Date: 2024-01-11Category: Not ApplicableState: Union GovernmentCountry: India
Evaluation of certain pre 1988 permitted Fixed Dose Combinations FDCs de novo for manufacture for sale in the country without due approval from Central Licensing Authority
**Executive Summary:**
This notice outlines the evaluation process for pre-1988 Fixed Dose Combinations (FDCs) manufactured and sold without Central Licensing Authority approval, following Supreme Court orders and the recommendations of an Expert Committee. It details required actions for manufacturers holding State Licensing Authority (SLA) licenses, including data generation, clinical trials, and application submissions, with a deadline of six months for existing license holders to apply. It also describes the conditions for granting product licenses for FDCs declared as rational.
**Key Points / Main Content:**
* **Background:**
* Follows up on a 2013 request for manufacturers to prove the safety and efficacy of FDCs approved by State Licensing Authorities (SLAs) without DCGI approval.
* Considers Supreme Court orders from 2017 and 2019 and the findings of an Expert Committee constituted in 2021.
* **Expert Committee Recommendations (1st Notice):**
* **Paracetamol IP 500mg/Phenylephrine Hydrochloride IP 10mg/Caffeine Anhydrous IP 32mg tablets:** Continued manufacturing and marketing permitted, contingent on conducting a Phase IV Clinical Trial within one year to generate safety and efficacy data.
* **Caffeine Anhydrous IP/Paracetamol IP/Phenylephrine Hydrochloride IP/Chlorpheniramine Maleate IP (various strengths):** Continued manufacturing and marketing permitted with conditions: retail sale only on RMP prescription, package insert warnings for cardiovascular patients, and a minimum paracetamol dose of 500mg. A Phase IV Clinical Trial is also required within one year.
* **Paracetamol IP 250mg/Propyphenazone 150mg/Caffeine 30mg tablets:** Continued manufacturing and marketing permitted for mild to moderate headaches under conditions: usage limited to 5-7 days, retail sale only on RMP prescription, and an Active Post Marketing Surveillance (PMS) study within one year.
* **Application Requirements:**
* **Manufacturers with SLA licenses before 01.10.2012:**
* Form CT21
* Fees as per New Drugs and Clinical Trials Rules, 2019
* FDC name and composition
* SLA Product Permission
* Manufacturing license copy (Form 25/28)
* Phase IV trial/PMS protocol commitment.
* **New Manufacturers:**
* Form CT21
* Fees as per New Drugs and Clinical Trials Rules, 2019
* FDC name and composition
* SLA Product Permission in Form 29
* Manufacturing license copy (Form 25/28)
* 6-month accelerated stability data
* FDC test specifications and method of analysis
* Phase IV trial/PMS protocol commitment.
* **Deadline for Existing Manufacturers:** Manufacturers holding licenses from SLAs before 01.10.2012 who haven't applied to DCGI must submit applications within 6 months.
* **Expert Committee Recommendations (2nd Notice):**
* **Imipramine Hydrochloride IP 25mg/Diazepam IP 2mg, 5mg tablets:** Continued manufacturing and marketing permitted for comorbid anxiety conditions. Treatment duration should not exceed 6-8 weeks.
* **Chlorpheniramine Maleate IP/Ammonium Chloride IP/Sodium Citrate IP (various strengths) Syrup:** Continued manufacturing and marketing permitted, contingent on modifying the prescribing information/label to clearly mention dose schedules for adults and children, keeping in view of the dose range without exceeding the maximum permissible dose.
* **Product License Pathway:**
* Applicants must submit requisite fees through Bharatkosh to CDSCO for each FDC.
* Submit application to SLA as per Drugs and Cosmetics Rules 1945 with details of FDCs, stability data, test specifications, label and other documents.
* SLA to grant product license without NOC from DCGI if license conditions are fulfilled and quality is verified.
* Manufacturers must submit Periodic Safety Update Reports (PSURs) as per New Drugs and Clinical Trial Rules, 2019 to the Central Licensing Authority (DCGI).
* **General Compliance:**
* All manufacturers must comply with the Expert Committee's recommendations regarding prescribing information/label revisions.
**Impact Analysis:**
* **State/UT Drugs Controllers:**
* *Impact:* Responsible for ensuring manufacturers in their jurisdiction comply with the notice, including informing them of the requirements and deadlines. They are also responsible for granting product licenses after quality verification as well as sending information to manufacturers for FDCs declared rational.
* *Action Required:* Inform manufacturers of the requirements, verify FDC quality before license grants, and ensure compliance with application submission deadlines.
* **Manufacturers (Existing and New):**
* *Impact:* Must adhere to the application process, data generation requirements (including clinical trials/PMS), and labeling revisions as outlined in the notice to continue manufacturing and selling pre-1988 FDCs.
* *Action Required:* Prepare and submit applications with required documentation by the specified deadlines, conduct necessary clinical trials/PMS, and revise product labeling as per the Expert Committee's recommendations.
* **Central Drugs Standard Control Organization (CDSCO):**
* *Impact:* Oversees the evaluation process, receives applications, and ensures compliance with the established procedures.
* *Action Required:* Process applications, monitor compliance, and enforce the regulations outlined in the notice.
Key Entities Referenced
Fixed Dose Combinations: FDCs, the primary subject of the policy, referring to combinations of multiple active pharmaceutical ingredients in a single dosage form.
Central Drugs Standard Control Organization: CDSCO, the national regulatory body for pharmaceuticals and medical devices in India, responsible for drug approval and regulation.
State Licensing Authority: SLA, the state-level authority responsible for issuing manufacturing licenses for drugs within their respective states.
Ministry of Health and Family Welfare: The Indian government ministry responsible for health policy and programs.
Dr. M. S. Bhatia: Professor Head, Do Psychiatry, University College of Medical Sciences, New Delhi; Chairman of the Expert Committee constituted to examine pre-1988 FDCs.
New Drugs and Clinical Trials Rules 2019: The regulatory framework governing new drug approvals and clinical trials in India.
Drugs and Cosmetics Act, 1940: The primary legislation in India governing the import, manufacture, distribution, and sale of drugs and cosmetics.
New Delhi: Location of Ministry of Health and Family Welfare, Nirman Bhawan, New Delhi
File No. 4-01/2013-DC (Misc. 13-PSC) (Pt. Il) (Sub Part-1)
Govt. of India
Directorate General of Health Services
Central Drugs Standard Control Organization
(FDC Division)
Dated:
41 JAN 202
NOTICE
Subject: Evaluation of certain pre 1988 permitted Fixed Dose Combinations
(FDCs) de novo for manufacture for sale in the country without due
approval from Central Licensing Authority -regarding.
This is with reference to this office letter dated 15.01.2013 whereby all the
State/UT Drugs Controllers were requested to ask the concerned manufacturers
in their State to prove the safety and efficacy of FDCs within 18 months which
were permitted by State Licensing Authorities without due approval from the office
of DCG(I).
In continuation to Hon'ble Supreme Court order dated 15.12.2017 and
14.02.2019, Accordingly, Ministry of Health & Family Welfare vide order No.
X11035/53/2014-DFQC (Part-IV) dated 02.02.2021 constituted an Expert
Committee under the Chairmanship of Dr. M. S. Bhatia, Professor & Head, D/o
Psychiatry, University College of Medical Sciences, New Delhi for examining
certain pre-1988 FDCs denovo licensed for manufacturing for sale in the country
without due approval from Central Licensing Authority.
The Expert Committee submitted its report accordingly on these 19 FDCs claimed
to be pre-1988 after holding a series of meetings as well as by providing hearing
to the stakeholders wherein, the Committee after detailed deliberation
recommended for generation of data w.r.t. following 03 FDCs:-
Sr.No. | Name of FDC as per the | Recommendations
public notice
1. Paracetamol IP 500mg +/The committee recommended for
Phenylephrine continued manufacturing and marketing
Hydrochloride IP 10mg + | of the FDC with the condition to generate
Caffeine Anhydrous’ IP | safety and efficacy data by way of
32mg tablets conducting Phase IV Clinical Trial.
Accordingly, Phase IV Clinical Trial is
required to be conducted to generate the
data within time frame of one year.2. Caffeine Anhydrous IP + The committee recommended _ for
Paracetamol IP + continued manufacturing and marketing
Phenylephrine of FDC with following conditions:
Hydrochloride IP + a. FDC shall be sold by retail
on the prescription of a
Chlorpheniramine Maleate
R.M.P. only
IP (15mg + 500mg + 5mg +
b. Package insert should also
2mg, 30mg + 500mg +
mention caution for patients
5mg + 2mg, 30mg + 500mg
suffering from
+ 10mg + 2mg, 30mg +
cardiovascular diseases.
500mg + 10mg + 4mg &
c. Dose of Paracetamol in the
30mg + 650mg + 10mg +
FDC should be minimum
2mg) tablets
500mg
The Committee also recommended to
conduct a Randomized comparative,
Phase IV Clinical Trial comparing the
FDC with the individual ingredients
present in the FDC.
Accordingly, Phase IV Clinical Trial is
required to be conducted to generate the
data within time frame of one year.
3 Paracetamol IP 250mg + The committee recommended _ for
Propyphenazone 150mg + continued manufacturing and marketing
Caffeine 30mg tablets of the FDC for mild to moderate
Headache with the conditions that:
a. FDC shall not be taken more than
5 to 7 days
b. FDC to be sold by retail on the
prescription of a R.M.P. only’.
c. Further, the firm(s) shall conduct
Active PMS study to generate
safety and efficacy data on the
FDC.
Accordingly, Active Post Marketing
Surveillance is required to be conducted
to generate the data within time frame of
one year.
With the approval of Ministry, it has been now decided to follow the pathway for
clearance of such subsequent applications as under:-
1. Documents required in case of manufacturers already holding licenses from
State Licensing Authority (SLA) before 01.10.2012 for the proposed FDCs
shall at least contains:-
a) Form CT-21 (duly filled, signed and stamped)
b) Fees as specified in sixth schedule of New Drugs and Clinical Trials
Rules 2019 through Bharatkosh.
c) Name and composition of the FDC
d) Product Permission issued by SLA
e) Copy of Manufacturing license in Form 25/28f) Phase IV trial protocol / commitment. for conducting Active Post
Marketing Surveillance study protocol, as the case may be.
2. Documents required in case of new manufacturers for the proposed FDCs
shall at least contain:-
a) Form CT-21 (duly filled, signed and stamped)
b) Fees as specified in sixth schedule of New Drugs and Clinical Trials
Rules 2019 through Bharatkosh.
c) Name and composition of the FDC
d) Product Permission issued by SLA in Form 29
e) Copy of Manufacturing license in Form 25/28
f) Stability studies data (06 months accelerated)
g) Test Specifications of the FDC alongwith Method of Analysis
h) Phase IV trial protocol / commitment for conducting Active Post
Marketing Surveillance study protocol, as the case may be.
3. All the manufacturers who are already holding licenses from State Licensing
Authorities for such FDCs before 01.10.2012 and did not apply to DCG (I) are
required to submit their applications to this Directorate at the earliest but not
later than 6 months, failing which their applications will not be considered and
their licenses will be considered as without legal validity.
4. Manufacturers shall comply with the recommendation of the expert committee
w.r.t. revision of the prescribing information/label.
In view of above, all concerned stakeholders are required to follow above
procedure for clearance of such cases.
Yours/faithfully
Qu)
(Dr. Rajeev Singh Raghuvapyishi)
Drugs Controller General (Ifidia)
To:-
All State/UT Drugs Controllers/All Zonal/Sub Zonal offices of CDSCO.
Copy to:-
1. PPS to Secretary/AS(F&D)/JS(R), Ministry of Health and Family Welfare,
Nirman Bhawan, New Delhi.
2. Indian Drug & Pharmaceuticals Associations/Website of CDSCO.File No. 4-01/2013-DC (Misc. 13-PSC) (Pt. Il) (Sub Part-1)
Govt. of India
Directorate General of Health Services
Central Drugs Standard Control Organization
(FDC Division)
Dated: 4 | JAN 2024
NOTICE
Subject: Evaluation of certain pre 1988 permitted Fixed Dose Combinations
(FDCs) de novo for manufacture for sale in the country without due
approval from Central Licensing Authority -regarding.
This is with reference to this office letter dated 15.01.2013 whereby all the
State/UT Drugs Controllers were requested to ask the concerned manufacturers
in their State to prove the safety and efficacy of FDCs within 18 months which
were permitted by State Licensing Authorities without due approval from the office
In continuation to Hon'ble Supreme Court order dated 15.12.2017 and
14.02.2019, Ministry of Health & Family Welfare accordingly, vide order No.
X11035/53/2014-DFQC (Part-IV) dated 02.02.2021 constituted an Expert
Committee under the Chairmanship of Dr. M. S. Bhatia, Professor & Head, D/o
Psychiatry, University College of Medical Sciences, New Delhi for examining 19
pre-1988 FDCs denovo licensed for manufacturing for sale in the country without
due approval from Central Licensing Authority.
The Expert Committee submitted its report on these 19 FDCs claimed to be pre-
1988 after holding a series of meetings as well as by providing hearing to the
stakeholders wherein, the Committee after detailed deliberation considered
following 02 FDCs as rational with certain conditions: -
Sr. | Name of FDC as per the public | Recommendations
No. | notice
ala Imipramine Hydrochloride IP +] The committee recommended for
Diazepam IP (25mg + 2mg & 25mg + | continued manufacturing and
5mg) tablets marketing of the FDC. FDC shall be
indicated for co-morbid anxiety |
conditions and duration of the :
treatment should not exceed 6 to 8 :
weeks. ;
2. Chlorpheniramine Maleate IP + The committee noted that the firms are |
Ammonium Chloride IP + Sodium | manufacturing the FDC in different |
Citrate IP (2mg + 100mg + 50mg/5ml | strengths. The committee also noted |
& 2.5mg + 125mg + 55mg/5ml Syrup | that as per literature available, Sodium
Citrate is administratered 0.3gm to 1gm
in divided doses in a day and |
Chlorpheniramine Maleate is |
|
administratered 4mg to 16mg in divided
doses in a day.
After detailed deliberation, the
Committee recommended forcontinued manufacturing and
marketing of the FDC with the condition
that the firm should modify the
prescribing information/label by clearly
mentioning the dose schedule for
adults and children keeping in view of
the above stated dose range without
exceeding the maximum permissible
dose.
Accordingly, with the approval of the Ministry of Health and Family Welfare, it has
been now decided to follow the following pathway for grant of product license by
SLAs for these FDCs:
1. Applicants shall submit the requisite fees preferably through Bharatkosh for
each FDC to CDSCO as specified under Drugs and Cosmetics Act, 1940
and existing Rules thereunder.
2. The applicant shall submit application to the concerned SLA as per the
provisions of Drugs and Cosmetics Rules 1945 for grant of product
manufacturing license giving the details of FDCs, stability studies data (06
months accelerated), Test Specification of the FDC alongwith Method of
Analysis as well as label and other documents as required for grant of
product license under Drugs and Cosmetics Rules.
3. State Licensing Authority shall grant the product license of such FDCs
without NOC from DCG (|), if conditions of license under the Drugs and
Cosmetics Rules, which need to be verified by SLA, are found to have
been fulfilled. The SLAs shall verified the quality of such FDCs of each
applicant/manufacturer, before grant of license.
4. Every manufacturer permitted to manufacture these FDCs shall submit the
periodic safety update reports (PSURs) as per New Drugs and Clinical
Trial Rules, 2019 to the Central Licensing Authority as defined in Rule ‘3’
i.e. DCG(l). Failure to submit the PSURs shall be considered as
contravention of these Rules.
5. Manufacturers shall comply with the recommendation of the expert
committee w.r.t. revision of the prescribing information/label.
In view of above, you are requested to ask the concerned stakeholders to follow
the above procedure for obtaining the manufacturing license w.r.t. FDCs declared
as rational by Dr. M. S. Bhatia Committee.
Yours faithfully,
To:-
All State/UT Drugs Controllers/All Zonal/Sub Zonal offices of CDSCO.
Copy to:-
1. PPS to Secretary/AS(F&D)/JS(R), Ministry of Health and Family Welfare,
Nirman Bhawan, New Delhi.