This document discusses regulatory approval pathways for vaccines in India and WHO prequalification. It provides an overview of the Indian regulatory pathway, which involves approvals from regulatory bodies like the Central Drugs Standard Control Organization and State Licensing Authority. The process includes import/manufacturing licenses, clinical trials approval, post-trial manufacturing license, and other approvals. It also summarizes the WHO prequalification process, which provides an independent assessment of vaccine quality, safety and efficacy. The process involves dossier submission and evaluation, sample testing, site inspections, annual reporting by manufacturers, and reassessments.

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VACCINES
Regulatory Approval Path way in
India &
W.H.O. Prequalification.
by
Y.SRINIVASA RAO; M.S. (Drug Development &
Regulatory Affairs)

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Overview
 Introduction.
 Regulatory pathway in India.
 WHO_ Prequalification.

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Introduction
Definition: A biological preparation that provides active acquired immunity to a
particular infectious disease.
o Typically contains an agent that resembles a disease-causing microorganism.
o Made from weakened or killed forms of the microbe, its toxins, or one of its
surface proteins.
o Stimulates the body's immune system.
o Protect against many different diseases.

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Introduction
Types –
1. Live, attenuated
MMR (Measles, mumps, rubella ) Varicella, Influenza, Rotavirus.
2. Inactivated/Killed
Polio (IPV), Hepatitis.
3. Toxoid (inactivated toxin)
Diphtheria, tetanus.
4. Subunit/conjugate
Hepatitis B, Influenza (injection), Haemophilus influenza type b (Hib),
Pertussis, Pneumococcal.

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Introduction
Components:
• Antigens
‒ Derived from the structure of disease-causing organisms.
• Stabilizers
‒ Maintain its effectiveness during storage.
• Adjuvants
‒ a component that potentiates the immune responses to an antigen and/or modulates it
towards the desired immune responses.
• Antibiotics
‒ To prevent bacterial contamination of the tissue culture cells.
• Preservatives
‒ Added to multidose vaccines to prevent bacterial and fungal growth.

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Regulatory pathway in India

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Regulatory pathway in India
Regulations:
 All vaccines are considered as new drugs (Rule 122-E of D & C act).
 Schedule C and C1.
 Applications through SUGAM portal.
 Applicable Guidelines.
– Regulations and Guidelines for r- DNA Research and Bio containment 2017.
– Generating preclinical and clinical data for r-DNA vaccines, diagnostics and other biological
Guidelines, 1999.
– Guidelines and Handbook for Institutional Biosafety Committees (IBSCs), 2020.
– Drugs and Cosmetics Act, 1940 and Drugs & cosmetics Rules, 1945.
– New Drugs and Clinical Trials rules 2019.
– CDSCO guidance for industry, 2008.

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Regulatory pathway in India
Application Forms

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Regulatory pathway in India
1. Import of Cell bank
̽Annexure-III: Revised simplified procedure/guidelines on import, export and exchange of regulated Items, 2020
Application to import (Form B1) OF GMO
and products thereof for R& D to IBSC
IBSC evaluates completeness of application and ensures
institutional capacity in safe handling, storage and disposal of
materials as per DBT guidelines and recommends to RCGM
IBSC recommends to
RCGM, if quantities
exceeds set limits for
Category 1˟ or 2˟
IBSC recommends to
RCGM, if items not
covered in simplified
guidelines
IBSC approves,
if items belongs
to Category 1˟
RCGM Secretariat approves
in consultation with experts
on case by case studies
Require approval
by RCGM / RCGM
Secretariat
On request secretariat will
issue NOC / permit to
facilitate custom clearance

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Regulatory pathway in India
2. Test License to Manufacture
Application (Form CT- 10) to CDSCO –Zonal Office
for permission to manufacture New Drug for CT or
examination, test and analysis
Grant of Permission
(Form CT-11)
Application (Form 30) to SLA for
Licence to manufacture New Drug for
CT or examination, test and analysis
SLA Grants License (Form 29)
Joint inspection by Expert/ SLA / CDSCO Follows
based on the risk based approach

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Regulatory pathway in India
3. Pre-Clinical & Safety studies
Application (Form C3) to RCGM
(To Conduct Preclinical SafetyStudies)
IBSC evaluates CMC data and protocols, completeness of application
and ensures institutional capacity in safe handling, storage and disposal of
materials as per DBT guidelines and recommends to RCGM.
RCGM approves Protocol after evaluation of
CMC data to conduct PCT studies
Applicant submits PCT
report (Form C5)
IBSC verifies completeness of PCT
report and recommends to RCGM
RCGM issues NOC to DCGI to conduct CT
CPCSEA / IAEC Approval
for experiments in animals
(Form- B)

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4. Clinical Trials
Application (Form CT- 04) & protocol submission
to CDSCO for conduct of Clinical studies
Review of application in consultation with SEC
Approval of CT (Form CT-06)
Submission of CT Study Report,
Review in consultation with SEC
Regulatory pathway in India

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5. Manufacturing License for Sale & Distribution
Application (Form CT-21) to CDSCO for Grant of
Permission to Manufacture for sale/Distribution
CDSCO issues Permission (Form CT-23)
Application (Form 27D) to SLA for License
to Manufacture for sale or distribution
SLA Grants License (Form 28D)
Regulatory pathway in India

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Regulatory pathway in India
• Requirements for Form C1, B1, C3:
• Sequence map of the gene.
• Vector Map.
• Copy of the permit, if issued earlier.
• Utilization certificate.
• Copy of the minutes of IBSC meeting in which the proposal was approved.
• Material Transfer Agreement.
• References if any
• Requirements for Form C5:
• Colured Copy of the minutes of IAEC meeting .
• Colured Copy of the minutes of IBSC meeting .
• Copy of the permit, if issued earlier.
• Flow chart depicting fermentation/ production & purification process highlighting key features.
• Stability data of DS & DP.
• Acceptability criteria/ Certificate of Analysis.
• Pre-clinical safety studies & immunogenicity study reports.
• References if any

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Regulatory pathway in India
• Requirements for Form CT 10
• Copy of approval of GEAC/RCGM/Ministry of Agriculture, if any
• Manufacturing site layout for manufacture of proposed Vaccine
• Details of the proposed site
• Process flow chart with IPQC parameters
• List of equipments
• Mfg Lic
• Copy of previous joint inspection of the proposed site
• Legal Undertaking by applicant
• Requirements for Form CT 04
• Information and documents as specified in the Second Schedule and fee as specified in the Sixth
Schedule
• Requirements for Form CT 23
• Second Schedule: Requirements and Guidelines for permission to import or manufacture of new drug for
sale or to undertake clinical trial; New Drugs and Clinical Trials rules 2019

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Regulatory pathway in India
 Other approvals required:
• GEAC,
• National Biodiversity Authority (NBA)
• DHAD,
• DGFT,
• Institutional Animal Ethics Committee (IAEC)_ Form B .

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W.H.O. VACCINE PREQUALIFICATION

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W.H.O. VACCINE PREQUALIFICATION
Outline
 Introduction
 Conditions for PQ evaluation for Vaccines
 Prequalification process
 Post Prequalification

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W.H.O. VACCINE PREQUALIFICATION
Introduction:
• A service provided to UN purchasing agencies.
• Provides independent opinion/advice on the quality, safety and efficacy of vaccines for
purchase.
• Provides independent opinion/advice on the quality, safety and efficacy of vaccines for
purchase.
• Ensures that candidate vaccines are suitable for the target population and meet the needs of
the programme.
• Ensures continuing compliance with specifications and established standards of quality.
• Countries can rely on PQ assessment, inspection, lot testing, etc.
• started 1987.
• 153 vaccines prequalified to-date (245 presentations).

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W.H.O. VACCINE PREQUALIFICATION
Introduction:
Applicable guidelines:
• Recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological
medicinal products and for the characterization of cell banks WHO TRS 878, Annex 3.
• GMP for biological products WHO TRS 822, Annex 1.
• WHO guidelines on nonclinical evaluation of vaccines. WHO TRS 927; Annex1.
• Guidelines on clinical evaluation of vaccines: regulatory Expectation WHO TRS 1004, Annex 9.
• Procedure for assessing the acceptability, in principle, of vaccines for purchase by United Nations agencies.
WHO TRS 978, Annex 6.
• Guidance on Variations to a Prequalified Vaccine V.7. July 2015.
• Quality assurance for biological products, guidelines for national authorities WHO TRS 822, Annex 2.
• Guidelines on regulatory expectations related to the elimination, reduction or replacement of thiomersal in
vaccines WHO TRS 926, Annex 4
• WHO Guidelines on TSE in relation to Biological and Pharmaceutical Products.

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W.H.O. VACCINE PREQUALIFICATION
Conditions for PQ evaluation for Vaccines
• Listed in the PQ vaccine priority list.
• The candidate vaccine meets the mandatory characteristics for programmatic
suitability, as defined in the document Assessing the programmatic suitability of
vaccine candidates for WHO prequalification.
• Vaccine is licensed/registered by the responsible NRA.
• “Functional” NRA.
• Communicating with WHO
• Variations.
• Serious AEFI.
• Problems that may impact the quality, safety, efficacy or timely supply of product .
• Regular updates of safety profile.

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W.H.O. VACCINE PREQUALIFICATION
Steps of the procedure
Official request and response
• Application letter with expected date of file submission.
• Acceptance of the application letter by e-mail, with a copy to the NRA.
Meetings with manufacturers
• Not necessary.
• This pre-evaluation meeting should be scheduled as early as possible, with a predefined
agenda addressing questions sent to WHO in advance by the manufacturer.
Product Summary File
• 1 hard copy and 5 electronic copies (on CD-ROM), in either Microsoft Word or PDF
format of PSF.

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W.H.O. VACCINE PREQUALIFICATION
Steps of the procedure
Product Summary File
WHO format:
Chapter 1: General information;
Chapter 2: Personnel;
Chapter 3: Premises and equipment;
Chapter 4: Vaccine composition, presentations and schedules;
Chapter 5: Production;
Chapter 6: Quality control;
Chapter 7: Stability;
Chapter 8: Clinical experience;
Chapter 9: Production and distribution data;
Chapter 10: Update on regulatory actions.

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W.H.O. VACCINE PREQUALIFICATION
Steps of the procedure
Product Summary File
• CTD format can be accepted so long as
– A detailed cross-referencing of contents is presented; and
– Those aspects required by WHO but not included in the CTD requirements are
presented.
• Three deadlines per year for the submission of PSFs.
– 31 January;
– 31 May and
– 30 September.

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W.H.O. VACCINE PREQUALIFICATION
Steps of the procedure
PSF evaluation
• Initial review - 3 months.
• complementary information must be submitted in a single package containing one hard copy and five
electronic copies within 3 months. If not WHO reserves the right to terminate this procedure.
• The time frame for review of complete complementary information will be 3 months.
Initial testing of vaccine samples
• Submit an appropriate number of samples (between 25 and 200, depending on the vaccine type and
presentation offered) of 3 to 5 final lots for independent testing.
• WHO will send the vaccine samples to the contracted laboratories for the initial testing.
• Usually, potency and toxicity are tested.
• 3 Months.

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W.H.O. VACCINE PREQUALIFICATION
Steps of the procedure
WHO site audits
• The site audit will take place as soon as possible after satisfactory test results are available, and
usually within 2 months.
• The final report with findings, recommendations and conclusions is prepared by the team and
sent to the company, with a copy to the NRA, within 30 days of completion of the visit.
Report and outcome of the assessment
• The prequalified status of a vaccine is valid until a new reassessment is scheduled by WHO.
• The frequency, scope and need for reassessment will be based on quality risk management
principles.

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W.H.O. VACCINE PREQUALIFICATION
Steps of the procedure
Dossier Submission
Screening
NRA Functionality/ Maturity
level 3
Programmatic suitability
Laboratory
Testing
Inspection
Dossier
Review
CAPA
Follow-up
Inspection
CAPA
Prequalification Decision

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W.H.O. VACCINE PREQUALIFICATION
 Fast-Track Procedure
• Applicable to licensed vaccines (marketing authorization available) that are part
of routine immunization programmes, or those that are used only in an
emergency response.
• Not applicable in the case of novel vaccines not yet introduced or recently
introduced into routine immunization programmes.
• Considered in the following situations.
– An acute shortage of a vaccine.
– An emergency situation.
– Declaration of a pandemic of a disease.
– Need for alternatives to existing vaccines.
• Deadlines for submission of PSFs do not apply.

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W.H.O. VACCINE PREQUALIFICATION
Post Prequalification
 Annual Reporting
 Variations
 Reassessment (frequency defined on risk analysis basis)
 Targeted testing program with contracted laboratory
 Monitoring/Investigation of vaccine quality and cold chain complaints
 Monitoring/investigation of Adverse Events following immunization (AEFI) (with
collaboration of the responsible NRA)
 Collaborative National Registration
 Technical Review of tenders for UNICEF

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W.H.O. VACCINE PREQUALIFICATION
Post Prequalification
Annual reporting
1 year after the date of prequalification, with subsequent submissions each year on
the same date.
• Summary of changes/variations
• Testing results from the ongoing stability programme.
• Production and distribution data
• Details of GMP inspections
• Summary update on implementation of post-prequalification commitments
• Periodic safety update report (electronic data only).

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W.H.O. VACCINE PREQUALIFICATION
Post Prequalification
Variations˟
Type N_ Immediate Notification
within one month after approval by the responsible NRA
Type R_ Annual Reporting
Type A_ Approval before implementation
Evaluation timeline- 90 days
˟Guidance on variations to a prequalified vaccine v.7. july 2015

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THANK YOU
Y Srinivasa rao, M.S. (DDRA)
9901010002,
cnu0002@gmail.com