confederation of indian industry recommendations for guideline changes in the vaccine approval...

INDEX

Proposed process for issuance of Form 29 [Rule 89] and proposal on usage of product for commercial supply 1

Proposed process for issuance of Form 45/ 45A, 41 & Form 10 [Rule 122A &122DA, 24A,23 & 27A] & condition of import of bulk having not less than 60% of residual 3

Proposed process for obtaining NOC for Clinical Trials 7

Proposed regulatory pathway for approval and commercialization of vaccines - Manufacturing of drug substance in parallel to new drug approval 11

Proposed recommendation for revision of Schedule Y requirements (to harmonize

with WHO guidelines) for Novel/Follow-up/Conventional Vaccines 13

Proposed recommendation on AEFI reporting 14

Proposed recommendation for the process of endorsement of manufacturing license in Form-28-D by CDSCO 15

Proposed process of vaccine batch testing by CDL, Kasauli 16

Proposed timelines for approval of different categories of post approval change by CDSCO 19

Proposal for omission of grant of license on Form 28-D 20

Other recommendations for Ease Of Doing Business 21

Abbreviations 22

PROPOSED PROCESS FOR ISSUANCE OF FORM 29 [Rule 89] AND PROPOSAL ON USAGE

OF PRODUCT FOR COMMERCIAL SUPPLY

Issuance of Test license on Form 29 by SLA with three working days

Confirmation of receipt to SLA

1. For New Chemical &

Biological Entities

B. For Known Vaccines

& Biosimilars Entities

Submission of application on Form 30 for grant of Form 29 test license to SLA and CLAA along with prescribed self declaration in hard copy as well as through email (Ref – Office memorandum from

DCGO dated 13.12.16)

Same procedure for both cases.

No prior joint inspection and

No NOC required from DCGI

NO NOC required for export of finished product manufactured under this license for test and analysis including Clinical Trial

Product manufactured under this license can not be used for commercial purpose ( Ref DCGI Circular dated 13.12.16)

Validity of form 29 is one year

1. Validity of Form 29 test license

may be extended for 3years.

2. Product manufactured under Form 29 should be allowed for commercial supply if the product has remaining shelf life greater than 9 months and is tested and cleared by CDL

Limited quantity of primary filled container meant for testing, stability, CDL testing and clinical trial shall be labeled as ‘Under license on Form 29’.

Remaining quantity of filled containers shall be kept unlabeled at prescribed storage temperature in segregated manner under relevant security. This shall be labeled upon receipt of permission for commercial use post licensure and sample shall be sent to CDL Kasuali for

record purpose only.

Current Process Analysis Recommendations

Joint inspection after issuance of test license in risk based

approach

1

Category:

Category Conditions to be fulfilled Supporting Data

Commercial usage of product post licensure manufactured under Test license on Form 29

Allowed 1- 6 1 - 5

Not Allowed 1-2, 4-6 Not Applicable

Sr. No. Conditions :

1 Product is manufactured in GMP compliant facility

2 Manufacturing license on Form 28 D has been obtained

3 Product has remaining shelf life of > 9 months at the time of grant of license

4 Safety and efficacy has been established through Clinical trial / bridging studies

5 Batches are tested and released by CDL

6 The consistency and process validation on drug product has been established

Sr. No. Supporting Documents

1 GMP Certificate and manufacturing license

2 CDL release report

3 Long term stability data

4 Process validation report

5 Revised label artwork

2

Analysis Recommendations

A. For New Product

Registration for Import

PROPOSED PROCESS FOR ISSUANCE OF FORM 45/ 45A, 41 & FORM 10 [Rule 122A&122DA,

24A,23 & 27A] & CONDITION OF IMPORT OF BULK HAVING NOT LESS THAN 60% OF RESIDUAL SHELF LIFE.

B. For Renewal of already

registered and licensed

product

Current Process

Import of bulk drug substance /new drug ( Form 45/ 45 A)

Submission of Form 44 application for grant of Form 45/45A to DCGI along with Product File as per following documents: 1. Covering letter2. TR-6 Challan3. Company authorization letter4. Manufacturing facility address5. Name of the drug to be imported 6. Dosage form7. Composition of the formulation8. Test specification active and inactive substances 9. Pharmacological classification of the drug substance 10. Manufacturer of the drug substance 11. Patent status12. Module 313. Bulk label (IP compliant)/label14. Undertaking letter

15. Registration status world wide

Submission of Form 40 application for grant of Form 41 to DCGI along with product file as per the following check list contains: 1.Covering letter

2. TR-6 Challan3. Power of Attorney 4. Import permission in Form 45/45A5. Wholesale or manufacturing license 6. Company authorization letter7. Schedule D(I) & D(II)8. Plant master file9. GMP certificate10. CoPP11. Regulatory status of the drug in the country of origin 12. Regulatory status of the drug worldwide 13. Free sale certificate14. Module 3/DMF15. Annex C

As per Rule 122A, an applicationfor the grant of permission to import a new drug/new bulk drugsubstance shall be made in Form 44 to the Licensing Authority

The application on 44 for grant of Form 45/45A for follow up vaccines/ biosimilars to be considered on parallel basis to Form 40 to reduce the approval timelines.

RC is valid for a period of three years and if the RC renewal application is made nine months before the expiry of the existing RC, the same shall be deemed to continue in force until orders are passed. (Rule No. 28-A)

Nine months time period is a too long / early requirement time for filling renewal application.

Generally it should take

maximum 2 months for

renewal of form 41 and Form 10 as the complete data/ information about product is available and already reviewed by the officials of DCGI at the time of grant of fresh /first time RC.

Existing Approval Timeline: Form 45A – 180 days Form 41 – 270 days Form 10 – 45 days

Total timeline to get Form 10 – 495 days

1) The timelinesfor grant of Fresh RC and import license (first time in India) should be reduced to maximum 6months.

2) The renewalprocess of RC of already registered products may be re-defined based on certain conditions.

3) Extend thevalidity of Registration Certificate (Form 41) and importlicense on Form 10 from three years to five years.

Proposed Approval Timeline For newRC: Form 45A – 90 days

Form 41 – 90 days

Form 10 – 30 days


Proposed Approval Timeline: Form 41 – 60 days Form 10 – 15 days


Not applicable

As per Rule 24-A, Application for RC is filed along with the requirements and process takes about 9 months for the grant of fresh RC.

As per Rule 24-A, the requirement of inspection is optional.

As per Rule 24-A, the requirement of testing is optional.

As per Rule 27-A; The period of nine months for registration is too long period and might hamper the timelines for product development and its launch.

Submission of Form 8 application for grant of Form 10 to DCGI along with product file as per the following check listcontains: 1. Cover letter

2. TR-6 challan3. Import permission Form 45/45A4. Wholesale / mfg. license5. Company authorization letter6. Form 41 (RC).7. Undertaking in Form 9.

8. labels

As per Rule 23 & Rule 24

As per Rule 27 & Rule 28

Registration Certificate (Form 41)

Import License of Drugs ( Form 10)

3

2nd Provision states “providedfurther that the Licensing authority shall not allow the import of any drug having less than 60% residual shelf life

period as on the date of import.

As per Rule 31

Residual Shelf life of bulk

at the time of import

This restriction in the residual shelf life is generally applicable for drug substance / API of Pharmaceutical products keeping in view of specific requirement of shelf life of drug product should not exceed the overall assigned shelf life of its corresponding drug substance/API.

The above requirement shall not be applicable on vaccines bulk/antigen being Biological in nature and as per below mentioned guidelines:-

WHO TRS 962, Annexure 3 “Guidelines on stability evaluation of vaccines”, under sub-section 5.3 : “Cumulative age of an antigen in the final product” clearly states – 1. “The stability of the

characteristics of a final product shouldbe guaranteedduring

the whole shelf-life,

irrespective of the age of the intermediates at the time they are used in the productionprocess”.

2. “In practice, stabilitydata on the finalproduct should include the datagenerated on theintermediatesof different agesused in the finalformulation“.

Thus, in view of above the existing restriction

The restriction of having residual shelf life not less than 60% at the time of import should be deleted in case of vaccine bulk/antigen.

The import of vaccine bulk /antigen should be permitted irrespective of its shelf life.

4

STEP WISE 'PROPOSED' PROCESS FOR ISSUANCE OF Form 45/45A, FORM 41 & FORM 10

A) FOR NEW PRODUCT REGISTRATION FOR IMPORT

B) FOR RENEWAL OF ALREADY REGISTERED AND LICENSED PRODUCT (FORM 41 &Form 10)

Application along with supporting data (including Form 44 and Form 40 along with TR-6 challans) for grant of Form 45/45A

and/or Form 41 from Licensing Authority (CLAA / DCGI)

Application in Form 8 to be applied to DCGI along with supporting data and TR-6 challan

Issuance of Form 10 based on the evaluation of

submitted supporting data by DCGI

Issuance of Form 45/45A and/or Form 41 based on evaluation of

supporting data by DCGI

Application on Form 8 to be applied to DCGI along with supporting data and TR-6 challan

Issuance of Form 10 CLAA / DCGI based on

the evaluation of submitted supporting data

Issuance of Form 41 based on Evaluation of

Supporting data by DCGI

Application in Form 40 along with supporting data and TR-6 challan for grant of Form 41 from

Licensing Authority (CLAA / DCGI)

Proposed Approval Timeline For new RC: Form 45A – 90 days

Form 41 – 90 days

Form 10 – 30days


Proposed Approval Timeline: Form 41 – 60 days Form 10 – 15 days


5

Category of application:

Category of application for Renewal of RC & Import license:


The RC and license may be deemed to continue in force

a) if the application for renewal issubmitted one months prior to expiry

1-3 1 - 4

b) if the application for renewal issubmitted six months prior to expiry

None 1, 4


1

There is no change or the change is minor with respect to product, production facility,

process, control or specifications, shelf life of registered product as declared by the

manufacturer as per CDSCO guidelines on Post Approval Change.

2

DCGI approval has been sought during valid registration period for any Supplement /

Notifiable change with respect to product, production facility, process, control or

specifications of registered product.

3 The granted RC and license on Form 10 is not temporarily suspended during the valid

period.


1 Supporting document as per CDSCO pre-screening check list for Re-registration on Form 41 and Import license on Form 10 (as applicable).

2 Declaration by the manufacturer on the changes with respect to product, production facility, process, control or specifications of registered product (if any).

3 Copy(s) of approval(s) of post approval change under Notifiable or supplement category under taken with respect to product, facility and process during the current validity of RC/Import license.

4 Copy of valid RC (Form 41) and import license (Form 10).

6

`


1. For New Chemical &

Biological Entities (Novel

vaccines)

B. For Follow on /

conventional Vaccines*

and Biosimilars

PROPOSED PROCESS FOR OBTAINING NOC FOR CLINICAL TRIALS

1) Availability of panel

experts at same time is

challenging in organizing

IND/SEC meetings at

frequent intervals.

2) IND/SEC panel(s)

generally consists of

experts on clinical trials.

Experts with

manufacturing and testing

experience.

In compliance to the order of

Hon’ble Supreme Court of India

dated 03. 01.2013, a system for

review of CT by 3 tier review

mechanism was devised for

New Chemical Entities (NCE).

Review of protocol for

grant of NOC by TC &

Apex committee for

follow on vaccines /

biosimilar, delays the

approval without any

value

Follow on vaccines*:

Vaccines which are

manufactured using

similar process/

technology to the already

licensed similar

vaccine(s) in India or

anywhere in globe and

which have been used

successfully for

immunization of

population.

9 Recommendations of TC are

deliberated further in Apex

Committee (AC) for some of the

proposals

1. Application to DCGI for grant

of permission to undertake

clinical trial on Form – 44

along with TR-6 challan as per

CDSCO guidelines

2. Query generated if application

found deficient

4. Proposal is presented to

IND/SEC and is deliberated in

6. Response submitted by

applicant (as applicable)

8. Recommendation of IND/SEC

are deliberated in Technical

Committee (TC)

10. Approval granted by DCGI

office as recommended by

IND/SEC /TC/Apex Committee

(Apex committee involvement is

on case to case basis)

Clinical Trial Application to be

filed as per Rule 122 DA

1) Same pathway is

applicable for obtaining

NOC for follow on /

conventional vaccines

as in case of NCE or

NBE (Novel vaccines).

2) The whole process is

quite long and affects

the timelines of product

development.

1. On-line review of documents submitted by applicant by SEC panelists for all vaccines will save time.

2. Clarifications sought in SEC meeting (if not critical) should be reviewed and approved by SEC and DCGI officials through an on-line system- or electronically within a fixed time frame without waiting for re-deliberation in the next schedule meeting.

3. Among subject experts,there should be at leastone clinician and one expert from vaccine manufacturing and testing background.

4. In case of follow on /conventional vaccines / biosimilars, a generic, already approved, protocol design for similar product for clinical trial (s) shall be followed.

5. Follow on vaccines should be considered differently than NCE/NBE category. Hence should not be forwarded to TC and Apex for review and approval should be granted based on the SEC review of Generic protocol.

6. There should be no need for a separate IND committee

3. Clarification response

submitted by the firm

Clinical Trial Application

to be filed as per Rule 122

DA

Re deliberation of clarification

response in the next IND/SEC

delays an application by an

average of 2 months’ time

5. Query/ clarification raised by

IND/SEC (if any)

7. Clarifications submitted are

re-deliberated in the next

IND/SEC

7

STEP WISE 'PROPOSED' PROCESS FOR ISSUANCE OF NOC FOR CLINICAL TRIAL(s)

A) FOR NEW CHEMICAL & BIOLOGICAL ENTITIES (Novel Vaccine)

1. Application to DCGI for grant of permission to undertake

clinical trial on Form – 44 along with TR-6 challan as per

CDSCO guidelines

2. Query generated if application found deficient

4. Online circulation and review of Proposal by SEC members

(password protected) followed by SEC meeting incase required

6. Response submitted by applicant (as applicable)

8. Recommendation of SEC are deliberated in Technical

Committee (TC)

10. Approval granted by DCGI office as recommended by

SEC/TC/Apex Committee (as applicable)

3. Clarification response submitted by the firm

5. Query/ clarification raised by SEC (if any)

7. Clarifications submitted are reviewed (on line) and approval

granted by SEC members

9 Recommendations of TC are deliberated further in Apex

Committee (AC) for some of the proposals

8

B) FOR FOLLOW ON & CONVENTIONAL VACCINES AND BIOSIMILARS

1.Application to DCGI for grant of permission to undertake

clinical trial on Form – 44 along with TR-6 challan based on

already approved protocol design for similar product /

bridging studies for similar type of product

2. Query generated if application found deficient

4. Online circulation (password protected)and review of Proposal by SEC members

6. Response submitted by applicant (as applicable)

8. Approval granted by DCGI office as recommended by SEC

3. Clarification response submitted by the firm

5. Query/ clarification raised by SEC (if any)

7. Clarifications submitted are reviewed (on line) and approval

granted by SEC members

9

Category of application :


Novel product None 1

Follow on/ conventional product

1 - 2 1 - 3

1 - 4 1-2, 4


1 Similar type of product is licensed in India or anywhere in globe and which have been used

successfully for immunization of population.

2 Already approved protocol design on similar product is used for proposed Clinical Trials

3 Adequate supporting documentation related to quality, safety and efficacy is available

4 Formulation with respect to active ingredients and key excipients are same as that of licensed vaccine


1 Application on Form 44 as per CDSCO guidelines with new CT protocol

2 Application on Form 44 as per CDSCO guidelines with approved protocol design onsimilar product/ Protocol for bridging studies on case to case basis

3 Information and supporting data on safety and efficacy of already licensed similar finishedproduct

10


Phase III CT completion

Application in Form 27D to SLA

Grant of MA in Form 46/46A

SEC/TC and joint inspection

License in Form 28D for

endorsement by CDSCO

Start of DS and DP

manufacturing

In-house testing and release

CDL testing and release

Product launch (1st lot

commercialized)

Grant of license in Form 28D

+

8 – 12

month

s

MA application in Form 44 toCDSCO

6 – 8

months

Dedicated

facilities

are idle

for 12

months

PROPOSED REGULATORY PATHWAY FOR APPROVAL AND COMMERCIALIZATION OF

VACCINES - MANUFACTURING OF DRUG SUBSTANCE IN PARALLEL TO NEW DRUG APPROVAL

Manufacturing DS and DP before Form

46 / Form 28D in approved commercial

facility or new commercial facility.

As per Rule 122 B, 76 and 78 of Drugs &Cosmetics Act 1940 and Rules 1945, no new drug should be manufactured forsale unless it is approved by theLicensing Authority (grant of manufacturing license – Form 28D)

Implications:

Vaccine approval process involves

several tier reviews by CDSCO, SEC,

TC, APEX and Joint Inspection and

State Licensing Authority, which

takes anywhere between 10 – 12

months.

Vaccine manufacturing and testing (In-

house and CDL) takes anywhere

between 6-8 months and much longer

for complex vaccines (10-12 months)

such as Pneumococcal and

combination vaccines where multiple

drug substances are required to be

manufactured and tested (more than

20 drug substances in some cases)

US/Europe:

Companies are allowed to manufacture

commercial inventory for drug

substance and drug products before

the letter of approval is received by

FDA or EMA. Product is only sold upon

grant of license.

Proposed Change:

Manufacturers should be allowed to

produce drug substance with

manufacturing procedure that was

submitted in theMarketing

Authorization (MA), with a

commitment that the formulation

and filling of drug product will be

done only post granting license

(Form 46 and 28D). A declaration to

that effect from manufacturer can

be submitted along with MA

Benefits:

This will significantly accelerate

product launch for the companies

in India against external

competition and ensure

availability of product to Indian

population much more rapidly

This will allow the manufacturers to

comply with CDSCO requirement to

launch the product within 6 months

from the approval. (CDSCO notice,

Dt. 10 Jan 2013), which may not

always be possible in case of

complex polyvalent vaccines.

11



Use of drug substance manufactured for Phase III / during Phase III CT in commercial batches of drugproduct post licensure ()

i. Allowed 1 -5 1-4

ii. Not Allowed None Not applicable


1 Approved commercial facility

2 Process validation has been performed

3 Phase III clinical trial completed successfully

4 Analytical method validation has been performed

5 Stability of the Drug substance has been demonstrated

6 Manufacturing of Drug substance being done in line with dossier submitted for grant of clinical trial NOC / Marketing authorization.

Sr. No. Supporting documents

1 Phase III clinical trial study report

2 manufacturing license of facility

3 GMP certificate of facility

4 Information on production process, process validation and stability studies of drug substance

5 Declaration / Commitment that formulation and filling of drug product will be carried out only upon obtaining Form 46 and 28-D

Proposed Regulatory Pathway for Approval and Commercialization of Vaccines

12

PROPOSED RECOMMENDATION FOR REVISION OF SCHEDULE Y REQUIREMENTS (TO HARMONIZE WITH WHO GUIDELINES) FOR

NOVEL/FOLLO-WUP/CONVENTIONAL VACCINES

Pre-clinical toxicity studies requirements as

per Schedule Y

For Novel/Follow-up/ConventionalVaccines

Recommendations for revision (to harmonize with WHO guidelines) for

Novel/Follow-up/Conventional Vaccines

Two species study requirement (single dose and repeat dose in two species):

1. Single dose toxicity studyin mice

2. Single dose toxicity studyin rats

3. Local tolerance toxicitystudy in rabbits

4. Repeated dose toxicitystudy in mice or rats

5. Repeated dose toxicitystudy in mice or rats andin rabbits

1. This is extensive study requirement in two

species without any potential advantage and does not meet global regulatory requirement.

2. As per WHO guidelines (WHOguidelines on nonclinical evaluation for Vaccines (2005): the preclinical toxicity

study should be adequate to identify and characterize potential toxic effects of a vaccine to allow investigators to conclude that it is reasonably safe to proceed to clinical investigation. The parameters to be considered in designing animal toxicology studies are the relevant animal species and strain, dosing schedule and method of vaccine administration, as well as timing of evaluation of end-points (e.g. sampling for clinical chemistry, antibody evaluation and necropsy). The route of administration should correspond to that intended for use in the clinical trials.

3. The above requirement for safety analysiscan be addressed with one study i.e. repeat dose toxicity study in sensitive species as per clinical schedule of vaccine administration (n+1= ); n= is proposed no of doses for human administration

1.Repeat dose toxicity study including localtolerance in sensitive species with following parameters/study design:

Animal species: The safety profile of a product

should be characterized in a species sensitive to the biological effects of the vaccine being studied (should develop an immune response to the vaccine antigen). One sensitive species of animal with intended route of administration should be sufficient

Dose, route of administration and control groups: The toxicity study should be performed

using a dose that maximizes exposure of the animal to the candidate vaccine and the immune response induced, The number of doses administered to the test animals should be equal to or more than the number of doses proposed in humans (n+1). To better simulate the proposed clinical usage, vaccine doses should be given at defined time intervals rather than as daily doses; the dosing interval used in the toxicity study may be shorter (e.g. an interval of 1-2 weeks) than the proposed interval in clinical trials in humans.

Parameters: Toxicity studies should address

the potential of the product for causing local inflammatory reactions, and possible effects on the draining lymph nodes, systemic toxicity and on the immune system. Parameters to be monitored should include daily clinical observations, weekly body weights, weekly food consumption, Local tolerance, clinical chemistry, histopathology etc.

2.Developmental toxicity studies:

- Developmental toxicity studies are usually not required for vaccines indicated for immunization during childhood.

- if vaccine is intended for pregnant women and women of childbearing potential, then development toxicity studies need to be performed

Current Requirement Analysis Recommendations

13

`

Current Process Challenges / Analysis / Other

guidelines

Recommendations

PROPOSED RECOMMENDATION ON AEFI REPORTING

Pre Licensure Safety Reporting

1. All SAEs reported in separate

colored envelopes as per

their outcome, by sponsor

2. All SAE to be reported within

15 calendar days

3. SAEs reported in “Form XI”

format

4. All AEs reported as interim or

final Clinical Study Report

5. All safety events are reported

as paper hard copy to

CDSCO.

Post Licensure Safety Reporting

1. All SUSARS/ SAEs reported

to CDSCO within 15 days of

knowledge, by MA holder

2. All ADRs reported to CDSCO

with no specific timelines of

reporting

3. Routine PSURs reported to

CDSCO at pre-specified

intervals

4. Parallel reporting to PvPI is

voluntary but not mandatory

5. All reports to CDSCO is

paper based reporting and to

PvPI is through VigiflowTM.

CHALLENGES:

Paper based reporting of all safety events

including SAE/ AEs in clinical studies,

AEFIs during post marketing period (ADR

and SUSARS) and PSURs during fixed

reporting intervals after approval

No data base for vaccine safety events is

available to identify clustering, increased

incidence over baseline, at CDSCO

SAE expert committees review individual

safety events without prospective

comparison to others events within same

of parallel studies

Safety Database not integrated with EPI

and direct AEFI reporting’s’ by doctors, to

PvPI

Manual entry at PvPI for all safety events

which are forwarded to PvPI by CDSCO

Lack of common database for all safety

events which are reported by various

stakeholders in India

To use and operationalize VAEIMS tool, developed and operational by WHO in countries like Sri Lanka and Chile, for sustainable safety data management in India using two prong approach:

1. To adopt a common safetyreporting and collection tool which can be used by vaccine manufacturers and also otherreporters for AE/SAE, AEFI and PSUR reporting.

2. To build a common safetydatabase which can be simultaneously used by NRA, PvPIcenters and expert committees on vaccine safety (AEFI and SAEexpert committee).

The new IT tool/ system will be installed in

standalone windows based computers at

point of safety data reporting at vaccine

manufactures and at CDSCO. The data entry

and edit facilities will be available for

registered users with computers. There will

be a built-in system to track the recent and

new reporting which will be updated in safety

database at CDSCO along with information

on when & who updated it. On the receipt of

the e-mail by the focal person of the central

database at CDSCO, the upload button will

be clicked and the reporting form (SAE/ AEFI

and PSUR) will be uploaded to the central

database system. The system will be

accessible only to the authorized users.

Each manufacturer/ reporter will have a

unique user ID (e-mail address) and

password to access the VAEIMS. The

database administrator (at a level decided by

the DCGI) will provide access the system.

The rights will be decided by the

requirements requested by DCGI. Entry and

edit facilities for safety reporting will be

available at all registered

manufacturers/users with computers.

The VAEIMS will provide CDSCO with

capability to rapidly detect and analyse

vaccine safety concerns on real time basis.

Systems will not only monitor vaccine safety

during clinical trials (where only relatively

common events can be detected) but in the

post introduction phase as well. Integration

of the tool with PvPI centres in India, so that

AEFI data can be shared and managed by

stakeholders collectively. This is in line with

the strategic objective 4 (Develop

internationally harmonized tools and

methods for vaccine pharmacovigilance) of

the Global vaccine safety blueprint and

under objective 2 of the Global Vaccine

Action Plan (GVAP) 2011-2020.

14

Parenterals and vaccines & Sera.

Recommendations

PROPOSED RECOMMENDATION FOR THE PROCESS OF ENDORSEMENT OF

MANUFACTURING LICENSE IN FORM-28-D BY CDSCO

Current Process Analysis

New Drug Approval in Form-46

granted by CDSCO 1. The step of endorsing the

manufacturing license by CDSCO may be abolished andSDCA be authorized to directly grant manufacturing license inForm 28-D based on New DrugApproval.

2. State Licensing Authorities may be authorized to issue manufacturing licenses without need of any additionalinspections post grant of new drug permission in line withother injectable products like Anticancer, Hormones, andSteroids etc.

Application in form 27-D is applied to SDCA for the grant of manufacturing license in Form-28-D

Joint Inspection is conducted by SDCA, CDL, zonal and central CDSCO

CAPA submission, if Applicable

Form-28-D is forwarded by SDCA

to CDSCO for Endorsement

CDSCO endorses the manufacturing license and returns back to SDCA for final

release of Form-28-D

The process of endorsing of Form-28-D by CDSCO is an additional activity and does not

create any value.

SDCA, then finally releases the Manufacturing License in Form-

28-D

1. Rule 122 B, 76 and 78 ofDrugs & Cosmetics Act 1940and Rules 1945, ‘no new drugshould be manufactured forsale unless it is approved by the Licensing Authority (grantof manufacturing license – form 28D)’

2. Repeated Joint Inspection are conducted by SDCA and CDSCO including the inspections for CAPA verifications.

3. This leads to wastage of lot of time and resources of government and the industry.

4. This delays the product launch and access of vaccines to public even afterthe New Drug permission has

been granted by CDSCO.CAPA compliance and verification

inspection

Current Provision: As defined in Drugs & Cosmetics Act under the Drug Control-Functions of Central and State Governments, CDSCO functions as Central Licensing Approving Authority to approve/endorse the manufacturing licenses for manufacturing of certain categories of drugs i.e. for Blood Banks, Large Volume Parenterals and vaccines & Sera.

Suggested Provision: The power to approve the manufacturing license for products like vaccines & Sera may solely be vested with

SDCA.

15

Current Process

Currently, CDL, Kasauli has a practice to test the batches and also releases the same on scrutiny of Lot Summary Protocols and other relevant documents as submitted by the company.

The samples of first Three batches of new product is sent to CDL Kasauli along with the CMC data for approval/NOC before release into the market.

Subsequently, every batch is sent to CDL along with the Lot Summary Protocols, CoAs and other relevant documents for testing and further release for supply.

As per Rule 78 of D&C act, conditions of license in [Form 28, Form-28-B or Form-28-D], the licensee shall either in his own laboratory or in any laboratory approved by the Licensing Authority test each batch or lot of the rawmaterial used by him for the manufacture of his product and also each batch of the final product and

shall maintain records or registers.

Analysis

1. Only vaccines procured by Government of India and UN agencies, if requested by them, be tested and released as per existing process at CDL, Kasauli.

Vaccine batches testing be limited to not more than 10% of the batches manufactured by a vaccine manufacturer for a particular vaccine subject to minimum 3 batches per vaccine per year.

2.Remaining 90% of vaccine batches be released on submission of scrutiny of samples, lot summary protocols, CoA and samples within 10 working days post submission as part of ease of doing business in India.

Recommendations

Testing & release of vaccine batches by CDL,

Kasauli

PROPOSED PROCESS OF VACCINE BATCH TESTING BY CDL, KASAULI

Suggestions in line withD&C Act

Requirement of testing for

every batch of vaccines by

CDL not mandatory as per

D&C Act

16


Testing and release of vaccine batches by CDL, Kasauli:


The requirement of CDL testing of each batch before release to market

a) CDL testing and release of first threebatches of vaccines required, if

1 1-6

b) CDL Testing and release of eachbatch of vaccine required, if

2 2- 5

c) CDL release of vaccine batches basedon scrutiny of submitted lot summaryprotocols , documents and samples ,

3 2-5


1 If there is no change in the manufacturing &testing process and in the scale of production.

2 If the supply of vaccines intended for Government of India (GOI) and UN agencies and

testing and release, if requested by the concerned agencies.

3 Considering not more than 10% testing of overall batches manufactured, subject tominimum 3 batches per vaccine per year.


1 Chemistry Manufacturing Control (CMC)

2 Vaccine Samples

3 Lot Summary Protocol (LSP)

4 Company CoA

5 In vivo Potency Probit Sheet

6 Active Raw Materials (ARMs) CoA

17

Suggestions:

1. More CDL regional testing laboratories be set up in existing Govt. Institutes and laboratories in UtterPradesh, Andhra Pradesh/ Telangana , Maharashtra , Tamil Nadu and Gujarat to release vaccine forsale in order to align with increase in vaccine manufacturers country wide as part of attractinginvestments by these state governments.

Some of the exiting Govt. Institutes/Laboratories could be:

1) National Institute of Biologicals (NIB)(Ministry of Health & Family Welfare)Government of India, Plot No. A-32, Sector-62Institutional Area,NOIDA-201 309 (U.P.), INDIA.Telephone-: +91 120-2400022, 120-2400072Fax: +91 120- 2403014.Email: [email protected]

2) Haffkine Institute for Training, Research and TestingAcharya Donde Marg, Parel, Mumbai -400012, MaharashtraTelephone - +91 22-24160947, 22-24160961, 22-24160962Fax: +9122-24161787.Email: [email protected]

3) Pasteur Institute of India, Connor, Tamil Nadu.Coonoor - 643 103,Nilgiris,.Tamil Nadu, India.Telephone- +91 423-22 31 350, 423- 22 31 846

Fax: +91 423-22 31 655 Email: [email protected]

4) Institute of Preventive Medicine,

PH Labs & Food (H) Administration,

Narayanaguda,

Hyderabad 500029, Telangana, India.

Telephone- +91 40-27560191

FAX: +91 40- 27567894

Mobile: +919849905227 (Director)

Benefit of above Proposal

NCL ,CDL Kasauli can invest its time and resources in following :

Developing vaccine strains needed for developing new vaccines in India in line with country'srequirements.

Developing national biological reference Standards, Master cell banks, characterizing biologicalproducts during development needed by vaccine industry in developing and releasing vaccines.

Harmonizing analytical methods across different companies and international accredited labs byWHO.

Act as teaching faculty in all Indian universities.

Provide training to students in GLP, staring development, reference standard development asindustrial training curriculum as part of skill development program relevant to industry.

Auditing manufacturers in QC at least once a year ensuring manufacturers own responsibility oftheir products and be accountable.

18

Current Process Analysis

Level I-Supplement Change

Level II-Notifiable Change

Recommendation

Change Categories as per CDSCO Post Approval Change

guidelines

CDSCO may withdraw the pointno 1 of notification dated05th August 2010, so as to reinstate its previous provisionof deemed approval of the postapproval changes (Supplement/ Notifiable) in light ofstreamlining the regulatory processes for better and timely accessibility of vaccines to the public.

Approval Process ProposedRecommendations

PROPOSED TIMELINES FOR APPROVAL OF DIFFERENT CATEGORIES OF POST APPROVAL

CHANGE BY CDSCO

As per the guidelines on PostApproval Change (No. PAC/1108, Version 1.1), if within 30 days of the date ofthe acknowledgement ofreceipt of a valid supplementchange notification, the DCGIhas not sent the holder its opinion, the change shall be deemed to have been

accepted by DCGI.

As per the guidelines on PostApproval Change, if within 15 days of the date of the acknowledgement of receiptof a valid Notifiable change notification, the DCGI has notsent the holder its opinion; the change shall be deemed to have been accepted by

DCGI.

The provision of aforesaid deemed approvals on Post Approval changes underSupplement Change &Notifiable change was omitted by CDSCO vide clarification & amendments notification dated 05th August

2010.

19

PROPOSAL FOR OMISSION OF GRANT OF LICENSE ON FORM 28-D

Current

Process

Form 46A/46

[Permission /

Approval for

manufacture of

new bulk drug

substance / new

drug

formulation].

Form 28D

[Licence to

manufacture for

sale or for

distribution of

Large Volume

Parenterals/Sera

and Vaccines

specified in

Schedules C and

C(I) excluding

those specified

in Schedule X)].

Form 46A/46 [Permission /

Approval for manufacture of

new bulk drug substance / new

drug formulation].

AND

Commercial manufacturing of

drug substance and drug

product cannot be initiated until

manufacturing license in Form

28D.

Analaysis

There is no

such

conditions

What

happens in

US/Europe

Recommendations

Shall have only Form 46A/46

[(Permission/Approval for

manufacture of new bulk drug

substance / new drug

formulation for sale or for

distribution of Large Volume

Parenterals / Sera and

Vaccines specified in

Schedules C and C(I)

excluding those specified in

Schedule X)].

Form 28D can be omitted.

The Form 46A/46 number

(Bulk /MF-XXX/YYYY) shall be

included in all the artworks in

place of existing manufacturing

license number (i.e. Form 28D

number).

20

Sr. No Topic Current Process in India What happensin US/Europe

Recommendations

1. Various committeeapprovals

Involvement of number of government agencies and review committees fordevelopment of vaccines (DCGI, GEAC, RCGM, SEC,TRC, APEX, State DCA etc.).

Not known To have a single windowclearance/committee fornecessary approval.

2. Schedule M section 3.10: Temperature and humidity in the aseptic areas shall be 27 ± 2 degree centigrade and relative humidity 55% ± 5, respectively

Not known To be changed RH limit to < 65 %R.H. to > 30 % in-line with ISO 14644-4: Section No: F.2.6 requirements.

3. Schedule M section 3.10: Air Borne Particulate Classification for Manufacture of Sterile Products.

Not known To be revised as per ISO guidelines.

4. Schedule M section 4.2: Recommended limits for microbiological monitoring of clean areas“ in operation” ; air sample CFU/m2, settle plate exposure for 2 hours.

Not known To be revised; air sample CFU/m3 and not CFU/m2, settle plateexposure for 4 hours instead of 2 hours.

5. NOC, PostApproval changes

New requirement of joint inspection for approval of notifiable changes (Level-II) is resulting in delay of review and approval of these moderate changes.

Not known State DCA to develop capabilities of vaccine experts at zonal level rather to support joint inspection. Delegation of power to CDSCO, Zonal office to issue NOC for grant of test license and grant of ExportNOC for vaccines and biologicals.

6. Price Control The prices of raw materials arerising day by day but the cost of the products remains the same or goes down (as per NPPA).

Not known Drug Prices Control Order is oneof the challenges for the industry.The raw material cost can be considered before raising the product price.

7. Packaging For small container (such as e.g. vaccine vial), the composition may be printed on the package in which suchsmall container is issued for sale.

Not known Currently this rule is only applicable to ampoules, however for multivalent vaccines the length of the text of composition is way big to fit on tiny label. Composition of vaccine will be included next packaging levels where more space available.

8. Banning of PET - Vaccines, biologicals and other products which are stored at low temperatures.

Not known Exclude the Banning of PET - Vaccines, biologicals and other products which are stored at low temperatures (GSR - 701(E) dated 29 Sep 2014).

OTHER RECOMMENDATIONS FOR EASE OF DOING BUSINESS

21

ABBREVIATIONS

AC Apex Committee ADR Adverse Drug Reaction AE Adverse Event AEFI Adverse Event Following Immunization CAPA Corrective and Preventive Action CDL Central Drugs Laboratory CFU Colony Forming Unit CLAA Central Licensing Appellate Authority CMC Chemistry and Manufacturing Control COOPP Certificate of Pharmaceutical Product CT Clinical Trial D&C Act Drug and Cosmetics Act DP Drug Product DS Drug Substance EMA European medicines agency EPI Expanded Program on Immunization FDA Food and Drug Administration GEAC Genetic Engineering Approval Committee GMP Good Manufacturing Practice IND Investigational New Drug ISO International Organization for Standardization MA Marketing Authorization MA Marketing Authoristion NBE Novel Biological Entity NCE Novel Chemical Entity NRA National Regulatory Authority PSUR Periodic Safety Update Report PvPI Pharmacovigilance Programme of India QC Quality Control RC Registration Certificate RH Relative Humidity SAE Serious Adverse Event SDCA State Drug Controller Authority SEC Subject Expert Committee SLA Service Level Agreement SUSARs Suspected Unexpected Serious Adverse Reactions TC Technical Committee TRC Technical Review Committee VAEIMS Vaccine Adverse Events Information Management System WHO World Health Organization

22

confederation of indian industry recommendations for guideline changes in the vaccine approval...

Healthcare