previously demonstrated
similarity provided in the original approval of the SBP may be considered by CDSCO on a
case-by-case basis. For example, a new indication given to the reference product after
approval of an SBP should not automatically be given to the SBP. However, when new safety
information on the reference product is added after the original approval of the SBP, the
labelling information changes of the SBP should follow the changes made for the referenceGuidance for Industry
Central Drugs Standard Control Organization Page 22 of 119
product unless it can be demonstrated that the new information on the reference product is
not relevant to the SBP.
4. POST APPROVAL CHANGES (BIOLOGICALS)
The change examples presented below are intended to assist with the classification
of changes made to the Quality, Safety, Efficacy and administrative information of biological
products. The information summarized in the tables provides recommendations for:
a. The conditions to be fulfilled for a given change to be classified under reporting category
as a either a Level I - Supplement, a Level II - Notifiable Change, or a Level III - Annual
Notification.
b. The supporting data for a given change, either to be submitted to the CDSCO and/or
retained as part of the drug product’s record by MA holder. If any of the supporting data
outlined for a given change are not provided, are different or are not considered
applicable, adequate scientific justification should be provided.
The supporting data should be provided in the appropriate sections of the CTD modules and
in the separate documents, wherever required.Guidance for Industry
Central Drugs Standard Control Organization Page 23 of 119
3.2.S DRUG SUBSTANCE
3.2.S.1 General Information
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
1. Change in the name of the drug
substance,
(e.g, change in name of drug substance
for seasonal influenza vaccine, Covid- Annual
1 1-3
19 vaccine, change in compendial Notification
name of drug substance, or change
from in-house to compendial name of
the drug substance)
Conditions
1. Confirmation that information on the drug substance has not changed as a result of the
submission (e.g., cross reference(s) should be provided to the previously approved drug
submission, quoting the date approved and approval number(s)).
Supporting Data
1. Product Monograph [e.g. Title Page, Storage and Stability (Part I), Dosage Forms,
Composition, Packaging] and Revised product labelling information (Package Insert, Inner
and Outer Labels), as applicable.
2. Information on the changed nomenclature of the drug substance (e.g., Recommended
INN, compendial name, chemical name(s)) (3.2.S.1.1).
3. Evidence that the changed name for the drug substance is recognized (e.g., proof of
acceptance by WHO, a copy of recommended INN, USAN, BAN).
3.2.S.2 Manufacture
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
2. Change to a drug substance manufacturing facility / suite or site / premises,
involving:
a. Replacement or addition of
1-6, 8-12, 15,
manufacturing facility / suite in a new 11 Supplement
16
geographical site / premises and / orGuidance for Industry
Central Drugs Standard Control Organization Page 24 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
manufacturer of the drug substance,
or any intermediate of the drug
substance
Note: MA holder shall submit MA application in Form CT-21/Form CT-18 in SUGAM with
applicable fees along with supporting documentation as described for the post approval
change category, for addition of manufacturer or for addition of manufacturing facility/suite,
for a drug substance, in a new geographical site/ premises, followed by an amendment /
endorsement of the current Form 28 D license, as applicable.
A declaration to state that no change to other remaining section/s of the MA dossier,
including impact on safety/efficacy, shall be submitted, as applicable.
b. replacement or addition of
manufacturing facility / suite to
1-6, 8-12, 15, Notifiable
manufacture drug substance or any 1-6
16 Change
intermediate of the drug substance in
existing manufacturing site / premises
c. conversion of a drug substance
Notifiable
manufacturing facility / suite from 4, 5 11, 12, 15
Change
single-product to multi-product
d. Conversion of production and related
Notifiable
area(s) from campaign to concurrent 5, 7 13, 15
Change
for a multiproduct facility / suite
e. introduction of yeasts/bacterial cell
Notifiable
culture into a multi-product microbial 3-5 11-13, 15
Change
fermentation facility / suite
f. Introduction of microbial hosts into a
multi‐product mammalian cell culture None 12, 14 Supplement
facility / suite or vice versa
g. introduction of a different host/media- Annual
8 7, 15
type into an approved multi-product NotificationGuidance for Industry
Central Drugs Standard Control Organization Page 25 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
facility / suite.
h. addition of product(s) to an approved
Annual
multi - product manufacturing suite / 4, 5, 8 12, 13
Notification
facility.
i. deletion of a manufacturing facility /
suite or manufacturer for a starting Annual
9, 10 None
material, bulk intermediate, or drug Notification
substance.
Conditions
1. The proposed manufacturing facility/suite is a CDSCO approved drug substance
manufacturing site / premises for the same MA holder.
2. No changes have been made to the validated manufacturing process and controls, and
identical or equivalent equipment are used.
3. The production process and controls are the same as those used by the. MA holder within
the existing approved facility.
4. No changes have been made to the approved and validated cleaning and change-over
procedures.
5. The proposed change does not involve additional containment requirements.
6. The facility / suite or site / premises is under same Quality system oversight
7. The manufacturing process is a closed process for shared areas.
8. No changes to the cleaning protocol are necessary to support the introduction of new
products (no changes in acceptance criteria, and no new materials have been introduced
that need to be evaluated for clearance in a cleaning step
9. There should remain at least one site/manufacturer, as previously authorized, performing
the same function as the one(s) to be deleted.
10. The deletion should not be due to critical deficiencies in manufacturing (for example,
recurrent out-of-specification events, environmental monitoring failures, etc.).
11. No changes have been made to the starting material and the expression system
Supporting Data
1. Updated or relevant DMF (CMC Module 3 Quality) data of drug substance. (3.2.S)Guidance for Industry
Central Drugs Standard Control Organization Page 26 of 119
2. Name, address, and responsibility of the changed production facility or facility involved in
manufacturing and testing. (3.2.S.2.1)
3. For drug substances obtained from or drug substances manufactured with reagents
obtained from sources that are at risk of transmitting BSE/TSE agents (e.g., ruminant
origin), information and evidence that the material does not pose a potential BSE/TSE risk
(e.g., name of manufacturer, species and tissues from which the material is a derivative,
country of origin of the source animals, its use and previous acceptance). A TSE
Certificate of Suitability (CEP) from a qualified laboratory, if available, is acceptable for
raw materials, auxiliary materials, and reagents only. This is also applicable for
substances used in conjugation or linkages processes. (3.2.S.2.3)
4. Information on the controls performed at critical steps of the manufacturing process and
on the intermediate of the changed drug substance, if revised (3.2.S.2.4).
5. Process validation and/or evaluation studies (e.g., for aseptic processing and
sterilization). (3.2.S.2.5).
6. Comparability of the approved and changed product with respect to physico–chemical
characterization, biological activity, impurity profile, comparability of the equipment and
operating principles for the manufacturing processes including technology transfer
documentation as applicable for the product at the existing vs the proposed new
facility/suite (3.2.S.2.6). (Occasionally, the manufacturer may be required to undertake
bridging non-clinical or clinical studies, to support the quality data, when quality data is
insufficient to establish comparability)
7. Information on the in-process control testing to demonstrate lack of carry-over or cross-
contamination (3.2.S.2.2).
8. Description of the batches, certificates of analyses, summary of in-process control results
and summary of results as quantitative data, in a comparative tabular format, for at least
three (3) commercial scale batches of the approved and changed drug substance
Matrixing, bracketing, use of smaller-scale batches, use of fewer than three batches
and/or leveraging data from scientifically justified representative batches, or batches not
necessarily manufactured consecutively, may be acceptable where justified (refer ICH
Q1D) (3.2.S.2.5 & 3.2.S.4.4)
9. Results of a) accelerated stability testing (usually a minimum of three (3) months) and b) a
minimum of three (3) months of real time/real temperature testing on three (3) commercialGuidance for Industry
Central Drugs Standard Control Organization Page 27 of 119
scale batches of the proposed changed drug substance, as well as commitment to submit
the stability report when completed and to notify CDSCO of any failures in the ongoing
stability studies (3.2.S.7.3). Matrixing, bracketing, the use of smaller scale batches and
use of fewer than 3 batches for stability testing of proposed changed drug substance may
be acceptable if scientifically justified (refer ICH Q1D) by the manufacturer /MA holder to
CDSCO.
10. Updated post-approval stability protocol and stability commitment to place the first
production scale batch of the drug product manufactured using the changed drug
substance into the stability programme, as applicable (3.2.S.7.2).
11. Information on the changed production facility involved in manufacturer of Drug
substance, including the complete set of floor plans and flow charts (drawings, room
classification, water systems, HVAC systems), as well as the cleaning and shipping
validation, as appropriate. (3.2.A.1)
12. Information describing the change-over procedures for shared product contact
equipment’s and the segregation procedures, as applicable. If no revisions, a statement
from the manufacturer that no changes were made to the change-over procedures.
13. Data demonstrating lack of carry-over or cross-contamination
14. Results of the environmental monitoring studies in critical classified areas.
15. Information on the cleaning procedures (including data in a summary validation report and
the master cleaning protocol for the introduction of new products, as applicable)
demonstrating lack of carry over or cross contamination
16. Evidence of GMP compliance of the facility
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
3. Change/Modification in a facility/ premises involved in the manufacture of a drug
substance, such as:
a. for an active ingredient manufactured
in an open system, any changes
Notifiable
which affect the trends or action limits None 1, 2, 5
Change
of the environmental monitoring
programGuidance for Industry
Central Drugs Standard Control Organization Page 28 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
b. relocation of equipment to another
room in the same facility/suite/
premises or another approved facility / Annual
1-3 3-5
suite/ premises, Qualification of a new Notification
room or change in classification of an
existing room
c. Modification to a manufacturing area
or to an existing service / system Annual
1, 2 3-5
(e.g., change to WFI systems or Notification
HVAC systems, moving a wall).
d. change in the location of steps in the
Annual
production process within the same 1 1, 4, 5
Notification
facility
Conditions
1. The change in the location of steps has no impact on the risk of contamination or cross-
contamination and is supported by validated cleaning procedures.
2. The modification has no direct product impact.
3. Re-qualification of the equipment follows the original qualification protocol, if applicable.
Supporting Data
1. Information on the in-process control testing (3.2.S.2.2).
2. Process validation and/or evaluation studies or the proposed validation protocol of the
changed drug substance, including technology transfer validation, equipment qualification,
as appropriate (3.2.S.2.5).
3. Information demonstrating re-qualification of the equipment or re- qualification of the
change (operational qualification, performance qualification), as appropriate. (3.2.A.1)
4. Information on the modified production facility/area involved in manufacturing, including
the floor plans and flow charts (drawings, room classification, water systems, HVAC
systems). (3.2.A.1)
5. Results of the environmental monitoring studies in critical classified areas.Guidance for Industry
Central Drugs Standard Control Organization Page 29 of 119
Conditions to Supporting Reporting
Description of change
be fulfilled data category
4. Change to the drug substance fermentation, viral propagation or cellular
propagation process, involving:
a. a critical change with high potential to
have an impact on the quality of the
antigen / drug substance or final None 1-5, 7-11 Supplement
product (e.g. incorporation of
disposable bioreactor technology)
b. a change with moderate potential to
have an impact on the quality of the
1-5, 7, 8, 12, Notifiable
drug substance or final product (e.g. 2, 4
13 Change
extension of the in-vitro cell age
beyond validated parameters)
c. a non-critical change with minimal
potential to have an impact on the
quality of the drug substance or drug
product, such as
(e.g., change in harvesting and/or
pooling procedures which does not
affect the method of manufacture, Annual
1-5, 7-10, 12 1-6, 8, 12
recovery, storage conditions, Notification
sensitivity of detection of adventitious
agents, or production scale; or
duplication of a fermentation train; or
addition of identical or similar /
comparable bioreactors).
5. Change to the drug substance purification process involving:
a. a critical change (a change with high
potential to have an impact on the None 1-3, 5, 7-11 Supplement
quality of the drug substance or finalGuidance for Industry
Central Drugs Standard Control Organization Page 30 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
product)
(e.g. a change that could potentially
have an impact on the viral clearance
capacity of the process or the impurity
profile of the drug substance)
b. a change with moderate potential to
have an impact on the quality of the
drug substance or final product
1-3, 5, 7-9, Notifiable
(e.g. a change in the chemical 2, 4
11, 13 Change
separation method, such as ion-
exchange HPLC to reverse-phase
HPLC)
c. a noncritical change with minimal
potential to have an impact on the
quality of the drug substance or final Annual
1-5 1-3, 6, 8, 12
product (e.g. addition of an in-line Notification
filtration step equivalent to the
approved filtration step)
6. Change in scale of the manufacturing process:
a. at the fermentation, viral propagation Notifiable
3-5, 8, 9, 11, 12 2, 4, 7-10
or cellular propagation stage Change
Notifiable
b. at the purification stage 1-3, 5, 9 2, 7-10
Change
7. Change in the parameters of an
Notifiable
approved holding step or addition none 7, 16
Change
of a new holding stepGuidance for Industry
Central Drugs Standard Control Organization Page 31 of 119
Conditions
1. The change does not concern the method of sterilization of a sterile drug substance.
2. The change does not impact the viral clearance data or the source of a chemical nature of
an inactivating agent.
3. No change in the drug substance specifications outside of the approved limits.
4. No change in the impurity profile of the drug substance outside of the approved limits.
5. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
6. The change does not result in a change to the drug substance specification.
7. The scale-up consists in the addition of identical bioreactors/fermenter or new
fermentation train is identical to the to the approved fermentation train(s)
8. The change does not affect the purification process.
9. The scale-up is linear with respect to proportionality of production parameters and raw
materials.
10. No change in the approved in-vitro cell age
11. The change is not expected to have an impact on the quality, safety or efficacy of the final
product
12. The change in scale involves the use of the same bioreactor (i.e., does not involve the
use of a larger bioreactor)
Supporting Data
1. Justification for the classification of the change(s) as critical, moderate or non-critical as it
relates to the impact on the quality of the antigen/drug substance.
2. Flow diagram (including process and in-process controls) of the changed manufacturing
process(es) and a brief narrative description of the changed manufacturing process(es)
(3.2.S.2.2).
3. Information on the quality and controls of the materials (e.g., raw materials, starting
materials, solvents, reagents, catalysts) used in the manufacture of the changed drug
substance when there is change in the raw material (3.2.S.2.3)
4. If the change results in an increase in the number of population doublings or
subcultivations, information on the characterization and testing of the post-production cell
bank for recombinant product, or of the drug substance for non-recombinant product.Guidance for Industry
Central Drugs Standard Control Organization Page 32 of 119
(3.2.S.2.3)
5. For drug substances obtained from or manufactured with reagents obtained from sources
that are at risk of transmitting BSE/TSE agents (e.g., ruminant origin), information
assessing the risk with respect to potential contamination with adventitious agents and
evidence that the material does not pose a potential BSE/TSE risk, and there is no impact
on the viral clearance studies(e.g., name of manufacturer, species and tissues from which
the material is a derivative, country of origin of the source animals, its use and previous
acceptance) (3.2.S.2.3).
6. Information on the controls performed at critical steps of the manufacturing process and
on intermediates of the changed drug substance (3.2.S.2.4).
7. Process validation and/or evaluation studies (e.g., for aseptic processing and sterilization,
new reprocessing step, new or revised holding step) (3.2.S.2.5).
8. Comparability of the approved and changed product with respect to physico-chemical
characterization, biological activity, and impurity profile. Occasionally, bridging non-clinical
and/or clinical studies may be required when quality data are insufficient to establish
comparability. The extent and nature of nonclinical and/or clinical studies should be
determined on a case-by-case basis taking into consideration the quality comparability
findings, the nature and level of the knowledge of the biological, existing relevant
nonclinical and clinical data, and aspects of biological use (3.2.S.2.6).
9. Description of the batches, certificates of analyses, and summary of in-process and
release testing results as quantitative data, in a comparative tabular format, for at least
three (3) commercial scale batches of the approved and changed drug substance
(3.2.S.2.5 & 3.2.S.4.4). Matrixing, bracketing, the use of smaller scale batches, and/or the
use of less than 3 batches may be acceptable where justified (refer ICH Q1D)
10. Results of accelerated (usually a minimum of three (3) months) and a minimum of three
(3) months of real time/real temperature testing on three (3) commercial scale batches of
the changed drug substance as well as commitment to submit the stability report when
completed and to notify CDSCO of any failures in the ongoing stability studies (3.2.S.7.3).
Matrixing, bracketing, the use of smaller scale batches and use of fewer than 3 batches
for stability testing of proposed changed drug substance may be acceptable ifGuidance for Industry
Central Drugs Standard Control Organization Page 33 of 119
scientifically justified (refer ICH Q1D).
11. Updated post-approval stability protocol and stability commitment to place the first
production scale batch of the drug product manufactured using the changed drug
substance into the stability programme, as applicable (3.2.S.7.2).
12. Description of the batches and summary of in-process and release testing results as
quantitative data, in a comparative tabular format, for one (1) commercial batch of the
approved and proposed drug substance (3.2.S.2.5 & 3.2.S.4.4)
13. Comparative pre and post-change test results for the manufacturer’s characterised key
stability indicating attributes with at least one (1) commercial scale batch produced with
the proposed changes under real time/real temperature testing conditions. Comparative
pre-change test results do not need to be generated concurrently; relevant historical
results for lots on the stability programme are acceptable. The data should cover a
minimum of 3 months testing unless otherwise justified (3.2.S.7.3)
14. Rationale for considering the bioreactors as similar/comparable, if applicable
15. Data describing the root cause triggering the reprocessing as well as validation data (e.g.,
extended hold times, resistance to additional mechanical stress) to support that the
reprocessing does not have an impact on the antigen/drug substance.
16. Demonstration that the new or revised holding step has no negative impact on the quality
of the drug substance (data from one scientifically justified representative drug substance
batch should be provided). (3.2.S.2.5)
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
8. Changes to the cell bank:
a. generation of new Master Cell Bank
(MCB) from the same expression Notifiable
1 1, 5-8
construct with same or closely related Change
cell line; orGuidance for Industry
Central Drugs Standard Control Organization Page 34 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
generation of a new MCB from a
different expression construct with the
same coding sequence and the same
None 1-8 Supplement
cell line, or
adaptation of a MCB into a new
fermentation medium.
b. generation of a new MCB for a Notifiable
1 1-3, 5-7
recombinant product or a viral vaccine Change
c. generation of a new Working Cell Annual
2-4 1, 2
Bank (WCB) Notification
d. Extension of Shelf-life of the MCB or Annual
7 1, 2
WCB Notification
9. Changes to the Seed Bank/Lot:
a. new Master Seed Bank/Lot
None 1, 3-8 Supplement
(MSB/MSL).
b. Working Seed Bank/Lot (WSB/WSL)
Notifiable
extended beyond an approved None 3-8
Change
passage level.
Annual
c. Generation of a new WSB/WSL. 2-4 3, 4
Notification
10. Change in cell bank / seed bank/lot Notifiable
None 1, 2, 9
manufacturing site Change
11. Changes in cell bank / seed bank/lot Annual
5, 6 9
testing / Storage site Notification
Notifiable
None 10, 11
12. Change in cell bank / seed bank/lot Change
qualification protocol Annual
6, 8 11
NotificationGuidance for Industry
Central Drugs Standard Control Organization Page 35 of 119
Conditions
1. The new MCB is generated from the original clone or a pre-approved Master or Working
Cell Bank or the new MSL is generated from a pre-approved MSL or WSL.
2. The new cell/seed bank is generated from a pre-approved MCB/MSB/pre-master
bank/parent strain.
3. The new cell/seed bank is at the pre-approved passage level.
4. The new cell/seed bank is released according to a pre-approved protocol.
5. No changes have been made to the test or acceptance criteria used for the release of cell
bank/ seed lot.
6. No changes have been made to the storage conditions used for the cell bank/seed lot and
transport conditions of the cell bank/ seed lot has been validated.
7. The testing to support the extension of shelf‐life is performed according to the pre‐
approved protocol.
8. The protocol is considered more stringent (that is, addition of new tests or narrowing of
acceptance criteria).
Supporting Data
1. Qualification of the cell bank or seed lot. (3.2.S.2.3)
2. Information on the characterization and testing of the post-production cell bank for
recombinant product, or of the product for non-recombinant product. (3.2.S.2.3)
3. Comparability of the approved and changed product with respect to physico-chemical
characterization, biological activity, and impurity profile
4. Description of the batches, certificates of analyses, and summary of results as
quantitative data, in a comparative tabular format, for the new seed lot (3.2.S.2.3).
5. Description of the batches, certificates of analyses, and summary of in-process and
release testing results as quantitative data, in a comparative tabular format, for at least
three (3) commercial scale batches of the drug substance derived from the new cell/seed
bank (. Matrixing, bracketing, the use of smaller-scale batches, and/or the use of fewer
than 3 batches may be acceptable where justified (refer ICH Q1D) (3.2.S.2.5 & 3.2.S.4.4).
6. Results of accelerated (usually a minimum of three (3) months) and a minimum of three
(3) months of real time/real temperature testing on three (3) commercial scale batches of
the proposed changed drug substance as well as commitment to submit the stability
report when completed and to notify CDSCO of any failures in the ongoing stabilityGuidance for Industry
Central Drugs Standard Control Organization Page 36 of 119
studies (3.2.S.7.3). Matrixing, bracketing, the use of smaller-scale batches, the use of
fewer than 3 batches and/or use of accelerated temperature conditions for stability testing
may be acceptable where justified (refer ICH Q1D).
7. Updated post-approval stability protocol and stability commitment to place the first
production scale batch of the drug product using the changed drug substance into the real
time/real temperature stability programme (3.2.S.7.2).
8. Supporting non-clinical and clinical data or a request for a waiver of in-vivo studies.
9. Evidence that the new company or facility is GMP compliant.
10. Justification of the change to the cell bank/seed lot qualification protocol (3.2.S.2.3)
11. Updated cell bank/seed lot qualification protocol (3.2.S.2.3)
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
13. Change in product-contact equipment / material used in drug substance
manufacturing process, such as:
a. Introduction of equipment having Notifiable
None 1-3, 5-7
different operating principles / Change
properties and different product Annual
1-3 1-3, 7
contact material Notification
Notifiable
b. Introduction of new equipment having None 1, 5-7
Change
same operating principles / properties
Annual
but different product contact material 1-3 1, 3, 6, 7
Notification
c. Introduction of new equipment having Notifiable
None 1, 2, 5, 7
different operating principles/ Change
properties but same product contact Annual
3 1-3, 5, 7
material Notification
d. Replacement of product contact
Annual
equipment for an identical/ equivalent 6 1, 3, 5, 7, 8
Notification
equipment.
e. product‐contact equipment change Annual
4, 5 1, 4
from dedicated to shared NotificationGuidance for Industry
Central Drugs Standard Control Organization Page 37 of 119
Conditions
1. The change does not affect equipment used in the Fermentation process.
2. The manufacturing process is not impacted by the change in the product contact
equipment.
3. The change has no impact on product quality.
4. The site is approved as multi‐product facility by CDSCO.
5. The change has no impact on the risk of cross‐contamination and is supported by
validated cleaning procedures.
6. The change is considered “like for like” (e.g., change in supplier of the same filter).
Supporting Data
1. Information on the in-process control testing. (3.2.S.2.2)
2. Process validation and/or evaluation studies or the proposed validation protocol of the
changed drug substance, including technology transfer validation, as appropriate.
(3.2.S.2.5)
3. Information on qualification or demonstrating re-qualification of the equipment or re-
qualification of the change
4. Information describing the change‐over procedures for the shared product‐contact
equipment.
5. Description of the batches and summary of results as quantitative data, in a comparative
tabular format, for one commercial scale batch of the drug substance produced with the
approved and proposed product contact equipment/material. Batch data on the next two
full-production batches should be made available on request and reported by the MA
holder if outside specification (with proposed action). (3.2.S.4.4)
6. Information on leachables and extractables as applicable.
7. Information on the new equipment and comparison of similarities and differences
regarding operating principles and specifications between the new and the replaced
equipment
8. Demonstration that performance of the proposed equipment is equivalent to the approved
equipment (i.e. data from one batch)
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data CategoryGuidance for Industry
Central Drugs Standard Control Organization Page 38 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
14. Change in the specifications of materials, involving:
a. Change in supplier of auxiliary Notifiable
None 12, 13-16
materials / reagents of biological Change
origin (e.g., fetal calf serum, insulin, Annual
16 12, 13
human serum albumin, trypsin) Notification
b. Change in source of auxiliary Notifiable
None 6, 12, 14-16
materials / reagents of biological Change
origin (e.g., fetal calf serum, insulin, Annual
16 6, 12
human serum albumin, trypsin) Notification
c. raw materials/intermediates: Notifiable
None 1, 3, 4, 6, 7
widening of the approved Change
specifications limits for starting
materials, which may have a
Annual
significant effect on the overall 1-3, 12, 13 1, 3-8, 12
Notification
quality of the drug substance and/or
final product.
d. raw materials/intermediates:
Narrowing of the approved Annual
1, 2, 6, 7 1, 3-5, 7, 13
specification limits for starting Notification
materials/ intermediates
Annual
e. solvents, reagents, catalysts 1, 2, 7 1, 3-5
Notification
Annual
f. Change in raw materials testing site 6 11
Notification
15. Change to the in-process test and/or acceptance criteria applied during the
manufacture of drug substance or on Intermediate, involving:
Notifiable
None 2, 13, 14
Change
a. narrowing of in-process limits
Annual
1, 3, 8, 9 2, 7
NotificationGuidance for Industry
Central Drugs Standard Control Organization Page 39 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
b. replacement or addition of new in- Annual
2-5, 8-11 2-5, 7-9, 13, 14
process test Notification
c. deletion of a non-significant in- 1-3, 5, 8, 12, 14, Annual
2, 7, 10, 13
process test 15 Notification
d. widening of the approved in-process Notifiable
None 2-9, 13, 14
limits, which may have a significant Change
effect on the overall quality of the Annual
1-3, 12 2, 6-9
drug substance Notification
e. deletion of an in-process test which
may have a significant effect on the Annual
None 2, 6, 7, 9
overall quality of the antigen/drug Notification
substance
f. addition or replacement of an in-
Notifiable
process test as a result of a safety None 2-7, 9
Change
or quality issue
g. revision as per updated Annual
1, 2 2
pharmacopoeia Notification
16. Change in in-process control
testing site
Note: Transfer of in-process control testing
Annual
to a different facility within a GMP-
1-3, 8, 11 11
compliant site is not considered to be a Notification
reportable change but is treated as a minor
GMP change (Level IV) and is reviewed
during inspections
Conditions
1. No change in the drug substance specifications outside of approved ranges, except for
revision as per updated pharmacopoeia.
2. No change in the impurity profile of the drug substance outside the approved limits.
3. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.Guidance for Industry
Central Drugs Standard Control Organization Page 40 of 119
4. Any new analytical procedure does not concern a novel non-standard technique or a
standard technique used in a novel way.
5. The change does not affect the principle of sterilization of a sterile drug substance.
6. The change in specification for the materials is within the approved limit except for
revision as per updated pharmacopoeia.
7. The grade of the materials is same or is of higher quality, where appropriate.
8. No change in the in-process controls outside the approved limits.
9. The test procedure remains the same, or changes in the test procedure are minor.
10. The test method is not a biological/immunological/immunochemical or physicochemical
method or a method using a biological reagent (does not include standard
pharmacopoeial microbiological methods).
11. The replaced analytical procedure maintains or tightens precision, accuracy, specificity
and sensitivity, if applicable.
12. The test does not concern the critical attribute (e.g. content, impurity, any physical
characteristics or microbial purity.)
13. The change has no significant effect on the overall quality of the drug substance and/or
drug product and there are no changes to the cell banks
14. The deleted test has been demonstrated to be redundant with respect to the remaining
tests
15. The deleted test is not for a viral clearance/removal step
16. The change is for compendial auxiliary materials/reagents of biological origin (excluding
human plasma derived materials).
Supporting Data
1. Revised information on the quality and controls of the materials (e.g., raw materials,
starting materials, solvents, reagents, catalysts) used in the manufacture of the changed
drug substance (3.2.S.2.3).
2. Revised information on the controls performed at critical steps of the manufacturing
process and on intermediates of the changed drug substance (3.2.S.2.4).
3. Updated specifications of the drug substance, if affected by the change (3.2.S.4.1).
4. Copies or summaries of analytical procedures, if new analytical procedures are used
(3.2.S.4.2).
5. Copies or summaries of validation reports, if new analytical procedures are usedGuidance for Industry
Central Drugs Standard Control Organization Page 41 of 119
(3.2.S.4.3).
6. Description of the batches, certificates of analyses, and summary of in-process and
release testing results (as quantitative data), in a comparative tabular format, for at least
three (3) commercial scale batches of the approved and changed drug substance.
(3.2.S.2.5 & 3.2.S.4.4). Matrixing, bracketing, the use of smaller-scale batches, the use of
fewer than three batches and/or leveraging data from scientifically justified representative
batches, or batches not necessarily manufactured consecutively, may be acceptable
where justified (refer ICH Q1D)
7. Comparative table or description, where applicable, of pre- and post-change in-process
tests/limits.
8. Results of accelerated and a minimum of three (3) months of real time/real temperature
testing on three (3) commercial scale batches of the proposed changed drug substance
are available as well as commitment to submit the stability report when completed and to
notify CDSCO of any failures in the ongoing stability studies (3.2.S.7.3). Matrixing,
bracketing, the use of smaller scale batches and use of fewer than 3 batches for stability
testing of proposed changed drug substance may be acceptable if scientifically justified
(refer ICH Q1D) by the manufacturer /MA holder and agreed by CDSCO.
9. Justification for the new in-process test and limits.
10. Justification/risk assessment showing that the attribute is non-significant.
11. Evidence that new company/facility is GMP-compliant.
12. For drug substance obtained from, or manufactured with, reagents obtained from sources
that are at risk of transmitting bovine spongiform encephalopathy/ transmissible
spongiform encephalopathy (BSE/TSE) agents (for example, ruminant origin), information
and evidence that the material does not pose a potential BSE/TSE risk (for example,
name of manufacturer, species and tissues from which the material is a derivative,
country of origin of the source animals, use and previous acceptance of the material)
(3.2.S.2.3)
13. Description of the batches, certificates of analyses, and summary of in-process and
release testing results (as quantitative data), in a comparative tabular format, for at least
one (1) commercial batch of the approved and changed drug substance. Batch data on
the next two full-production batches should be made available on request and reported by
the MA holder if outside specification (with proposed action). The use of a smaller-scaleGuidance for Industry
Central Drugs Standard Control Organization Page 42 of 119
batch may be acceptable where justified. (3.2.S.2.5 & 3.2.S.4.4)
14. Rationale for the change supported by data.
15. Information demonstrating comparability of the auxiliary materials/reagents or starting
materials of both sources
16. Information assessing the risk with respect to potential contamination with adventitious
agents (eg. Impact on the viral clearance studies, BSE/TSE risks)
Conditions to be Supporting Reporting
Description of Change
Fulfilled Data Category
17. Change in the approved design space, involving:
a. establishment of a new design space None 1 Supplement
b. expansion of the approved design
None 1 Supplement
space
c. reduction in the approved design
space (any change that reduces or Annual
1 1
limits the range of parameters used to Notification
define the design space
Conditions
1. The reduction in design space is not necessitated by recurring problems having arisen
during manufacture.
Supporting Data
1. Manufacturing development data to support the establishment or changes to the design
space (including changes to process parametric release for sterile products) (3.2.S.2.6)
3.2.S.3 Characterization
There are not any quality change examples for this section at the present time that have not
been addressed in other sections.
3.2.S.4 Control of the Drug Substance
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
18. Change in the standard / monograph (i.e., specifications) claimed for the drugGuidance for Industry
Central Drugs Standard Control Organization Page 43 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
substance, involving:
a. change from the Pharmacopoeial
Notifiable
standard or a monograph to an in-house None 1-3, 5, 7
Change
standard
b. change in the standard claimed for the Notifiable
None 1-6
drug substance (e.g., from in-house to Change
pharmacopoeial standard) or from one
pharmacopoeial standard/monograph to Annual
1-3 1-3
a different/pharmacopoeial Notification
standard/monograph
c. change in the specifications for the drug
substance to comply with an updated
pharmacopoeial monograph
Note: Change in specifications and
Annual
analytical procedures for the drug 1, 2 1-3
Notification
substance to comply with an updated
pharmacopoeial monograph within 6
months of pharmacopoeia update should be
captured under Level IV changes
Conditions
1. The change is made exclusively to comply with the (applicable) pharmacopoeia /
standard.
2. No change to the specifications for functional properties of the drug substance, outside
the approved ranges.
3. No deletion or relaxation to any of the tests, analytical procedures, or acceptance criteria
of the approved specifications except to comply with pharmacopoeial standard /
monograph.
Supporting Data
1. Revised product labelling information (Package Insert, Inner and Outer Labels), as
applicable.Guidance for Industry
Central Drugs Standard Control Organization Page 44 of 119
2. Updated, copy of changed/proposed drug substance specifications (3.2.S.4.1).
3. Where an in-house analytical procedure is used and a standard is claimed, results of an
equivalency study between the In-house and compendial methods.
4. Description of the batches, certificates of analyses, and summary of results, in a tabular
format, for at least three (3) commercial scale batches of the changed drug substance
(3.2.S.4.4).
5. Justification of the changed drug substance specifications (e.g., demonstration of the
suitability of the monograph to control the drug substance, including impurities)
(3.2.S.4.5).
6. Demonstration that consistency of quality and of the production process is maintained.
7. Copies or summaries of validation reports, if new analytical procedures are used
(3.2.S.4.3).
Conditions to be Supporting Reporting
Description of Change
Fulfilled Data Category
19. Changes in the control strategy of the drug substance, involving:
a. Change from end‐product testing to
upstream controls for some test(s)
None 1-5 Supplement
(e.g., Real‐Time Release Testing,
process analytical technology)
b. Addition of a new Critical Quality Notifiable
None 1-5
Attribute (CQA) in the control strategy Change
c. Deletion of a Critical Quality Attribute Notifiable
None 1, 5
(CQA) from the control strategy Change
Conditions:
None
Supporting Data
1. Information on the controls performed at critical steps of the manufacturing process and
on intermediates of the proposed drug substance (3.2.S.2.4)
2. Updated, copy of the changed/proposed drug substance specifications (or where
applicable, the final version of the specifications to be signed by QC after CDSCO
approval), if changed (3.2.S.4.1)
3. Copies or summaries of analytical procedures, if new analytical procedures are used.Guidance for Industry
Central Drugs Standard Control Organization Page 45 of 119
(3.2.S.4.2)
4. Copies or summaries of validation reports, if new analytical procedures are used.
(3.2.S.4.3)
5. Justification and supporting data for each proposed change to the control strategy.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
20. Changes affecting the quality control (QC) testing of the drug substance (release
and stability), involving:
a. transfer of the QC testing activities for Notifiable
None 1, 2
a non-pharmacopoeial assay (in‐ Change
house) to a new company/premises,
to a different facility within the same
company/premises or to a different Annual
1-4 1, 2
laboratory within the same facility not Notification
approved in the current market
authorization or license.
b. transfer of the QC testing activities for Notifiable
None 1, 2
a pharmacopoeial assay to a new Change
company/premises not approved in
Annual
the current market authorization or 2 1, 2
Notification
license.
Conditions
1. The transfer involves the relocation of the equipment and laboratory staff to the new
laboratory or facility.
2. The transferred QC test is not a potency assay or a bioassay.
3. No changes are made to the test method.
4. The transfer is within a facility approved in the current marketing authorization for the
performance of other tests
Supporting Data
1. Information demonstrating technology transfer qualification for the non‐pharmacopoeial
assays or verification for the pharmacopoeial assays (3.2.S.2.5).Guidance for Industry
Central Drugs Standard Control Organization Page 46 of 119
2. Evidence that the new company/facility is GMP compliant.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
21. Change in the test for Drug Substance at Release / Shelf life involving:
Notifiable
None 1, 6, 7
Change
a. deletion of a test
Annual
1, 7 1, 6
Notification
Notifiable
None 1-6
Change
b. replacement or addition of a test
Annual
1, 2, 8 1-3, 6
Notification
Notifiable
c. relaxation of an acceptance criterion None 1, 6, 7
Change
Annual
d. tightening of an acceptance criterion 1, 2, 4, 9 1
Notification
Conditions
1. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
2. The change is within the range of approved acceptance criteria.
3. Any new analytical procedure does not concern a novel, non-standard technique or a
standard technique used in a novel way.
4. Acceptance criterion for residuals are within recognized or approved acceptance limits,
e.g., within ICH limits for Class 3 residual solvent or pharmacopoeial requirements.
5. The deleted analytical procedure has been demonstrated to be redundant with respect to
the remaining analytical procedures.
6. The change does not concern sterility testing.
7. The analytical procedure/test is deleted in-line with the updated pharmacopoeia /
Standard; or there is no change in the compliance status of applicable pharmacopoeia /
Standard (e.g. The deleted test is the Abnormal Toxicity Test/General Safety Test).
8. The addition of test is not to monitor new impurity species.Guidance for Industry
Central Drugs Standard Control Organization Page 47 of 119
9. The analytical procedures remain the same or changes to analytical procedure are minor.
Supporting Data
1. Updated drug substance specifications (3.2.S.4.1).
2. Copies or summaries of analytical procedures, if new analytical procedures are used
(3.2.S.4.2).
3. Copies or summaries of validation reports, if new analytical procedures are used
(3.2.S.4.3).
4. Where an in -house analytical procedure is used and a Pharmacopoeial standard is
claimed, results of an equivalency study between the In-house and compendial methods.
5. Description of the batches, certificates of analyses, and summary of results, in a tabular
format, for at least three (3) commercial scale batches of the changed drug substance
(3.2.S.4.4).
6. Justification of the changed drug substance specifications (e.g., test parameters,
acceptance criteria, or analytical procedures) (3.2.S.4.5).
7. Documented evidence that consistency of quality and of the production process is
maintained.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
22. Change in the analytical procedures for the drug substance, involving
Notifiable
1 1, 5
Change
a. deletion of an analytical procedure.
Annual
1, 6 1, 5
Notification
Notifiable
None 1-5
b. replacement or addition of an analytical Change
procedure. Annual
5, 7, 8 1-5
Notification
c. minor changes to an approved Annual
1-3, 5, 8 1, 4, 5
analytical procedure. Notification
d. a change from an in-house analytical Annual
1, 5 1-3
procedure to a Pharmacopoeial NotificationGuidance for Industry
Central Drugs Standard Control Organization Page 48 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
analytical procedure.
e. change in animal species/strains for a
test (e.g., new species/strains, animals
Notifiable
of different age, new supplier where None 6, 7
Change
genotype of the animal cannot be
confirmed)
Conditions
1. No change in the acceptance criteria outside of the approved ranges.
2. The method of analysis is the same and is based on the same analytical technique or
principle (e.g., a change in column length or temperature, but not a different type of
column or method) and no new impurities are detected.
3. Results of method validation demonstrate that the proposed analytical procedure is at
least equivalent to the approved analytical procedure.
4. Any new analytical procedure does not concern a novel, non-standard technique or a
standard technique used in a novel way.
5. The change does not concern potency testing.
6. The analytical procedure is deleted in-line with the updated pharmacopoeia / Standard; or
there is no change in the compliance status of applicable pharmacopoeia / Standard.
7. The change is from a pharmacopoeial assay to another pharmacopoeial assay.
8. The modified analytical procedure maintains or improves performance parameters of the
method.
Supporting Data
1. Updated drug substance specifications (3.2.S.4.1).
2. Copies or summaries of analytical procedures, if new analytical procedures are used
(3.2.S.4.2).
3. Copies or summaries of validation reports, if new analytical procedures are used
(3.2.S.4.3).
4. Comparative results demonstrating that the approved and changed analytical procedures
are equivalent.
5. Justification of the changed drug substance specifications (e.g., test parameters,Guidance for Industry
Central Drugs Standard Control Organization Page 49 of 119
acceptance criteria, or analytical procedures) (3.2.S.4.5).
6. Data demonstrating that the change in animals/strains give comparable results with those
obtained using the approved animals/strains.
7. Copies of relevant certificate of fitness for use (e.g., veterinary certificate).
3.2.S.5 Reference Standards or Materials
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
23. Change in reference standards or materials used to release the drug substance,
involving
a. qualification of a new reference Notifiable
None 1
standard Change
b. update the reference standards from
Notifiable
pharmacopoeial / international None 1, 5
Change
standard to an in-house
c. update the reference standards from
Annual
an in-house to pharmacopoeial / 2 1, 5
Notification
international standard
d. Qualification of a new lot of
reference standard (except for a Annual
2 1, 5
bacterial or viral vaccine, bacterial Notification
toxin)
24. Qualification of a new lot of reference standard against the approved reference
standard for a bacterial or viral vaccine, bacterial toxin, involving:
a. reference standard used in a
qualitative test, physicochemical test, Annual
2 1
semi‐quantitative or quantitative Notification
biological assay
b. Change to reference standard Notifiable
None 3, 4
qualification protocol (except for a Change
bacterial or viral vaccine, bacterial Annual
4 3, 4
toxin) NotificationGuidance for Industry
Central Drugs Standard Control Organization Page 50 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
25. Change to reference standard qualification protocol for a bacterial or viral vaccine,
bacterial toxin, involving:
a. a reference standard used in a Annual
None 3, 4
qualitative test Notification
b. a reference standard used in a
physicochemical test, semi‐ Annual
4 3, 4
quantitative or quantitative biological Notification
assay.
26. Extension of reference standard Annual
3 2
shelf-life / Re-test period Notification
Conditions
1. The in -house reference standard is calibrated against an official (e.g., pharmacopoeial/
NIBSC/WHO/EDQM/NCL) reference standard.
2. Qualification of the reference standard is performed according to the approved protocol
(i.e. no deviation from the approved protocol).
3. The extension of the shelf-life / re-test is according to an approved protocol.
4. The protocol is considered more stringent (i.e., addition of new tests or tightening of
acceptance criteria). If deletion of tests is proposed, the tests proposed to be deleted
were not implemented to monitor the quality of the reference standard (e.g., was
implemented for research or validation work).
Supporting Data
1. Information demonstrating qualification of the changed reference standards or materials
(e.g., source, characterization, certificate of analysis). (3.2.S.5)
2. Summary of stability testing and results to support the extension of reference standard
shelf-life. (3.2.S.5)
3. Justification of change to the reference standard qualification protocol.
4. Updated reference standard qualification protocol.
5. Justification for change in the reference standard.Guidance for Industry
Central Drugs Standard Control Organization Page 51 of 119
3.2.S.6 Container Closure System
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
Notifiable
27. Change in the primary container None 1-3, 5
Change
closure system(s) for the storage
Annual
and shipment of the drug substance 1 1, 4, 5
Notification
Conditions
1. Proposed container closure system is at least equivalent to the approved container
closure system with respect to its relevant properties (including results of transportation or
compatibility studies, if appropriate).
Supporting Data
1. Information on the changed container closure system (e.g., description, specifications)
(3.2.S.6).
2. Results of accelerated and a minimum of three (3) months of real time/real temperature
testing of the 3 commercial scale batches of changed drug substance (3.2.S.7.3), as well
as commitment to submit the stability report when completed and to notify CDSCO of any
failures in the ongoing stability studies.
3. Data demonstrating the suitability of the container closure system (for example,
extractable/leachable testing) and compliance with pharmacopoeial standards, if
applicable.
4. Results demonstrating that the proposed container closure system is at least equivalent to
the approved container closure system with respect to its relevant properties (e.g. results
of transportation or interaction studies, extractable/leachable studies).
5. Comparative table of pre and post-change specifications.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
28. Change in the supplier for a primary container involving:
Notifiable
None 1-3
a. replacement or addition of supplier. Change
1, 2 None AnnualGuidance for Industry
Central Drugs Standard Control Organization Page 52 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
Notification
Annual
b. deletion of supplier. None None
Notification
Conditions
1. No change in the type of container closure, materials of construction or in the sterilization
process for a sterile container closure component.
2. No change in the specifications of the container closure component outside of the
approved ranges.
Supporting Data
1. Data demonstrating the suitability of the container closure system (e.g.,
extractable/leachable testing).
2. Information on the proposed container closure system (e.g., description, materials of
construction of primary packaging components, specifications).
3. Stability test results from: a) accelerated testing and b) a minimum of three (3) months of
real time/real temperature testing on three (3) commercial scale batches of the proposed
drug substance are available, as well as commitment to notify CDSCO of any failures in
the ongoing long term stability studies. (3.2.S.7.3).
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
29. Change in the specification/analytical procedure of the primary container system
for the Drug Substance, involving:
Annual
a. deletion of test 1, 2 1, 2
Notification
Annual
b. addition of test 3 1-3
Notification
c. replacement of an analytical Annual
6, 7 1-3
procedure Notification
d. minor changes to an analytical Annual
4-7 1-3
procedure Notification
e. widening of an acceptance criteria None 1, 2 NotifiableGuidance for Industry
Central Drugs Standard Control Organization Page 53 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
Change
Annual
f. narrowing of an acceptance criteria 8 1
Notification
Conditions
1. The deleted test has been demonstrated to be redundant compared to the remaining tests
or is no longer a pharmacopoeial requirement.
2. The change to the specification does not affect the functional properties of the container
closure component nor result in a potential impact on the performance of the antigen/drug
substance.
3. The change is not necessitated by unexpected recurring events arising during
manufacture or because of stability concerns.
4. There is no change in the acceptance criteria outside the approved limits.
5. The new analytical procedure is of the same type.
6. Results of method validation demonstrate that the new or modified analytical procedure is
at least equivalent to the approved analytical procedure.
7. The new or modified analytical procedure maintains or tightens precision, accuracy,
specificity and sensitivity.
8. The change is within the range of approved acceptance criteria or has been made to
reflect a new pharmacopoeial monograph specification for the container closure
component.
Supporting Data
1. Updated copy of the proposed specification for the primary container closure system.
(3.2.S.6)
2. Rationale for the change in specification for a primary container closure system.
3. Description of the analytical procedure and, if applicable, validation data. (3.2.S.6)
3.2.S.7 Stability
Conditions to be Supporting Reporting
Description of Change
Fulfilled Data Category
30. Change in the shelf life of drug substance or for a stored intermediate of the drugGuidance for Industry
Central Drugs Standard Control Organization Page 54 of 119
Conditions to be Supporting Reporting
Description of Change
Fulfilled Data Category
substance, involving:
Notifiable
None 1-4, 6
Change
a. Extension
Annual
1-5 1, 2, 5
Notification
Notifiable
None 1-5
Change
b. Reduction
Annual
6 2-4
Notification
Conditions
1. No change to the container closure system in direct contact with the drug substance or to
the recommended storage conditions of the drug substance.
2. The approved shelf life is at least 24 months.
3. Full long term stability data are available covering the changed shelf life and are based on
stability data generated on at least three production scale batches.
4. Stability data were generated in accordance with the approved stability protocol.
5. Significant changes (as defined in ICH’s Q1A guideline) were not observed in the stability
data.
6. The reduction in the shelf-life is not necessitated by recurring events arising during
manufacture or because of stability concerns.
Supporting Data
1. Summary of stability testing and results (e.g., studies conducted, protocols used, results
obtained). (3.2.S.7.3)
2. Proposed storage conditions and shelf life as appropriate.
3. Updated post-approval stability protocol and stability commitment. (3.2.S.7.2)
4. Justification of the change to the post-approval stability protocol or stability commitment.
5. Results of stability testing (i.e. full real time/real temperature stability data covering the
changed shelf life generated on at least three (3) production scale batches). (3.2.S.7.3).
For intermediates, data to show that the extension of shelf‐life has no negative impact on
the quality of the drug substance
6. Interim stability testing results and a commitment to notify CDSCO of any failures in theGuidance for Industry
Central Drugs Standard Control Organization Page 55 of 119
ongoing long term stability studies. Extrapolation of shelf‐life should be made in
accordance with ICH Q1E guideline. For intermediates, data to show that the extension of
shelf‐life has no negative impact on the quality of the drug substance (i.e., batch analysis
on three (3) commercial scale batches). (3.2.S.7.3).
Conditions to be Supporting Reporting
Description of Change
Fulfilled Data Category
31. Change in the labelled storage conditions for the drug substance, involving:
Notifiable
None 1-5
Change
a. addition of a cautionary statement.
Annual
1 1-5
Notification
Annual
b. deletion of a cautionary statement. None 2-4, 6
Notification
c. addition or change of storage Notifiable
None 1-5
condition for the drug substance (e.g. Change
widening or narrowing of a Annual
1, 2 2-5
temperature criterion). Notification
Conditions
1. The change is not necessitated by recurring events arising during manufacture or
because of stability concerns.
2. The change consists in the narrowing of a temperature criterion within the approved
ranges.
Supporting Data
1. Results of stability testing (i.e., full real time/real temperature stability data covering the
proposed shelf life generated on one (1) commercial scale batch) (3.2.S.7.3).
2. Revised product labelling information (Package Insert, Inner and Outer Labels), as
applicable.
3. Proposed storage conditions and shelf life.
4. Justification of the change in the labelled storage conditions/cautionary statement.
5. Updated post-approval stability protocol and stability commitment (3.2.S.7.2).
6. Results of stability testing (i.e., full real time/real temperature stability data covering the
proposed shelf‐life generated on at least three (3) commercial scale batches). (3.2.S.7.3)Guidance for Industry
Central Drugs Standard Control Organization Page 56 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
32. Change to the post-approval stability protocol of the drug substance, involving:
a. Major / significant change to the post- Notifiable
None 1-6
approval stability protocol or stability Change
commitment such as deletion of a test,
Annual
replacement of an analytical procedure, 1, 4 2-6
Notification
change in storage temperature.
b. addition of time point(s) into the post- Annual
None 2, 3
approval stability protocol. Notification
c. addition of test(s) into the post-approval Annual
2 2-6
stability protocol. Notification
d. deletion of time point(s) from the post-
Annual
approval stability protocol beyond the None 2, 3
Notification
approved shelf life.
e. deletion of time point(s) from the post-
Annual
approval stability protocol within the 3 2-4
Notification
approved shelf life.
Conditions
1. For the replacement of an analytical procedure, the new analytical procedure maintains or
tightens precision, accuracy, specificity and sensitivity.
2. The addition of test(s) is not due to stability concerns or to the identification of new
impurities.
3. Deletion of time point(s) is made according to ICH Q5C.
4. For the replacement of an analytical procedure, the results of method validation
demonstrate that the new analytical procedure is at least equivalent to the approved
analytical procedure
Supporting Data
1. Proposed storage conditions and shelf life as appropriate.
2. Updated post-approval stability protocol and stability commitment (3.2.S.7.2).
3. Justification of the change to the post-approval stability protocol or stability commitment.
4. If applicable, stability testing results to support the change to the post- approval stabilityGuidance for Industry
Central Drugs Standard Control Organization Page 57 of 119
protocol or stability commitment (e.g., data to show greater reliability of the alternate test).
(3.2.S.7.3)
5. Copies or summaries of analytical procedures, if new analytical procedures are used
(3.2.S.4.2).
6. Validation study reports, if new analytical procedures are used (3.2.S.4.3).Guidance for Industry
Central Drugs Standard Control Organization Page 58 of 119
3.2.P DRUG PRODUCT
3.2.P.1 Description and Composition of the Drug Product
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
33. Change in the description or composition of the drug product, involving:
a. addition of a dosage form or change
in the formulation (e.g. lyophilized
powder to liquid, change in the None 1-12, 16 Supplement
amount of excipient, new diluent for
lyophilized product)
b. addition of a new strength (e.g. 50 1, 2-6, 8, 10,
None Supplement
mg dose vs 100 mg dose) or change 11, 16
in the concentration of the active
Notifiable
ingredient (e.g. 20 unit/mL vs 20 1-3, 5 1, 2, 6, 8, 16
Change
unit/2 mL)
Note: For these changes that are considered as “New Drugs” as per “The New Drugs and
Clinical Trials Rules, 2019, MA holder should submit MA application in Form CT-21/Form CT-
18 in SUGAM, with applicable fee, along with supporting documentation as described for the
respective post approval change category, followed by an amendment / endorsement of
current Form 28 D license, as applicable.
A declaration to state that no change to other remaining section/s of the MA dossier shall be
submitted, as applicable.
c. addition of a new presentation (e.g.
addition of syringes to vial/ prefilled
syringe/cartridge where the approved 2, 3, 6, 8-10, Notifiable
None
presentation in a vial or vice a versa, 13-15 Change
addition of single dose or multi-dose
vial)
d. change in fill volume (same None 2, 6, 8, 10, 11 Supplement
concentration, different volume) 1, 4 2, 6, 8, 10 NotifiableGuidance for Industry
Central Drugs Standard Control Organization Page 59 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
Change
Annual
1, 4, 5 6, 8, 10
Notification
Conditions
1. No change in dose is recommended
2. New concentration is bracketed by existing approved concentrations
3. More than 2 concentration are already approved (i.e. linear PK/PD profile of the product
from at least three different concentration over the bracketed range has been
demonstrated and two extreme concentration of the bracketed range have been shown to
be bio-equivalent or therapeutically equivalent
4. No changes are classified as major in the manufacturing process to accommodate the
new fill volume
5. The change involves narrowing the fill volume while maintaining the lower limit of
extractable volume
Supporting Data
1. Updated or new relevant CMC (Module 3 Quality) data of drug product. (3.2.P)
2. Revised Drug Product Labelling information i.e. Package Insert, Inner and Outer Labels,
as applicable.
3. Confirmation that information on the drug substance has not changed as a result of the
submission (e.g., cross reference(s) should be provided to the previously approved drug
submission, quoting the date approved and file Number(s)) or revised information on the
drug substance, if any of the attributes have changed.
4. Description and composition of the dosage form, if there are changes to the composition
or dose (3.2.P.1).
5. Discussion of the components of the drug product, as appropriate (e.g., choice of
excipients, compatibility of drug substance and excipients, leachates, compatibility with
new container closure system)
6. Batch Formula, Description of Manufacturing Process and Process Controls, Controls of
Critical Steps and Intermediates, Process Validation and/or Evaluation in appropriate CTD
sections. (3.2.P.3.2, 3.2.P.3.3. 3.2.P.3.4 & 3.2.P.3.5)Guidance for Industry
Central Drugs Standard Control Organization Page 60 of 119
7. Control of Excipients, if new excipients are proposed (e.g., specifications, confirmation
that none of the excipients are prohibited by the Regulations) (3.2.P.4).
8. Information on Specification(s), Analytical Procedures (if new analytical methods are
used), Validation of Analytical Procedures (if new analytical methods are used) (3.2.P.5.1,
3.2.P.5.2, 3.2.P.5.3), Batch Analyses (certificate of analysis for three commercial-scale
batches should be provided). (3.2.P.5.4). Bracketing for multiple strength products,
container sizes and / or fill volumes may be acceptable if scientifically justified (refer ICH
Q1D).
9. Information (including description, materials of construction, summary of specifications) on
the container closure system, if any of the components have changed (3.2.P.7).
10. Comparative pre change and post change test results of three (3) months accelerated
and real time/real temperature testing on three (3) commercial scale batches of the
changed drug product, as well as commitment to submit the stability report when
completed and to notify CDSCO of any failures in the ongoing stability studies (3.2.P.8.3).
Matrixing, bracketing, the use of smaller scale batches and use of fewer than 3 batches
for stability testing of proposed changed drug product may be acceptable if scientifically
justified (refer ICH Q1D) by the manufacturer /MA holder to CDSCO.
11. Supporting clinical data or scientific/ clinical justification for not performing additional
clinical study
12. Data demonstrating comparability of the new dosage form and/or formulation.
13. Supporting clinical data (usually PK/PD only) or scientific/clinical justification for not
performing additional clinical study.
14. The new device (e.g., pre-filled syringes, cartridge or pens), approval letter from the
CDSCO, as applicable.
15. Information on container closure system and extractables /leachable if any of components
have changed.
16. Duly Signed Form CT-18/Form CT-21 with applicable fee.
3.2.P.1 Description and Composition of the Drug Product: Change to an adjuvant
Reporting
Conditions to Supporting
Description of Change
be Fulfilled Data CategoryGuidance for Industry
Central Drugs Standard Control Organization Page 61 of 119
Reporting
Conditions to Supporting
Description of Change
be Fulfilled Data Category
34. Change involving a chemical / synthetic adjuvant
Notifiable
None 3-6
a. change in supplier of a chemical / Change
synthetic adjuvant Annual
2, 3 4
Notification
Notifiable
None 2-6
b. change in manufacture of a chemical / Change
synthetic adjuvant Annual
2, 3 8-10
Notification
c. change in release specifications of a Notifiable
None 5, 6, 8-10
chemical/ synthetic adjuvant (including Change
the tests and/or the analytical Annual
2, 4 8-10
procedures Notification
35. Change involving a biological adjuvant
a. change in supplier of a biological
None 1-8, 11-13 Supplement
adjuvant.
1-6, 8, 11,
None Supplement
b. change in manufacture of a biological 12
adjuvant Notifiable
1 1-4, 8, 11
Change
5, 6, 8-10, Notifiable
c. change in the release specifications of a None
12 Change
biological adjuvant (including the tests
Annual
and/or the analytical procedure). 2, 4 8-10
Notification
Conditions
1. The change does not concern the source of the adjuvant.
2. The specification of the adjuvant is equal to or narrow than the approved limits (i.e.
narrowing of acceptance criterion).
3. The adjuvant is an aluminium salt.
4. The change in specification consists in the addition of a new test or in a minor change to
an analytical procedure.Guidance for Industry
Central Drugs Standard Control Organization Page 62 of 119
Supporting Data
1. Information on the quality and controls of the materials (e.g., raw materials, starting
materials, solvents, reagents, catalysts) used in the manufacture of the changed adjuvant.
2. Flow diagram of the proposed manufacturing process (es), a brief narrative description of
the proposed manufacturing process (es), and information on the controls performed at
critical steps of the manufacturing process and on intermediates of the changed adjuvant.
3. Process validation and/or evaluation studies (e.g., for manufacturing of the adjuvant).
4. Description of the general properties, characteristic features and characterization data of
the product
5. Description of the batches, certificates of analyses, and summary of results, in a
comparative tabular format, for at least three (3) commercial scale batches of the drug
product with the approved and changed adjuvant, as applicable. (3.2.P.5.4).
6. Results of accelerated and a minimum of three (3) months of real time/real temperature
testing on three (3) batches of the changed adjuvant as well as commitment to submit the
stability report when completed and to notify CDSCO of any failures in the ongoing
stability studies (3.2.P.8.3). Matrixing, bracketing, the use of smaller scale batches and
use of fewer than 3 batches for stability testing of proposed changed drug product may be
acceptable if scientifically justified (refer ICH Q1D) by the manufacturer /MA holder to
CDSCO.
7. Supporting non-clinical and clinical data or scientific/clinical justification for not performing
additional clinical studies if in vitro tests are sufficient to prove comparability.
8. Updated copy of the proposed specification for the adjuvant (3.2.P.4.1).
9. Copies or summaries of analytical procedures, if new analytical procedures are used
(3.2.P.4.2).
10. Validation study reports, if new analytical procedures are used (3.2.P.4.3).
11. Information assessing the risk with respect to potential contamination with adventitious
agents (e.g. impact on the viral clearance studies, BSE/TSE risk).
12. Comparability of the pre- and post-change adjuvant with respect to physicochemical
properties, biological activity, purity, impurities and contaminants, as appropriate.
Nonclinical and/or clinical bridging studies may occasionally be required when quality data
are insufficient to establish comparability. The extent and nature of nonclinical and clinical
studies should be determined on a case-by-case basis, taking into consideration the
quality comparability findings, the nature and level of knowledge of the adjuvant, existing
relevant nonclinical and clinical data, and aspects of vaccine use.Guidance for Industry
Central Drugs Standard Control Organization Page 63 of 119
13. Evidence of facility GMP compliance.
3.2.P.1 Description and Composition of the Drug Product: Change to a diluent
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
36. Change to the diluent, involving:
Notifiable
None 1-6, 12
a. replacement or addition of a source of a Change
diluent Annual
1-3 2, 4, 5
Notification
Notifiable
None 2-6
b. change in manufacturing process of a Change
diluent Annual
1, 3 2-5
Notification
Notifiable
c. change in specification of a diluent (Eg. None 2, 5, 7-11
Change
deletion or replacement or addition of
Annual
test) 5-10 2, 5, 7-11
Notification
Annual
d. tightening of an acceptance criteria 5, 6 2, 5, 7-11
Notification
Notifiable
e. relaxation of an acceptance criteria 5, 7-10 2, 5, 7-11
Notification
f. change in facility used to manufacture a Annual
1, 2 2, 4, 6
diluent (same company) Notification
Annual
g. addition of a diluent filling line 1, 2, 4 2, 4, 6
Notification
h. addition of a diluent into an approved Annual
1, 2 2-5, 13
filling line Notification
Annual
i. deletion of a diluent None None
Notification
ConditionsGuidance for Industry
Central Drugs Standard Control Organization Page 64 of 119
1. The diluent is water for injection or a salt solution (including buffered salt solutions) (i.e. it
does not include an ingredient with a functional activity, such as a preservative) and there
is no change to its composition.
2. After reconstitution, there is no change in the final product specification outside the
approved limits.
3. The proposed diluent is commercially available in the NRA country.
4. The addition of the diluent filling line is in an approved filling facility.
5. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
6. The change is within the range of approved acceptance criteria.
7. Any new analytical procedure does not concern a novel, non-standard technique or a
standard technique used in a novel way.
8. Acceptance criterion for any Class 3 residual solvent is within the ICH limits.
9. The change to the specifications does not result in a potential impact on the performance
of the drug product.
10. The change does not concern sterility testing.
Supporting Data
1. Demonstration that the changed diluent results in the same properties of the product as
with the approved diluent.
2. Description of the batches, certificates of analyses, and summary of results, in a
comparative tabular format, for at least three (3) commercial scale batches of the
approved and changed diluent.
3. Results of accelerated and a minimum of three (3) months of real time/real temperature
testing (3.2.P.8.3) of the changed diluent and updated stability of the product
reconstituted with the new diluent (3.2.P.8.3). Matrixing, bracketing, the use of smaller
scale batches and use of fewer than 3 batches for stability testing of proposed changed
diluent may be acceptable if scientifically justified (refer ICH Q1D) by the manufacturer
/MA holder to CDSCO.
4. Flow diagram including process and in-process controls of the proposed manufacturing
process(es) and a brief narrative description of the proposed manufacturing process(es).
5. Updated copy of the proposed specification for the diluent (3.2.P.5.1).
6. Evidence that the facility is GMP-compliant.Guidance for Industry
Central Drugs Standard Control Organization Page 65 of 119
7. Copies or summaries of analytical procedures, if new analytical procedures are used
(3.2.P.5.2).
8. Copies or summaries of validation reports, if new analytical procedures are used
(3.2.P.5.3).
9. Where a house analytical procedure is used and a Pharmacopoeial standard is claimed,
results of an equivalency study between the house and compendial method.
10. Justification of the changed diluent specifications (e.g. demonstration of the suitability of
the monograph to control the diluent, including degradation products.
11. Demonstration that consistency of quality and of the production process is maintained.
12. Revised product labelling information (Package Insert, Inner and Outer Labels), as
applicable.
13. Cleaning procedures (including data in a summary validation report) demonstrating lack of
carryover / cross contamination.
3.2.P.2 Pharmaceutical Development
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
37. Change in the approved design space, involving :
a. establishment of a new design
None 1 Supplement
space
b. expansion of the approved design
None 1 Supplement
space
c. reduction in the approved design
space (any change that reduces or Annual
1 1
limits the range of parameters used Notification
to define the design space
Conditions
1. The reduction in design space is not necessitated by recurring problems having arisen
during manufacture.
Supporting Data
1. Pharmaceutical development data to support the establishment or changes to the design
space (3.2.P.2)Guidance for Industry
Central Drugs Standard Control Organization Page 66 of 119
3.2.P.3 Manufacture
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
38. Changes involving a drug product manufacturing facility / premise (site):
a. replacement or addition of a drug None 1-10 Supplement
product manufacturing facility /
suite in new geographical site / Notifiable
1-6 1, 3, 4, 6, 7-10
premises. (including formulation / Change
filling and primary packaging)
Note: For these changes, MA holder shall submit MA application in Form CT-21/Form CT-18
in SUGAM with applicable fees along with supporting documentation as described for the
post approval change category, for addition of manufacturing facility/suite, for a drug product,
in a new geographical site/ premises, followed by an amendment / endorsement of the
current Form 28 D license, as applicable.
A declaration to state that no change to other remaining section/s of the MA dossier,
including impact on safety/efficacy, shall be submitted, as applicable.
None 3-6, 8-14 Supplement
b. replacement of a formulation /
3, 4, 6-10, 12- Notifiable
filling suite. 1, 7
13 Change
c. addition of an equivalent Notifiable
1 3, 4, 6, 8-10
formulation / filling suite Change
d. replacement or addition of a
secondary packaging including
Annual
secondary functional packaging / 2, 3 1-4
Notification
labelling / storage and distribution
facility
e. qualification of a new room or
Annual
change in classification of an 8, 9 11-13
Notification
existing room.
f. deletion of a drug product Annual
10 None
manufacturing facility NotificationGuidance for Industry
Central Drugs Standard Control Organization Page 67 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
g. modification to a manufacturing
area or modification to an existing
Annual
service/system (e.g., change to 8, 9 11-13
Notification
WFI systems or HVAC systems,
moving a wall)
Conditions
1. The formulation/filling facility is approved facility or site (premises) is approved by
licensing authority.
2. No change in the composition, manufacturing process or drug product specifications.
3. No change in the container/closure system and storage conditions.
4. The same validated manufacturing process is used.
5. The newly introduced product is in the same family of product(s) or therapeutic
classification as the one of those already approved at the site and uses the similar/
comparable filling process/equipment.
6. The Site / Premise are under same Quality system oversight and owned by same legal
entity.
7. The new formulation/filling suite is equivalent to the approved formulation/filling suite.
8. The change has no impact on the risk of contamination or cross‐contamination.
9. The modification has no product impact.
10. The deletion should not be due to critical deficiencies in manufacturing (for example,
recurrent out-of-specification events, environmental failures, etc.).
Supporting Data
1. Evidence that the facility is GMP-compliant.
2. Updated relevant drug product CMC (3.2.P) Sections.
3. Confirmation that information on the drug product has not changed as a result of the
submission (e.g., other than change in facility) or revised information on the drug product,
if any of the attributes have changed.
4. Name, address, and responsibility of the changed production facility involved in
manufacturing and testing.
5. Description of the manufacturing process if different from the approved process andGuidance for Industry
Central Drugs Standard Control Organization Page 68 of 119
information on the controls performed at critical steps of the manufacturing process and
on the intermediate of the changed drug product.
6. Process validation and/or evaluation studies (3.2.P.3.5) or the proposed validation
protocol of the changed drug product is acceptable, but data could be requested,
including technology transfer validation, equipment qualification, media fills, as
appropriate, bracketing for multiple strength products, container sizes and /or fills may be
acceptable if scientifically justified (refer ICH Q1D).
7. Description of the batches, certificates of analyses, and summary of results, in a
comparative tabular format, for at least three (3) commercial scale batches of the
approved and changed drug product (3.2.P.5.4), Bracketing for multiple strength products,
container sizes and /or fills may be acceptable if scientifically justified (refer ICH Q1D).
8. Results of a minimum of three (3) months of accelerated and three (3) months of real
time/real temperature testing on three (3) commercial scale batches of the changed drug
product as well as commitment to submit the stability report when completed and to notify
CDSCO of any failures in the ongoing stability studies (3.2.P.8.3). Bracketing for multiple
strength products, container sizes and /or fills may be acceptable if scientifically justified
(refer to ICH Q1D).
9. Rationale for considering the proposed formulation/filling suite as equivalent.
10. Commitment to place the first batch of the drug product manufactured using the proposed
formulation/filling suite into the stability programme, and to notify CDSCO of any failures
in ongoing long-term stability studies.
11. Information demonstrating re‐qualification of the equipment or re‐qualification of the
change (e.g. operational qualification, performance qualification), as appropriate.
12. Information on the proposed production facility involved in the manufacture of the drug
product, including the complete set of floor plans and flow charts (drawings, room
classification, water systems, HVAC systems), as well as the cleaning and shipping
validation, as appropriate.
13. Results of the environmental monitoring studies in classified areas.
14. Information describing the change‐over procedures for shared product‐contact equipment
or the segregation procedures, as applicable. If no revisions, a signed attestation that no
changes were made to the change‐over procedures.Guidance for Industry
Central Drugs Standard Control Organization Page 69 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
39. Change in a facility involved in the manufacture of a drug product, such as:
a. conversion of a drug product
Notifiable
manufacturing facility from single- None 1-3
Change
product to multiproduct
b. conversion of production and related
area(s) from campaign to concurrent Notifiable
1 1, 2, 4
for multiple product manufacturing Change
areas
c. introduction of new product into an
Annual
approved multiproduct formulation / 2-4 1-4
Notification
filling suite
Conditions
1. The manufacturing process is a closed process.
2. The newly introduced product does not introduce significantly different risk issues (i.e.,
cytotoxic drugs to cytokine manufacturing area).
3. The newly introduced product is not of significantly different strength (i.e., mg vs µg).
4. The maximum allowable carry-over is not affected by the introduction of the new product.
Supporting Data
1. Information on the cleaning procedures (including validation) demonstrating lack of carry-
over or cross-contamination.
2. Information describing the change-over procedures for shared product- contact
equipment or the segregation procedures, as appropriate. If there are no revisions, the
manufacturer should state that no changes were made to the changeover procedures.
3. Information on the product(s) which share the same equipment (e.g., therapeutic
classification).
4. Risk assessment summary.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
40. Changes involving a drug product manufacturing process:Guidance for Industry
Central Drugs Standard Control Organization Page 70 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
a. critical change with high potential to
Notifiable
have an impact on the quality of final None 1-6
Change
product
b. non critical change with low potential
Annual
to have impact on the quality of the of 1-4 1-5
Notification
final product
c. addition of a new step (e.g. filtration Notifiable
4 1-7
step) Change
d. scale-up of the manufacturing
process at the formulation / filling
Notifiable
stage (e.g. Increase in Blend size or 2, 4-6 1, 3-5, 8, 10
Change
increase of batch size loaded in the
lyophilizer)
e. addition of a new scale bracketed by
the approved scales or Scale-down of Annual
2, 4-7 1, 3-5, 8, 9
the manufacturing process at the Notification
formulation / filling stage
Conditions
1. No change in the drug product specifications.
2. The change does not affect the method of sterilization of the drug product.
3. No change in the excipients / preservative.
4. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
5. The scale-up or scale down uses the similar/ comparable approved equipment (Note:
Change in equipment size is not considered as using similar/comparable equipment).
6. Any changes to the manufacturing process and/or to the in-process controls are only
those necessitated by the change in batch-size (e.g., the same formulation, controls,
standard operating procedures (SOPs) are utilized).
7. Change does not affect the lyophilization step. If the proposed change affects the
lyophilization cycle, then lower and upper cycle should be validated.Guidance for Industry
Central Drugs Standard Control Organization Page 71 of 119
Supporting Data
1. Flow diagram of the changed manufacturing process (es) and a brief narrative
description of the changed manufacturing process (es) (3.2.P.3.3).
2. Information on the quality and controls of the materials (e.g., excipients) used in the
manufacture of the changed drug product (3.2.P.4).
3. Information on the controls performed at critical steps of the manufacturing process and
on intermediates of the changed drug product (3.2.P.3.4).
4. Process validation and/or evaluation studies (e.g., for aseptic processing and
sterilization) (3.2.P.3.5).
5. Description of the batches, certificates of analyses, and summary of results, in a
comparative tabular format, for at least three (3) commercial scale batches of the
approved and changed drug product (3.2.P.5.4).
6. Results of accelerated and three (3) months of real time/real temperature testing on three
(3) commercial scale batches of the changed drug product as well as commitment to
submit the stability report when completed and to notify CDSCO of any failures in the
ongoing stability studies (3.2.P.8.3). Matrixing, bracketing, the use of smaller scale
batches and use of fewer than 3 batches for stability testing of proposed changed drug
product may be acceptable if scientifically justified (refer ICH Q1D) by the manufacturer
/MA holder to CDSCO.
7. Information on leachable and extractables, as applicable.
8. Rationale for regarding the equipment as similar or comparable, as applicable.
9. Commitment to place the first production batch of the final product manufactured using
the proposed scale into the stability programme, and to notify the CDSCO if any failure in
the ongoing stability studies.
10. The results of stability studies that have been carried out under ICH conditions, on the
relevant stability parameters, on at least one pilot or industrial scale batch, covering a
minimum period of 3 months, and an assurance is given that these studies will be
finalised, and that data will be provided immediately to the competent authorities if
outside specifications or potentially outside specifications at the end of the approved
shelf life (with proposed action).
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data CategoryGuidance for Industry
Central Drugs Standard Control Organization Page 72 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
41. Change in equipment used in drug product manufacturing process, such as:
a. replacement or addition of new Notifiable
None 1-3, 5, 7-9
equipment used in a critical step Change
(e.g., lyophilizer, formulation tank, Annual
1 1, 3, 5, 6
filling line and head) Notification
Notifiable
b. product contact equipment change None 1, 3, 4
Change
from dedicated to shared (e.g.,
Annual
formulation tank, lyophilizer) 2, 3 1, 3, 4, 10
Notification
Conditions
1. Replacement of equipment with equivalent equipment; the change is considered “Like to
Like” (i.e. in terms of product contact material, equipment size, operating principle).
2. The site is approved as multi‐product facility by CDSCO.
3. The change has no impact on the risk of cross‐contamination and is supported by
validated cleaning procedures.
Supporting Data
1. Information on the in-process control testing, as applicable.
2. Process validation and/or evaluation studies (3.2.P.3.5) or the proposed validation
protocol of the changed drug product, including technology transfer validation, equipment
qualification, media fills, as appropriate.
3. Information demonstrating qualification of the equipment or qualification of the change.
4. Information on the cleaning procedures (including validation) demonstrating lack of carry-
over or cross-contamination.
5. Information on new equipment and comparison of similarities and differences regarding
operating principles and specifications between the new and the replaced equipment.
6. Rationale to support the equipment as similar/ comparable, as applicable.
7. Description of manufacturing process, if different from the approved process, and
information on the controls performed at critical steps of the manufacturing process and
on the intermediate of the proposed drug product. (3.2.P.3.3)
8. Description of the batches and the summary of in-process controls and release testingGuidance for Industry
Central Drugs Standard Control Organization Page 73 of 119
results as quantitative data in a comparative tabular format for at least three commercial
scale batches of the pre-change and post change drug product. (3.2.P.3.3)
9. Results of accelerated and three (3) months of real time/real temperature testing on three
(3) commercial scale batches of the changed drug product as well as commitment to
submit the stability report when completed and to notify CDSCO of any failures in the
ongoing stability studies (3.2.P.8.3). Matrixing, bracketing, the use of smaller scale
batches and use of fewer than 3 batches for stability testing of proposed changed drug
product may be acceptable if scientifically justified (refer ICH Q1D) by the manufacturer
/MA holder to CDSCO
10. Information describing the change‐over procedures for the shared product‐contact
equipment
Conditions to Supporting Reporting
Description of Change Conditions
be Fulfilled Data Category
42. Change in the controls (in-process tests and/or acceptance criteria) applied during
the manufacturing process or on intermediates
a. Deletion of an in-process test
which may have a significant effect Notifiable
None 1, 2, 4-6, 8, 11
on the overall quality of the drug Change
product
b. deletion of a non-significant in Annual
1, 4, 5, 7, 10, 13 2, 11, 12
process test Notification
c. replacement or addition of an in- Annual
1-4, 6-8 1, 2, 4, 6, 8
process test Notification
1, 2, 4, 6, 7, Notifiable
None
d. relaxation of an acceptance 10, 11 Change
criterion Annual
1, 7, 8 2, 6, 8, 11
Notification
e. tightening of an acceptance Annual
1, 2, 7, 12 1, 12
criterion Notification
f. addition or replacement of an in- Notifiable
None 1-4, 6, 8, 10,11
process test as a result of a quality ChangeGuidance for Industry
Central Drugs Standard Control Organization Page 74 of 119
Conditions to Supporting Reporting
Description of Change Conditions
be Fulfilled Data Category
and safety issue
g. change in in-process control testing
site.
Note: Transfer of in-process control
Annual
testing to a different facility within a GMP
1, 6-9, 11 9
compliant site is not considered to be a Notification
reportable change but it is treated as a
minor GMP change (Level IV) and
reviewed during inspections.
Conditions
1. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
2. The change is within the range of approved acceptance criteria.
3. Any new analytical procedure does not concern a novel, non-standard technique or a
standard technique used in a novel way.
4. The changed test does not affect the sterility of a sterile drug product. or no change in the
principle of the sterilization procedures of the drug product.
5. The deleted test has been demonstrated to be redundant with respect to the remaining
tests.
6. The replaced or added analytical procedure maintains or tightens precision, accuracy,
specificity, sensitivity.
7. No change in the impurity profile of the final product outside the approved limits.
8. No change in final product specification outside the approved limits.
9. No change in the in-process control limits outside the approved limits.
10. The deleted test is not for a viral clearance/removal step.
11. No Level II changes are made to the approved in‐process tests and/or acceptance
criteria.
12. Test procedure remains the same, or changing in test procedures are minor.
13. The test does not concern a critical attribute (for example, content, impurities, any critical
physical characteristics or microbial purity).
Supporting Data
1. Description of the changed process controls or acceptance criteria (comparative table ofGuidance for Industry
Central Drugs Standard Control Organization Page 75 of 119
current and proposed change).
2. Description of the changed process controls or acceptance criteria of the critical steps
and intermediates (3.2.P.3.4).
3. Method validation for any new analytical procedure. (3.2.P.5.3)
4. Copies or summaries of analytical procedures, if new analytical procedures are used.
(3.2.P.5.2)
5. Description of the batches, certificates of analyses, and summary of results, in a tabular
format, for at least one production scale batch (3.2.P.5.4).
6. Rationale/justification for change in process test and limits supported by data.
7. Data to show that the relaxation has not a negative impact on the quality of the batch.
Results for at least one (1) batch are required.
8. Description of the batches, certificates of analyses, and summary of results, in a
comparative tabular format, for at least three (3) commercial scale batches of the
approved and changed drug product (3.2.P.5.4). Batch data on next two full production
batches should be made available on request and reported by the MA holder if out-side
specification (with proposed actions). Use of smaller scale batch may be acceptable,
where justified.
9. Evidence that the new company/facility is GMP-compliant.
10. Updated Drug Product specification if changed (3.2.P.5.1)
11. Description of the batches and summary of in-process control and release testing results
as quantitative data, in a comparative tabular format for three commercial scale batches
of the pre-change and post change drug product (CoA should be provided) (3.2.P.3.5
and 3.2.P.5.4).
12. Justification/risk assessment showing that the attributes is non-significant.
3.2.P.4 Control of Excipients
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
43. Change in the standards / monograph for Excipients
Notifiable
a. change in the standard / monograph None 1-4
Change
claimed for the excipient (e.g., from an
Annual
in-house to pharmacopoeial standard) 1-3 1-4
NotificationGuidance for Industry
Central Drugs Standard Control Organization Page 76 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
b. change in the standard claimed for the
Notifiable
excipient (e.g., from pharmacopoeial None 1-4
Change
standard to in-house)
Conditions
1. The change is made exclusively to comply with the (applicable) Pharmacopoeia/
Standard.
2. No change to the specification for the functional properties of the excipient (e.g., particle
size distribution) outside the approved range, or that results in a potential impact on the
performance of the drug product.
3. No deletion of or relaxation to any of the tests, analytical procedures, or acceptance
criteria of the approved specification except to comply with pharmacopoeial standard/
monograph.
Supporting Data
1. Updated excipient specifications (3.2.P.4.1).
2. Where a In-house analytical procedure is used and a Pharmacopoeial standard is
claimed, results of an equivalency study between the In-house and compendial methods.
3. Justification of the changed excipient specifications (e.g., demonstration of the suitability
of the monograph to control the excipient and potential impact on the performance of the
drug product) (3.2.P.4.4). Comparative table/description wherever applicable of current
and proposed specifications
4. Demonstration that consistency of quality and of the production process is maintained.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
44. Change in the specifications used for release of the excipient, involving:
Note: This change excludes adjuvants
Notifiable
None 1-4
Change
a. deletion of a test
Annual
5, 7 1-4
Notification
b. replacement of a test None 1-4 NotifiableGuidance for Industry
Central Drugs Standard Control Organization Page 77 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
Change
Annual
1-4, 6, 8, 9 1-4
Notification
Notifiable
None 1-4
Change
c. addition of a test
Annual
4 1-3
Notification
Notifiable
None 1-4
Change
d. relaxation of an acceptance criterion
Annual
1, 3, 4, 6 1-4
Notification
Annual
e. tightening of an acceptance criterion 1-4, 6, 10 1-4
Notification
Conditions
1. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
2. The change is within the range of approved acceptance criteria or has been made to
reflect the new pharmacopoeial monograph specification for the excipient
3. Any new analytical procedure does not concern a novel, non-standard technique or a
standard technique used in a novel way.
4. Acceptance criterion for residual solvents are within the recognized or approved
acceptance limits (for example, within ICH limits for class 3 residual solvent or
pharmacopoeial requirements).
5. The deleted test has been demonstrated to be redundant with respect to the remaining
tests or is no longer a pharmacopoeial requirement.
6. The change to the specifications does not affect the functional controls of the excipient
(e.g., particle size distribution) nor result in a potential impact on the performance of the
drug product.
7. An alternative test analytical procedure is already authorized for this specification
attributes/test.
8. Results of method validation demonstrate that the proposed analytical procedures are atGuidance for Industry
Central Drugs Standard Control Organization Page 78 of 119
least equivalent to the approved analytical procedure.
9. The replaced analytical procedures maintain or improves precision, accuracy, specificity
and sensitivity.
10. The analytical procedures remain the same, or changes in the test procedure are minor.
Supporting Data
1. Updated excipient specifications (3.2.P.4.1).
2. Where an In-house analytical procedure is used and a Pharmacopoeial standard is
claimed, results of an equivalency study between the In-house and compendial methods.
3. Justification of the changed excipient specifications (e.g., demonstration of the suitability
of the monograph to control the excipient and potential impact on the performance of the
drug product) (3.2.P.4.4).
4. Demonstration that consistency of quality and of the production process is maintained.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
45. Change in the analytical procedures used for the excipient, involving:
Note: This change excludes adjuvants
Notifiable
None 1, 3, 4
Change
a. deletion of an analytical procedure
Annual
6 1
Notification
Notifiable
None 1-4
b. replacement or addition of an analytical Change
procedure Annual
3-5 1-4
Notification
c. minor changes to an approved Annual
1, 2 1-4
analytical procedure Notification
d. a change from an In-house analytical
Annual
procedure to a Pharmacopoeial None 1, 2
Notification
analytical procedure
Conditions
1. No change in the approved acceptance criteria.
2. The method of analysis is the same (e.g., a change in column length or temperature, butGuidance for Industry
Central Drugs Standard Control Organization Page 79 of 119
not a different type of column or method) and no new impurities are detected.
3. Results of method validation demonstrate that the proposed analytical procedure is at
least equivalent to the approved analytical procedure.
4. The replaced analytical procedure maintains or improves precision, accuracy, specificity
and sensitivity.
5. The change is within the range of approved acceptance criteria or has been made to
reflect the new pharmacopoeial monograph specification for the excipient.
6. An alternative analytical procedure is already authorized for the specification parameter/
test and this procedure has not been added through a minor change submission.
Supporting Data
1. Updated excipient specifications (3.2.P.4.1).
2. Where an In-house analytical procedure is used and a Pharmacopoeial standard is
claimed, results of an equivalency study between the In-house and compendial methods.
3. Justification of the changed excipient specifications (e.g., demonstration of the suitability
of the monograph to control the excipient and potential impact on the performance of the
drug product) (3.2.P.4.4).
4. Demonstration that consistency of quality and of the production process is maintained.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
46. Change in the source or manufacture of the excipient,
a. change in the source of an excipient
from a vegetable or synthetic source
None 2-7 Supplement
to a TSE risk or viral risk (e.g. human /
animal source)
b. change in the source of an excipient
Notifiable
from a TSE risk (e.g., animal) source None 1, 3, 5, 6
Change
to a vegetable or synthetic source
c. replacement in the source of an
excipient from a TSE risk source to a Annual
6, 7 2-7
different TSE risk source (e.g., Notification
different country of origin, differentGuidance for Industry
Central Drugs Standard Control Organization Page 80 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
animal species)
d. change in manufacture of a biological None 3-7, 9 Supplement
excipient
Notifiable
Note: excludes biological adjuvants, 2, 3 2, 3, 5-7
Change
refer to adjuvant specific changes for
Annual
details. 1-3 2, 3, 5
Notification
e. change in the supplier for a plasma-
None 3, 8 Supplement
derived excipient (e.g. human serum
Notifiable
albumin) 4, 5 5, 6, 9
Change
f. change in supplier for an excipient of Notifiable
None 2, 3, 5-7
non-biological origin or of biological Change
origin (excluding plasma-derived Annual
1, 5, 6 3
excipient) Notification
g. change in excipient testing site
Note: Transfer of testing to a different
facility within GMP compliant site is
Annual
not considered to be reportable 1 10
Notification
change but it is treated as a minor
GMP change (Level IV) and is
reviewed during inspection
Conditions
1. No change in the specifications of the excipient or drug product outside the approved
limit.
2. The change does not concern a human plasma-derived excipient.
3. Properties of the changed excipient are not different from those of the approvedGuidance for Industry
Central Drugs Standard Control Organization Page 81 of 119
excipient.
4. The human plasma-derived excipient from the new supplier is an approved medicinal
product and no manufacturing changes were made by the supplier of the new excipient
since its last approval by CDSCO.
5. The excipient does not influence the structure / conformation of the active ingredient.
6. The TSE risk source is covered by TSE certificate/declaration of suitability and is of the
same or lower TSE risk as the previously approved material.
7. Any new excipient does not require the assessment of viral safety data.
Supporting Data
1. Declaration from the manufacturer of the excipient that it is entirely of vegetable or
synthetic origin.
2. Details of the source or the excipient (animal species, country of origin) and the steps
undertaken in processing to minimize the risk of TSE exposure.
3. Information demonstrating comparability in term of physico-chemical characterization and
impurity profile of the changed excipient with the approved excipient.
4. Information on the manufacturing process and on the controls performed at critical steps
of the manufacturing process and on the intermediate of the changed excipient (
3.2.P.3.3)
5. Description of the batches, certificates of analyses, and summary of results, in a
comparative tabular format, for at least three (3) commercial scale batches of the drug
product without changed excipient and of the drug product with the changed excipient
(3.2.P.5.4).
6. Results from the stability testing (3 months accelerated testing and 3 months real
time/temperature) on three batches of the drug product with the changed Excipient
(3.2.P.8.3). Matrixing, bracketing, the use of smaller scale batches and use of fewer than
3 batches for stability testing of proposed changed drug product may be acceptable if
scientifically justified (refer ICH Q1D) by the manufacturer /MA holder to CDSCO.
7. Information assessing the risk with respect to potential contamination with adventitious
agents (e.g., impact on the viral clearance studies, BSE/TSE risk). (3.2.A.2)
8. Complete manufacturing and clinical safety data to support the use of the proposed
human plasma derived excipient.
9. Letter from supplier certifying that no changes were made to the plasma-derivedGuidance for Industry
Central Drugs Standard Control Organization Page 82 of 119
excipient compared to the currently approved corresponding medicinal product.
10. Evidence that the new company/facilityis GMP compliant.
3.2.P.5 Control of Drug Product
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
47. Changes in standard / monograph (specifications) claimed for the drug product,
involving
a. a change from a pharmacopoeial standard/ Notifiable
None 1-3, 5-7
monograph to in-house standard Change
b. change in the standard claimed for the drug Notifiable
None 1-6
product (e.g., from an in-house standard to Change
pharmacopoeial standard/monograph or
from one pharmacopoeial standard / Annual
1, 3 1-3, 6, 7
monograph to a different pharmacopoeial Notification
standard/monograph)
c. change in the specification for the drug
product to comply with an updated
pharmacopoeial monograph.
Annual
Note: Change in specifications and an analytical
1, 2 1-3, 6, 7
procedure for the Drug Product to comply with an Notification
updated pharmacopoeial monograph within 6
months of Pharmacopoeia update should be
captured under Level IV changes
Conditions
1. The change is made exclusively to comply with the pharmacopoeia.
2. No change to the specification that results in a potential impact on the performance of
the drug product.
3. No deletion of or relaxation to any of the tests, analytical procedures, or acceptance
criteria of the approved specification except to comply with pharmacopoeial standard/
monograph.Guidance for Industry
Central Drugs Standard Control Organization Page 83 of 119
Supporting Data
1. Revised Drug Product Labelling information, i.e. Package Insert and Inner and Outer
Labels, as applicable.
2. Updated, drug product specifications (3.2.P.5.1).
3. Where an In-house analytical procedure is used and a Pharmacopoeial standard is
claimed, results of an equivalency study between the In-house and compendial methods.
4. Description of the batches, certificates of analyses, and summary of results, in a tabular
format, for at least two batches (minimum pilot scale) of the drug product tested
according to the changed specification (3.2.P.5.4).
5. Justification of the changed drug product specifications (e.g., demonstration of the
suitability of the monograph to control the drug product, including degradation products)
(3.2.P.5.6).
6. Demonstration that consistency of quality and of the production process is maintained.
7. Copies or summaries of validation reports, if new analytical procedures are used
(3.2.P.5.3).
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
48. Change in the drug product release / shelf life specification, involving:
a. for sterile products, replacing the
sterility test with process parametric None 1, 2, 5, 8-10 Supplement
release
Notifiable
None 2, 9, 10
Change
b. deletion of a test
Annual
7 2, 9, 10
Notification
Notifiable
None 2-7, 9, 10
Change
c. replacement or addition of a test
Annual
1, 2, 8 2-4, 9
Notification
d. change in animal species/strains for
Notifiable
a test (e.g., new species/ strains, None 11, 12
Change
animals of different age, newGuidance for Industry
Central Drugs Standard Control Organization Page 84 of 119
supplier where genotype of the
animal cannot be confirmed)
Notifiable
None 2, 9, 10
Change
e. relaxation of an acceptance criterion
Annual
1, 3-6 2, 9, 10
Notification
Annual
f. tightening of an acceptance criterion 1, 2, 4, 9 2
Notification
Conditions
1. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
2. The change is within the range of approved acceptance criteria.
3. Any new analytical procedure does not concern a novel, non-standard technique or a
standard technique used in a novel way.
4. Acceptance criterion for any Class 3 residual solvent is within the ICH limits.
5. The change to the specifications does not result in a potential impact on the performance
of the drug product.
6. The change does not concern sterility or potency testing.
7. The test is deleted in-line with the updated Pharmacopoeia/ Standard; or there is no
change in the compliance status of applicable Pharmacopoeia/ Standard (E.g. The
deleted test is the abnormal toxicity test / general safety test).
8. The addition of test is not to monitor new impurity species.
9. The method of analysis is the same (i.e. a change in column length, temperature, but not
a different type of column or method) and no new impurities are detected.
Supporting Data
1. Process validation and/or evaluation studies (3.2.P.3.5) or the proposed validation
protocol of the changed drug product.
2. Updated drug product specifications (3.2.P.5.1).
3. Copies or summaries of analytical procedures, if new analytical procedures are used
(3.2.P.5.2).
4. Copies or summaries of validation reports, if new analytical procedures are used
(3.2.P.5.3).Guidance for Industry
Central Drugs Standard Control Organization Page 85 of 119
5. Where an In-house analytical procedure is used and a Pharmacopoeial standard is
claimed, results of an equivalency study between the In-house and compendial methods.
6. Information demonstrating qualification of the method and comparability with the
approved method.
7. Description of the batches, certificates of analyses, and summary of results, in a tabular
format, for at least two batches (minimum pilot scale) of the drug product tested
according to the changed specifications (3.2.P.5.4).
8. Description of the batches, certificates of analyses, and summary of results, of a sufficient
number of batches to support the process parametric release (3.2.P.5.4).
9. Justification of the changed drug product specifications (e.g., demonstration of the
suitability of the monograph to control the drug product, including degradation products)
(3.2.P.5.6).
10. Demonstration that consistency of quality and of the production process is maintained.
11. Copies of relevant certificate of fitness for use (e.g., veterinary certificate).
12. Data demonstrating that the change in animals gives comparable results with those
obtained using the approved animals.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
49. Change in the analytical procedures of drug product, involving:
Notifiable
None 1, 2-4
a. deletion of an analytical procedure Change
and/or an acceptance criteria Annual
5 1, 2-4
Notification
Notifiable
None 1, 3, 5-7
b. replacement or addition of an Change
analytical procedure Annual
1, 3, 4, 6-8 1, 3, 5-7
Notification
c. minor changes to an approved Annual
1-4, 8 3, 5-7
analytical procedure NotificationGuidance for Industry
Central Drugs Standard Control Organization Page 86 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
d. change from an In-house analytical
Annual
procedure to a Pharmacopoeial 1-4, 8 1, 5, 6
Notification
analytical procedure
Conditions
1. No change in the approved acceptance criteria.
2. The method of analysis is the same (e.g., a change in column length or temperature, but
not a different type of column or method) and no new impurities are detected.
3. Results of method validation demonstrate that the proposed analytical procedure is at
least equivalent to the approved analytical procedure.
4. The change does not concern sterility testing.
5. The analytical procedure is deleted in-line with the updated Pharmacopoeia/ Standard; or
there is no change in the compliance status of applicable Pharmacopoeia/ Standard.
6. Any new analytical procedure does not concern a novel, non-standard technique or a
standard technique used in a novel way.
7. The change is from a pharmacopoeial assay to another pharmacopoeial assay or
marketing authorization holder has demonstrated an increase understanding of the
relationship between method parameters and method performance define by a
systematic development approach including robustness studies.
8. The change does not concern the potency testing.
Supporting Data
1. Updated drug product specifications (3.2.P.5.1)
2. Description of the batches, certificates of analyses, and summary of results, in a tabular
format, for at least two batches (minimum pilot scale) of the drug product tested
according to the changed specification (3.2.P.5.4).
3. Justification for the change to the analytical procedure (e.g. demonstration of suitability of
the analytical procedure to monitor the drug product).
4. Demonstration that consistency of quality and of the production process is maintained.
5. Copies of summaries of analytical procedures, if new analytical procedures are used
(3.2.P.5.2).Guidance for Industry
Central Drugs Standard Control Organization Page 87 of 119
6. Copies of summaries of validation/qualification reports, if new analytical procedures are
used (3.2.P.5.3).
7. Comparative results demonstrating that the approved and proposed analytical
procedures are equivalent.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
50. Changes affecting the quality control (QC) testing of the final product (release and
stability), involving :
a. transfer of the QC testing Notifiable
None 1, 2
responsibilities for a non - Change
pharmacopoeial assay (in-house) to Annual
2 - 4 1, 2
a new company Notification
b. transfer of the QC testing
Annual
responsibilities for a pharmacopoeial None 1, 2
Notification
assay to a new company
c. transfer of the QC testing
responsibilities for a pharmacopoeial
assay or a nonpharmacopoeial assay
to a different site
Note #1: Change in specifications and an
analytical procedure for the Drug Product to
comply with an updated pharmacopoeial
Annual
monograph within 6 months of 1 1, 2
Notification
Pharmacopoeia update requires no
reporting.
Note #2: Transfer of testing to a different
facility within GMP compliant site is not
considered to be reportable change but it
treated as a minor GMP change (Level IV)
and is reviewed during inspection.
d. introduction of additional laboratory
Annual
in a facility to perform drug product None 2
Notification
testingGuidance for Industry
Central Drugs Standard Control Organization Page 88 of 119
Conditions
1. The new QC testing site/facility is under the central quality assurance .
2. The transfer is within a facility approved in the current MA for the performance of other
test
3. The transferred quality control test is not a potency assay or bioassay.
4. There is no change in the test methods.
Supporting Data
1. Evidence that the new company/facility is GMP compliant.
2. Information demonstrating technology transfer validation and equipment qualification, as
appropriate.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
51. Changes in the control strategy of the drug product, involving:
a. Change from end‐product testing to
upstream controls for some test(s)
None 1-5 Supplement
(e.g., Real‐Time Release Testing,
Process Analytical Technology)
b. Addition of a new Critical Quality Notifiable
None 1-5
Attribute (CQA) in the control strategy Change
c. Deletion of a Critical Quality Attribute Notifiable
None 1, 5
(CQA) from the control strategy Change
Conditions
None
Supporting Data
1. Information on the controls performed at critical steps of the manufacturing process and
on intermediates of the proposed product (3.2.P.3.4).
2. Updated, QC approved copy of the proposed drug product specifications (or where
applicable, the final version of the specifications to be signed by QC after CDSCO
approval), if changed (3.2.P.5.1).
3. Copies or summaries of analytical procedures, if new analytical procedures are used
(3.2.P.5.2).Guidance for Industry
Central Drugs Standard Control Organization Page 89 of 119
4. Copies or summaries of validation reports, if new analytical procedures are used
(3.2.P.5.3).
5. Justification and supporting data for each proposed change to the control strategy.
3.2.P.6 Reference Standards or Materials
Condition to be Supporting Reporting
Description of Change
Fulfilled Data Category
52. Change in reference standards or materials used to release the drug product,
involving
Notifiable
a. qualification of a Reference Standard None 1
Change
b. update the reference standards from Notifiable
1 1, 5
pharmacopoeial to in-house Change
c. update the reference standards from Annual
2, 3 1, 5
in -house to pharmacopoeial Notification
d. qualification of a new lot of reference
Annual
standard (except for a bacterial or 2 1, 5
Notification
viral vaccine, bacterial toxin)
53. Qualification of a new lot of reference standard against the approved reference
standard for a bacterial or viral vaccine, bacterial toxin, involving.
a. reference standard used in a
qualitative test, physicochemical test, Annual
2 1
semi‐quantitative or quantitative Notification
biological assay
54. Change to the reference standard Notifiable
None 2, 3
qualification protocol1 (except for a Change
bacterial or viral vaccine, bacterial Annual
5 2, 3
toxin) Notification
55. Change to reference standard qualification protocol for a bacterial or viral vaccine,
bacterial toxin involving:
a. a reference standard used in a Annual
None 3, 5
qualitative test NotificationGuidance for Industry
Central Drugs Standard Control Organization Page 90 of 119
Condition to be Supporting Reporting
Description of Change
Fulfilled Data Category
b. a reference standard used in a
physicochemical test, a semi‐ Annual
5 3, 5
quantitative or quantitative biological Notification
assay.
56. Extension of the shelf-life / re-test Annual
4 4
period of the reference standard Notification
Conditions
1. The In-house reference standard is validated against an official (e.g., pharmacopoeial/
NIBSC/WHO/EDQM/NCL) reference standard.
2. Qualification of the reference standard is performed according to the approved protocol
(i.e. no deviation from the approved protocol).
3. The change is necessitated due to Pharmacopoeial requirement to meet with the
regulatory requirements.
4. The extension of the shelf-life of the reference standard is carried out in accordance with
an approved protocol.
5. The protocol is considered more stringent (i.e., addition of new tests or tightening of
acceptance criteria). If deletion of test is proposed, the tests proposed to be deleted were
not implemented to monitor the quality of the reference standard (e.g., was implemented
for research or validation work.).
Supporting Data
1. Information demonstrating qualification of the changed reference standards or materials
(e.g., source, characterization, certificate of analysis).
2. Justification of the change to the reference standard qualification protocol.
3. Updated reference standard qualification protocol.
4. Summary of stability testing and results or retest data to support the extension of the
reference standard shelf-life.
5. Justification for change in the reference standard.
3.2.P.7 Container Closure System
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data CategoryGuidance for Industry
Central Drugs Standard Control Organization Page 91 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
57. Change in primary container closure component, involving
a. modification of a container closure
system (e.g., new coating, adhesive, Notifiable
None 1-7
stopper, prefilled syringe with Change
attached needle, prefilled syringe with
separate needle). Annual
1-3 3
Note: The addition of a new container Notification
closure system (e.g., addition of a pre‐filled
syringe where the currently approved Annual
4 3, 6
presentation is only a vial) is considered a Notification
change in presentation.
b. deletion of a container closure Annual
None 1
system Notification
c. change from a reusable container to
a disposable container with no
Notifiable
changes in product contact material None 1, 3-6
Change
(e.g. change from reusable pen to
disposable pen)
Conditions
1. No change in the type of container closure or materials of construction.
2. The container closure shape dimensions or specifications are equivalent.
3. The change is made only to improve quality of the container and does not modify the
product contact material (e.g., increase thickness of the glass vial without changing
interior dimensions).
4. The modified part is not in contact with the Drug Product
Supporting Data
1. Revised Product Labelling information i.e. Package Insert and Inner and Outer Labels, as
appropriate.
2. For sterile products, process validation and/or evaluation studies (3.2.P.3.5).
3. Information on the proposed changed container closure system, as appropriate (e.g.,
description, materials of construction of primary/secondary packaging components,Guidance for Industry
Central Drugs Standard Control Organization Page 92 of 119
specifications) (3.2.P.7).
4. Summary of stability testing and results of minimum three months of accelerated and a
minimum of three (3) months of real time/real temperature testing on three (3)
commercial scale batches of the changed drug product stored in the proposed container
as well as commitment to submit the stability report when completed and to notify
CDSCO of any failures in the ongoing stability studies (3.2.P.8.3). Matrixing, bracketing,
the use of smaller scale batches and use of fewer than 3 batches for stability testing of
proposed changed drug product may be acceptable if scientifically justified (refer ICH
Q1D) by the manufacturer /MA holder to CDSCO.
5. Summary of release testing results as quantitative data, in a comparative tabular format,
for at least three consecutive commercial-scale batches of the pre-change and post-
change drug product. Comparative pre-change test results do not need to be generated
concurrently; relevant historical testing results are acceptable. Bracketing for multiple-
strength products, container sizes and/or fills may be acceptable if scientifically justified.
6. Information demonstrating suitability of the changed container/closure system (e.g.,
results from last media fills, preservation of protein integrity, and maintenance of the
sterility in multi-dose container).
7. Results demonstrating protection against leakage, no leaching of undesirable substance,
compatibility with the product, and results from the toxicity and the biological reactivity
test.
Conditions to Supporting Reporting
Description of Change Conditions
be Fulfilled Data Category
58. Change in the supplier for a primary container closure component, involving:
Notifiable
None 1-3
a. replacement or addition of a Change
supplier Annual
1, 2 3, 4
Notification
Annual
b. deletion of a supplier None None
Notification
Conditions
1. There is no change in the type of container closure, materials of construction; andGuidance for Industry
Central Drugs Standard Control Organization Page 93 of 119
container closure shape, dimensions, specifications (or are equivalent) or in the
sterilization process for a sterile container closure component.
2. No change in the specifications of the container closure component outside of the
approved ranges.
Supporting Data
1. Data demonstrating the suitability of the container closure system (e.g., extractable/
leachable testing).
2. For sterile products, process validation and/or evaluation studies (3.2.P.3.5).
3. Information on the changed container closure system (e.g., description, materials of
construction of primary packaging components, specifications) (3.2.P.7).
4. Certificate of analysis, or equivalent, for the container provided by the new supplier and
comparison with certificate of analysis, or equivalent, for the approved container.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
59. Change in the specifications for a primary container closure component or
functional secondary container closure component, involving:
Annual
a. deletion of a test 4, 5 1, 2
Notification
Notifiable
None 1
Change
b. replacement or addition of a test
Annual
1-3 1, 2
Notification
c. relaxation of an acceptance Notifiable
None 1, 2
criterion Change
d. tightening of an acceptance Annual
1, 2 1
criterion Notification
Conditions
1. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
2. The change is within the range of previously approved acceptance criteria.
3. Any new analytical procedure does not concern a novel, non-standard technique or aGuidance for Industry
Central Drugs Standard Control Organization Page 94 of 119
standard technique used in a novel way.
4. The deleted test has been demonstrated to be redundant with respect to the remaining
tests or is no longer a pharmacopoeial requirement.
5. The change to the specifications does not affect the functional properties of the container
closure component nor result in a potential impact on the performance of the final
product.
Supporting Data
1. Updated changed specifications, for the primary or functional secondary container
closure component (3.2.P.7).
2. Rationale for the change in specification for a primary container closure component.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
60. Change in the analytical procedures for a primary container closure component or
functional secondary container closure component
Notifiable
3 1-3
a. deletion, replacement or addition Change
of an analytical procedure Annual
3, 4 1-3
Notification
b. minor changes to an analytical Annual
1-4 1-3
procedure Notification
Conditions
1. No change in the approved acceptance criteria outside the approved limits.
2. The analytical procedure is of the same type.
3. Results of method validation demonstrate that the proposed new or modified analytical
procedure is at least equivalent to the approved analytical procedure.
4. The new or modified analytical procedure maintains or tightens precision, accuracy,
specificity and sensitivity.
Supporting Data
1. Updated changed specifications. (3.2.P.7)
2. Description of the analytical procedure and, if applicable, validation data.
3. Rationale for the change in specification for a primary container closure component.Guidance for Industry
Central Drugs Standard Control Organization Page 95 of 119
3.2.P.8 Stability
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
61. Change in the shelf life for the drug product, involving:
a. extension (includes extension of Notifiable
None 1-4, 6, 7
shelf-life of the Drug Product as Change
packaged for sale, and hold time
Annual
after opening and after dilution or 1-3, 4, 5 1, 2, 5, 7
Notification
reconstitution)
Notifiable
b. reduction (includes reduction as None 1-4, 5, 7
Change
packaged for sale, after opening,
Annual
after dilution or reconstitution) 6 2-4, 7
Notification
Conditions
1. No change to the container closure system in direct contact with the drug product or to the
recommended storage conditions of the drug product.
2. The approved re-test period (or shelf life) is at least 24 months.
3. Full long term stability data are available covering the changed re-test period (or shelf life)
and are based on stability data generated on at least three production scale batches.
4. Stability data were generated in accordance with the approved stability protocol.
5. Significant changes (as defined in ICH's Q1A guideline) were not observed in the stability
data.
6. The reduction in the shelf life is not necessitated by recurring events arising during
manufacture or because of stability concerns.
Supporting Data
1. Summary of stability testing and results (e.g., studies conducted, protocols used, results
obtained) (3.2.P.8.3).
2. Proposed storage conditions and re-test period (or shelf life, as appropriate).
3. Updated post-approval stability protocol and stability commitment (3.2.P.8.2).
4. Justification of the change to the post-approval stability protocol or stability commitment.
5. Results of stability testing on both upright and inverted samples, except for lyophilized
products (i.e., full real time/real temperature stability data covering the changed re-testGuidance for Industry
Central Drugs Standard Control Organization Page 96 of 119
period (or shelf life) generated on at least three (3) production scale batches) (3.2.P.8.3).
6. Results of stability testing (i.e., less than full real time/real temperature stability data
covering the changed re-test period (or shelf life) and/or generated on less than three (3)
production scale batches), (3.2.P.8.3) and a commitment to submit the stability report
when completed and to notify CDSCO of any failures in the ongoing stability studies. Full
long term stability data are not available covering the changed shelf life or are not based
on stability data generated on at least three batches, the extrapolation is in accordance
with ICH's Q1E guideline.
7. Updated product labeling information, as applicable
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
62. Change in the labelled storage conditions for the drug product or the diluted or
reconstituted product, involving:
Notifiable
a. addition of a cautionary None 1, 2, 4, 5
Change
statement
Annual
(e.g. DO NOT FREEZE) 1 1, 2, 4, 5
Notification
b. deletion of a cautionary
Notifiable
statement None 1, 2, 4, 6
Change
(e.g. DO NOT FREEZE)
c. addition or change of storage Notifiable
None 1-5
condition for the drug product, Change
diluent or reconstituted drug
product Annual
1, 2 1-4
(e.g. relaxation or tightening of Notification
temperature criterion)
Conditions
1. The change is not necessitated by unexpected events arising during manufacture or
because of stability concerns.
2. The change consists in the tightening of a temperature criterion within the approved
ranges.Guidance for Industry
Central Drugs Standard Control Organization Page 97 of 119
Supporting Data
1. Revised product labelling information (Package Insert, Inner and Outer Labels), as
applicable.
2. Proposed storage conditions and shelf-life.
3. Updated post-approval stability protocol and stability commitment (3.2.P.8.2).
4. Justification of the change in the labelled storage conditions/cautionary statement.
5. Results of stability testing under appropriate stability conditions covering the proposed
shelf-life, generated on one (1) commercial scale batch unless otherwise justified
(3.2.P.8.3).
6. Results of stability testing under appropriate conditions covering the proposed shelf-life,
generated on at least three (3) commercial scale batches unless otherwise justified
(3.2.P.8.3).
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
63. Change to the post-approval stability protocol or stability commitment of final
product, involving
a. major change to the post-approval
Notifiable
stability protocol or stability None 1-7
Change
commitment, such a deletion of a
test, replacement of an analytical
Annual
procedure, or change in storage 1, 4 2, 3, 5, 6
Notification
temperature
b. addition of time point (s) into the Annual
None 2, 3
post-approval stability protocol Notification
c. addition of test (s) into the post- Annual
1 2, 3, 5, 6
approval stability protocol Notification
d. deletion of time point (s) from the
Annual
post-approval stability protocol 5 2, 3, 7
Notification
beyond the approved shelf lifeGuidance for Industry
Central Drugs Standard Control Organization Page 98 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
e. deletion of the time(s) from the
Annual
post-approval stability protocol 2 2, 3, 7
Notification
within the approved shelf-life
Notifiable
f. replacement of the sterility testing None 2, 3, 5-7
Change
by the container closure system
Annual
integrity testing 3 2, 3, 7
Notification
Condition
1. The addition of the test(s) is not due to stability concerns or to the identification of new
impurities.
2. The approved shelf–life of the final product is at least 24 months.
3. The method used to demonstrate the integrity of the container/closure system has
already been approved as part of a previous application.
4. For the replacement of an analytical procedure, the results of method validation
demonstrate that the new analytical procedure is at least equivalent to the approved
analytical procedure.
5. Deletion of the time-points is done according to relevant guideline (i.e. ICH Q5C).
Supporting Data
1. Proposed storage conditions and shelf life.
2. Updated post-approval stability protocol and stability commitment (3.2.P.8.2).
3. Justification of the change to the post-approval stability protocol or stability
commitment.
4. If applicable, stability testing results to support the change to the post-approval stability
protocol or stability commitment. (3.2.P.8.3)
5. Copies or summaries of analytical procedures, if new analytical procedures are used
(3.2.P.5.2).
6. Validation study reports, if new analytical procedures are used (3.2.P.5.3).
7. Comparative results demonstrating that the approved and proposed analytical
procedure are equivalent.Guidance for Industry
Central Drugs Standard Control Organization Page 99 of 119
5. POST-APPROVAL CHANGE MANAGEMENT PROTOCOL-PACMP
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
a. Introduction of a post-approval change
Notifiable
management protocol related to DS None 1-3
Change
and/or DP
b. Deletion of an approved post-approval
Annual
change management protocol related 1 3, 4
Notification
to DS and/or DP
c. Minor changes to an approved change Notifiable
None 3, 4
management protocol Change
Conditions
1. The deletion of the approved change management protocol related to the active
substance is not a result of unexpected events or out of specification results during the
implementation of the change(s) described in the protocol and does not have any effect
on the already approved information in the dossier.
Supporting Data
1. Description of the proposed change
2. Change management protocol
3. Amendment of the relevant CTD CMC sections
4. Justification for the proposed change
6. EFFICACY POST APPROVAL CHANGES
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
1. Change in the efficacy parameter
a. Addition of a new therapeutic indication
1 1-5 Supplement
and/or modification of an approved one
Note: The changes that are considered as “New Drugs” as per “The New Drugs and ClinicalGuidance for Industry
Central Drugs Standard Control Organization Page 100 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
Trials Rules, 2019, MA holder should submit the MA application in Form CT-21/Form CT-18
in SUGAM with applicable fee along with supporting documentation as described for the
respective post approval change category, followed by amendment / endorsement of current
Form 28 D license, as applicable.
Note: A declaration to state that no change to other remaining section/s of the MA dossier,
shall be submitted, as applicable.
Notifiable
b. Deletion of a therapeutic indication None 3
Change
c. modification of an approved safety claim,
indication or efficacy claim whether
explicit or implicit (e.g. expansion of the
1 1 - 5 Supplement
age of use or restriction of an indication
based on clinical studies demonstrating
lack of efficacy)
Conditions
1. No change in strength, dosage form and route of administration.
Supporting Data
1. Clinical data along with applicable preclinical data.
2. Copy of approval with new indication or any other regulatory certificate issued by other
recognized NRA or NRA of country of origin with new indication.
3. Copy of current Package Insert (PI) with proposed change,
4. Published data or relevant literature supporting the proposed change, if any.
5. Duly signed Form CT-18 or Form CT-21, with applicable fees (challan)
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
2. Change / modification in the approved claim
a. new route of administration, new
strength (potency), or increase in the 1 1-5 Supplement
recommended dose / dosage rangeGuidance for Industry
Central Drugs Standard Control Organization Page 101 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
Note: The changes that are considered as “New Drugs” as per “The New Drugs and Clinical
Trials Rules, 2019, MA holder should submit the MA application in Form CT-21/Form CT-18
in SUGAM with applicable fee along with supporting documentation as described for the
respective post approval change category, followed by amendment / endorsement of current
Form 28 D license, as applicable.
Note: A declaration to state that no change to other remaining section/s of the MA dossier,
shall be submitted, as applicable.
Conditions
1. No change in, dosage form and indication.
Supporting Data
1. Clinical data along with applicable preclinical data
2. Copy of approval with new route of administration or any other regulatory certificate
issued by other recognized NRA or NRA of country of origin with new route of
administration.
3. Copy of current PI with the proposed change.
4. Published data or relevant literature supporting the proposed change, if any.
5. Duly signed Form CT-18 or Form CT-21, with applicable fees (challan)
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
3. Other changes related to safety and efficacy, involving
a. change to add information on Notifiable
1 1-4
shedding and transmission Change
b. change in the recommended dose
and/ or dosing schedule (addition or
None 1-4 Supplement
modification new vaccination
regimen)
c. change to use in specific risk groups
Notifiable
(e.g. use in pregnant women or 1 1-4
Change
immunocompromised patients)Guidance for Industry
Central Drugs Standard Control Organization Page 102 of 119
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
d. change to add information on co-
Notifiable
administration with other vaccines or 1 1-4
Change
medicines
e. change to add a new delivery device 1 1-4 Supplement
f. Change in existing risk-management
measures:
(i) deletion of an existing route of
administration, dosage form and/or
Notifiable
strength due to safety reasons; 1 1-4
Change
(ii) deletion of a contraindication (for
example, use in pregnant women);
(iii) changing a contraindication to a
precaution.
Conditions
1. No change in strength, dosage form and indication.
Supporting Data
1. Published clinical data along with applicable non-clinical data.
2. Copy of approval for proposed change or any other regulatory certificate issued by other
recognized NRA or NRA of country of origin with proposed change
3. Copy of current PI with proposed change.
4. Published data or relevant literature supporting the proposed change, if any.
Conditions to Supporting Reporting
Description of Change
be Fulfilled Data Category
a. Changes or replacement to the active
substance of a seasonal, pre-pandemic Notifiable
None 1-3
or pandemic vaccine against human Change
influenza or COVID-19
Conditions
None
Supporting DataGuidance for Industry
Central Drugs Standard Control Organization Page 103 of 119
1. Revised CMC sections and labelling.
2. Pre-clinical data (Module 4) as applicable.
3. Clinical data (Module 5) as applicable.
7. ADMINISTRATIVE CHANGES
Conditions to Supporting Reporting
Description of the change
be fulfilled data category
1. Change in the name and/or
address of the marketing
Notifiable
1 1, 2
authorization holder that was
Change
granted the Marketing
Authorization for DS and / or DP.
Conditions
1. The marketing authorization holder shall remain the same legal entity.
Supporting data
1. Approval for change of name as per statutory requirements.
2. Notification of new name in the form of a MA holder signed letter if the manufacturer is
sold or merged with another company. Note that if address changes due to
manufacturing facility change then MA application needs to be resubmitted with fresh
quality; safety and efficacy data according to the manufacturing facility change
requirements
Conditions to Supporting Reporting
Description of the change
be fulfilled data category
Notifiable
2. Company sale, purchase, merger 1 1-3
Change
Conditions
1. The marketing authorization holder shall remain the same legal entity.
Supporting data
1. Approval for sale/purchase as per statutory requirements.
2. Notification of new name if the manufacturer is sold or merged with another company.
3. Revised labeling information.Guidance for Industry
Central Drugs Standard Control Organization Page 104 of 119
Conditions to Supporting Reporting
Description of the change
be fulfilled data category
3. Change in the (invented) name of Notifiable
1 1, 2
the product. Change
Conditions
1. The name is as per the updated Pharmacopeia.
Supporting data
1. Copy of the updated Pharmacopeia monograph.
2. Revised product labelling information (Package Insert, Inner and Outer Labels), as
applicable.Guidance for Industry
Central Drugs Standard Control Organization Page 105 of 119
8. PRODUCT LABELLING INFORMATION CHANGES
Product labelling information changes, which do not require clinical efficacy, safety data or
extensive pharmacovigilance (safety surveillance) data should be submitted. Product
labelling information changes require approval prior to implementation of the change.
The following are examples of product labelling information changes that are associated
with changes that have an impact on clinical use:
1. Addition of an adverse event that is identified to be consistent with a causal association
to biological product concerned.
2. Change in the frequency of occurrence of a given adverse reaction.
3. Addition of a contraindication or a warning (e.g. identification of a specific subpopulation
as being at greater risk, such as persons with a concomitant condition or taking
concomitant medicines, or a specific age group). These changes may include the
provision of recommended risk-management actions (e.g. required testing prior to
vaccination, specific monitoring following vaccination, ensuring patient awareness of
certain risks).
In some cases, the safety-related changes listed above may be urgent and may require rapid
implementation (e.g. addition of a contraindication or a warning). To allow for speedy
processing of such requests, the submission for these changes should be labelled as “Urgent
Product Labelling Information Changes”.Guidance for Industry
Central Drugs Standard Control Organization Page 106 of 119
9. APPENDICES
Appendix 1: Examples of Level IV Changes but not limited to
Non-critical changes to the licensed application including spelling mistakes, editorial
changes and remediations made to documents such as Validation Summaries and/or
Reports, Analytical Procedures, SOPs, Production Documentation Summaries, QOS, for
added clarity that have no impact to affect the safety, efficacy and quality of the product.
Replacement of the membrane (filter) used during the UF/DF step.
Replacement or addition of filter housing.
Change in stopper cap colour for an injectable product.
Modification to pretreatment stages of a WFI system, including purified water systems
used solely for pretreatment in WFI production.
Change in the floor plan that does not affect production process or contamination
precautions.
Addition of vial reject chute.
Change in the in-process controls performed at non-critical manufacturing steps or
change to a non-critical manufacturing area (see Glossary).
Transfer of in-process control testing to a different facility within a GMP-compliant site
Transfer of raw material / packaging material testing to a different facility within GMP
compliant site.
Transfer of Pharmacopoeial testing of drug substance / drug product to a different facility
within GMP compliant site.
Rooms upgrades, such as installation of improved finishes on floors/walls.
Addition of a new GMP storage warehouse for raw materials, master and working cell
banks and drug substance.
Installation of non-process-related equipment or rooms to improve the facility, such as
warehousing refrigerators or freezers.
Replacement of equipment with identical equipment (non-product contact equipment).
Introduction of additional laboratory in a facility to perform drug substance testing.
Change in supplier for non-critical excipients.
Change in tertiary packaging components of drug substance or drug product that do not
affect stability.
Minor changes to the layout of the product labelling information items or revision of
typographical errors without changing the content of the label.Guidance for Industry
Central Drugs Standard Control Organization Page 107 of 119
Appendix 2: ANNUAL REPORT FORM (Minor Changes)
January ________________ to December________________
1. Manufacturing site(s) or Area(s) involved
2. Product(s) involved
3. Description of change
4. Rationale of change
Conditions:
5. Reference to CDSCO guidelines
6. Implementation date
Cross reference to validation protocols
7.
and/ or SOP’s/STP’s/ Spec’s (If relevant)
Relevant data from studies and tests
8.
performed (Impact of change assessed)
Submitted by: Date:Guidance for Industry
Central Drugs Standard Control Organization Page 108 of 119
Appendix 3: Glossary
Adjuvant:
Component that potentiates the immune responses to an antigen/drug substance and/or
modulates it towards the desired immune responses. Adjuvant may be of pharmaceutical
origin (chemical/synthetic adjuvant) or of biological origin (biological adjuvant).
Batch:
A quantity of drug in dosage form, a raw material, or a packaging material, homogeneous
within specified limits, produced according to a single production order and as attested by the
signatories to the order. In the case of continuous manufacture, a batch corresponds to a
defined fraction of the production that is characterized by its intended homogeneity. It may
sometimes be necessary to divide a batch into a number of sub‐batches, which are later
brought together to form a final homogeneous batch.
Biological auxiliary material:
Raw material from a biological source which is intended to be used as a processing aid in the
fabrication of the drug. It may be absent from the drug or may remain as an impurity in the
drug at the end of the manufacturing process (e.g., biological additives used to supplement
cell culture medium in production fermenter, human antithrombin III used to complex and
remove human thrombin).
Biological starting material:
Raw material from a biological source which is intended to be used in the fabrication of a
drug and from which the active ingredient is derived either directly (e.g., plasma derivatives,
ascetic fluid, bovine lung, etc.) or indirectly (e.g., cell substrate, host/vector production cells,
eggs, viral strains, etc.).
Biotherapeutic product:
A biological medicinal product with the indication of treating human disease include all
biologically active protein products (including plasma-fractionated products) which are used
in the treatment of human diseases, and those intentionally modified by, for example, fusionGuidance for Industry
Central Drugs Standard Control Organization Page 109 of 119
proteins, PEGylation, conjugation with a cytotoxic drug or modification of rDNA sequences.
They also include protein products used for in vivo diagnosis (for example, monoclonal
antibody products used for imaging).
Certificate of suitability (CEP):
A certificate of compliance of a substance with the relevant requirements of the European
Pharmacopoeia monographs for use in medicinal products issued by the European
Directorate for the Quality of Medicine of the Council of Europe (EDQM).
Change:
Refers to a change that includes, but is not limited to; the product composition, manufacturing
process, quality controls, equipment, facilities or product labelling information made to an
approved marketing authorization or license by the marketing authorization holder. Also
referred to as variation.
Change‐over procedure:
A logical series of validated steps that ensures the proper cleaning of suites and equipment
before the processing of a different product begins.
Closed process/closed system:
Process equipment or process step in which the product is not exposed to the external
environment. A closed system requires that the quality of materials entering or leaving the
system and the manner in which these materials are added/removed from the system is
carefully controlled.
Comparability study:
The activities, including study design, conduct of studies and evaluation of data that are
designed to investigate whether the pre- and post-change products are comparable. In
addition to routine analysis performed during production and control of the antigen/drug
substance or final product, these evaluations typically include a comparison of manufacturing
process steps and parameters impacted by the change, characterization studies and an
evaluation of product stability following the change. In some cases, non-clinical or clinicalGuidance for Industry
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data might contribute to the conclusion.
Comparability protocol:
Establishes the tests to be done and acceptable limits to be achieved to demonstrate the lack
of a negative effect for specific manufacturing changes on the safety or efficacy of the
product. A comparability protocol is a highly specific, well defined plan for the future
implementation of a quality (i.e. manufacturing) change. Also referred to as post-approval
change management protocol.
Container closure system: refers to the following components:
A primary container closure system is a packaging component that is in, or may come
into, direct contact with the drug product dosage form (for example, vial or pre-filled
syringe) or components that contribute to the container/closure integrity of the primary
packaging material for a sterile product.
A secondary container closure system is a packaging component that is not, and will
not be, in direct contact with the dosage form (for example, carton or tray).
A functional secondary container closure system is a packaging material that is not in
direct contact with the product and that provides additional protection or serves to
deliver the product.
Control Strategy:
A planned set of controls, derived from current product and process understanding that
ensures process performance and product quality. The controls can include parameters and
attributes related to drug substance and drug product materials and components, facility and
equipment operating conditions, in‐process controls, finished product specifications, and the
associated methods and frequency of monitoring and control.
Critical manufacturing step:
A manufacturing process/step that may results in a potential change in the purity/impurity
profile or due to the nature of the starting materials or resulting product/intermediate, requires
containment within a specially designed manufacturing area or production facility, for
example, the development and preparation of cell banks and seed lots, initial propagation,Guidance for Industry
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scale-up, blood and plasma pooling and fractionation, fermentation, harvesting, inactivation,
purification, addition of adjuvants or preservatives, the conjugation and pooling of bulk
concentrates and the final preparation of drug product including concentration/ diafiltration,
formulation, sterile filtration, filling and lyophilization.
Critical process parameter:
A process parameter whose variability has an impact on a critical quality attribute and
therefore should be monitored or controlled to ensure the process produces the desired
quality.
Critical Quality Attribute:
a physical, chemical, biological or microbiological property or characteristic that is selected
for its ability to indicate the consistent quality of the product within an appropriate limit, range
or distribution to ensure the desired product quality.
Design space:
The multidimensional combination and interaction of input variables (e.g., material attributes)
and process parameters that have been demonstrated to provide assurance of quality.
Working within the design space is not considered as a change. Movement out of the design
space is considered to be a change and would normally initiate a regulatory post approval
change process. Design space is proposed by the applicant and is subject to regulatory
assessment and approval.
Different host/media‐type:
Mammalian cells or any micro‐organisms involved in the manufacture of a drug substance
which are different from the existing hosts in the facility or use a cell culture or fermentation
medium with significantly differing composition.
Dosage form:
A drug product that has been processed to the point where it is now in a form in which it may
be administered in individual doses.
Drug product:Guidance for Industry
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The dosage form in the final immediate packaging intended for marketing.
Drug substance:
The active pharmaceutical ingredient and associated molecules that may be subsequently
formulated to produce the drug product.
Equivalent equipment:
Equipment with the same technical parameters and fabricated with product- contact material
of same or higher grade quality. Equivalent equipment should give a product of same quality
as the one processed by the previous equipment.
Excipient:
Any component of the drug product, other than the active component/drug substance and the
packaging material, generally added during formulation. Also referred to as “inactive
ingredient” in other documents.
Facility/ Suite/Building:
A Facility/ Suite / building in which a specific manufacturing operation or multiple operations
take place, and for the purposes of this guidance only, the product-contact equipment housed
within the aforementioned Facility/ Suite / building.
Fermentation train:
Equipment and conditions involved in the stepwise expansion of the cell culture process.
Final batch:
A collection of sealed final containers that is homogeneous with respect to the composition of
the product. A final batch must have been filled in one continuous working session.
Formulated bulk:
An intermediate in the drug product manufacturing process, consisting of the final formulation
of drug substance and excipients at the concentration to be filled into primary containers.
HVAC (Heating, Ventilation, and Air Conditioning):Guidance for Industry
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Industry term for the systems and technology responsible for the heating, ventilation, and air
conditioning in buildings. HVAC systems regulate comfort (temperature and humidity), energy
efficiency, and air quality.
In-process control:
Check performed during production in order to monitor and, if necessary, to adjust the
process to ensure that the finished product conforms to its specifications. The control of the
production environment or equipment may also be regarded as part of in-process control.
Intermediate:
A material produced during steps in the manufacture of a biotherapeutic product that
undergoes further processing before it becomes the drug product.
Manufacturer:
Any person or legal entity engaged in the manufacture of a product subject to marketing
authorization or licensure.
Marketing authorization:
A formal authorization for a medicine to be marketed. Once an NRA approves a marketing
authorization application for a new medicine, the medicine may be marketed and may be
available to be prescribed by physicians.
Marketing authorization application:
A formal application to the NRA for approval to market a new medicine. The purpose of the
marketing authorization application is to determine whether the medicine meets the statutory
standards for safety, efficacy, product labelling information and manufacturing.
Marketing Authorization holder (MA holder):
Any person or legal entity or sponsor, or manufacturer or importer / license manufacturer to
manufacture / market a medicinal product that has received marketing authorization or
licensure to manufacture and/or distribute a medicine. It also refers to a person or legal entity
allowed to apply for a change to the marketing authorization or license and is referred to as
the manufacturer or applicant in this or other documents.Guidance for Industry
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Master cell bank (MCB):
An aliquot of a single pool of cells which generally has been prepared from the selected cell
clone under defined conditions, dispensed into multiple containers and stored under defined
conditions.
Mock-Up (i.e. Label, Carton, PI):
A full colour, actual size copy of the labels and a colour representation of the packages
intended to be used for the sale of the drug, including all presentation/design elements,
proposed graphics, fonts, colours and text
Multi-product facility/Suite:
A facility where more than one product of the same type or products from different classes
are fabricated (e.g., pharmaceutical and biological products).
Non‐critical area:
Area that does not encompass process steps.
Non‐critical excipient:
Excipient with no active function, e.g., solution used to adjust pH.
Non-critical manufacturing step:
A manufacturing process/step that has no impact upon purity and impurity profile or requires
no specific facility considerations, for example, buffer and media preparation, storage of
intermediates, and packaging (note that some biological products may require critical
temperature and/or light control during packaging).
Open system:
Any steps in a manufacturing process where in‐process materials or components are
exposed to the external environment.
Pilot scale:
A batch of a drug substance or drug product manufactured by a procedure fully representative
of and simulating that to be applied to a full production scale batch.Guidance for Industry
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The methods of cell expansion, harvest, and product purification should be identical except
for the scale of production.
Presentation:
Container that contains the drug product. The container may be used directly or indirectly in
the administration of the drug (e.g., vials, pre-filled syringes, pre-filled pens).
Primary container closure component:
Packaging material in direct contact with the product.
Primary packaging site:
Site involved in the activity of putting a drug in its primary container which is, or may be, in
direct contact with the dosage form.
Process validation:
Documented evidence which provides a high degree of assurance that a specific process will
consistently result in a product that meets its predetermined specifications and quality
characteristics.
Product labelling information:
Refers to printed materials that accompany a prescription medicine and all labelling items,
namely:
prescribing information (an instruction circular that provides product information on
indication, dosage and administration, safety and efficacy, contraindications, warnings
and a description of the product for health-care providers (also referred to as
“summary of product characteristics” or “package insert” in various countries);
patient labelling or consumer information;
inner label or container label;
outer label or carton.
Quality attribute:
A physical, chemical, biological or microbiological property or characteristic.Guidance for Industry
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Quality change:
A change in the manufacturing process, product composition, quality control testing,
equipment or facility. Also referred to as “chemistry manufacturing and control (CMC)
change” in other documents.
Raw materials:
A general term used to denote the culture media components, reagents or solvents intended
for use in the production of starting material, drug substance, intermediates or drug products.
Real-time release testing:
Testing that provides the ability to evaluate and ensure the quality of in-process and/or final
product based on process data, which typically include a valid combination of measured
material attributes and process controls.
Reference standards/materials:
Well-characterized materials used as references against which batches of biological products
are assessed. These materials remain fundamental to ensuring the quality of biological
products as well as the consistency of production, and are essential for the establishment of
appropriate clinical dosing.
Reprocessing:
Subjecting all or part of a batch or lot of an in-process drug, a bulk process intermediate (final
biological bulk intermediate) or a bulk drug of a single batch/lot to a previous step in the
validated manufacturing process due to failure to meet predetermined specifications.
R-DNA products:
Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of
genetic recombination (such as molecular cloning) that bring together genetic material from
multiple sources, creating sequences.
Re-test period:
For biologics, also sometimes known as shelf life.Guidance for Industry
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Safety and efficacy change:
A change that has an impact on the clinical use of the biotherapeutic product in relation to
safety, efficacy, dosage and administration, and that requires data from clinical or post-
marketing studies, and in some instances clinically relevant nonclinical studies, to support the
change
Secondary packaging facility:
Site involved in packaging activities using a packaging component that is not, and will not be,
in direct contact with the dosage form (for example, putting the primary container in the outer
container or affixing labels).
Shelf life (also referred to as expiration period):
The period of time during which a drug substance or drug product, if stored under the
conditions defined on the container label, is expected to comply with the specification, as
determined by stability studies on a number of batches of the product. The expiry date is
assigned to each batch by adding the shelf-life period to the date of manufacture.
Similar Biologics:
“Similar biologic” means a biological product which is similar in terms of quality, safety and
efficacy to reference biological product licenced or approved in India, or any innovator
product approved in International Council of Harmonisation (ICH) member countries.
Site/Premises:
The land occupied legally by company, which contains one or more manufacturing
facilities/suites/buildings cumulatively shall be called as premises, which will have its own
manufacturing license number issued by licensing authority.
Specification:
A list of tests, references to analytical procedures and appropriate acceptance criteria which
are numerical limits, ranges or other criteria for the tests described. Specifications are criticalGuidance for Industry
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quality standards that are proposed and justified by the manufacturer and approved by the
regulatory authorities.
Starting materials:
Materials that mark the beginning of the manufacturing process, as described in a marketing
authorization or product license. Generally, starting material refers to a substance of defined
chemical properties and structure that contributes an important and/or significant structural
element(s) to the active substance (examples for vaccines: synthetic peptides, synthetic
glycans, and starting materials for adjuvants). The starting material for an antigen (drug
substance) obtained from a biological source is considered to consist of the 1) cells; 2)
microorganisms; 3) plants, plant parts, macroscopic fungi or algae; or 4) animal tissues,
organs or body fluid from which the antigen (drug substance) is derived.
Strength:
Quantity of medicinal ingredient in a particular dosage form. For solution, concentration of the
active pharmaceutical ingredient multiplied by the fill volume.
Vaccine:
A preparation that is used to stimulate the body’s immune response against diseases.
Validation:
The demonstration, with documentary evidence, that any procedure, process, equipment,
material, activity or system will consistently produce a result meeting predetermined
acceptance criteria. Working cell bank (WCB): the working cell bank is prepared from aliquots
of a homogeneous suspension of cells obtained from culturing the master cell bank under
defined culture conditions.
Working cell bank (WCB):
The working cell bank is prepared from aliquots of a homogeneous suspension of cells
obtained from culturing the master cell bank under defined culture conditions.Guidance for Industry
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10. REFERENCES
1. New Drugs and Clinical Trial Rules, 2019
2. Guidelines on Similar Biologics published by Department of Biotechnology and
CDSCO
3. Guidelines on procedures and data requirements for changes to approved
biotherapeutic products, Annex 3, WHO Technical Report Series 1011, 2018
4. Guidelines on procedures and data requirements for changes to approved vaccines,
Annex 4, WHO Technical Report Series 993, 2015
5. Post‐Notice of Compliance (NOC) Changes: Quality Document, Health Canada, 2019
6. Stability Testing of New Drug Substances and Products (Q1A)
7. Stability Testing: Photostability Testing of New Drug Substances and Products (Q1B)
8. Stability Testing for New Dosage Forms (Q1C)
9. Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and
Products (Q1D)
10. Evaluation of Stability Data (Q1E)
11. Stability Testing of Biotechnological/Biological Products (Q5C)
12. Guidelines on stability evaluation of vaccines. In: WHO Expert Committee on
Biological Standardization: Fifty-Seventh report. Geneva: World Health Organization;
2011: Annex 3 (WHO Technical Report Series, No. 962).