Vaccines Assessment: Quality and ClinicalRequirement
Joint UNICEF, UNFPA and WHO meeting with manufacturers
Copenhagen 2 – 4 December 2019
Godwin EnwereVAX Team | PQT/RPQ/MHP Cluster | HQ WHO, Geneva
Quality requirements for prequalification
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Specific aspects for Vaccines Prequalification General understanding of production process and quality control
methods – Quality
Production consistency at commercial scale (assessed by testing ofsamples of final product) – Quality
Compliance with GMP – Quality
Programmatically suitable presentation – Quality
Compliance with WHO recommendations and UN tender specificationsincluding labels and package inserts - Quality
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Guidance documents
Process as per a set of WHO Recommendations
Procedure for assessing the acceptability in principle, of vaccines for purchase byUnited Nations agencies TRS 978 Annex 6 2013. https://www.who.int/immunization_standards/vaccine_quality/
Assessing the programmatic suitability of vaccine candidates for WHOprequalification. https://www.who.int/immunization_standards/vaccine_quality/ps_pq/en/
List of WHO Good Manufacturing Practice (GMP) Guidelines.https://www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/
Guidance on reporting variations to a prequalified vaccine (Post PQrequirements). https://www.who.int/immunization_standards/vaccine_quality/variations_pq_vaccine/en/
WHO Vaccine-specific standardization. https://www.who.int/biologicals/vaccines/en/
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Format of submission
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Common Technical Document (CTD)[ICH M4]
Vaccine Prequalification Dossier (VPQD)
We shall continue to receive Product Summary File till the end of 2021
PQ Vaccines Assessment Team
WHO HQ
ICH M4
S.1 P.1S.2 P.2S.3 P.3S.4 P.4S.5 P.5S.6 P.6S.7 P.7
P.8
Module 1:• Specific module pertaining to
administrative and prescribing information It contains information not included in the other modules
but required to assess the product for prequalificationpurposes
PQ Vaccines Assessment Team
WHO HQ
Module 1 General Information Required to assess Vaccines for PQ purposes
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1.1 TABLE OF CONTENTS
1.2 CORRESPONDENCE1.2.1 Copy of the letter from the manufacturer1.2.2 Agreed minutes of pre-submission meetings.
1.3 SITE MASTER FILE (SMF) as per WHO TRS No 961, Annex 14, 2011
1.4 COMPLIANCE INFORMATION1.4.1 Certificate for establishment licensure by the NRA of the country of manufacture.1.4.2 Copy of GMP certificate or other evidence of GMP compliance.1.4.3 Copy of MAs for all formulations and presentations in the country of manufacture orcountry of reference for the vaccine submitted for PQ, or the EMA under Article 58.1.4.4. Policy for assignment of date of manufacture of intermediates as well as finalproduct, including diluents, as appropriate.1.4.5 If the vaccine contains or consists of GMO, a copy of the Environmental Risk Assessmentis needed.
Module 1 (cont.)1.5 VACCINE COMPOSITION, PRESENTATIONS AND SCHEDULING INFORMATION
1.5.1 Description of presentations available to UN agencies, including diluent, dosage forms, doses, sizes and type of containers and VVM type and location.1.5.2 Vaccine temperature stability profile: as required to support theassignment of VVM type. Extended Controlled Temperature Conditions(ECTC WHO TRS No. 999 Annex 5, 2016), it is critical studies properly designed and appropriate statistical analysis to justified the use after ECTCexposure.1.5.3 Description of immunization /administration devices, if any. Any devicesprovided with the vaccine must be prequalified, as applicable.1.5.4 Recommended schedule and route of administration.1.5.5 Artworks or mockups of labels (in English).1.5.6 Samples of package inserts (in English) to be used for supply throughUN agencies. Translation to French, Portuguese, Russian and Spanish, as required.
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1.5.7 Template of lot summary protocol (LSP).1.5.8 Self-assessment against programmatic suitability for prequalification (PSPQ).Mandatory characteristics will determine whether the application is accepted for review orrejected. Compliance with critical characteristics needs to be assessed.1.6 SUPPLEMENTAL PRE-CLINICAL & CLINICAL INFORMATION (PRE AND POST MA)1.7 REGULATORY ACTIONS
1.7.1 Information on refusals, withdrawals, suspensions, even including those initiated by the manufacturer.1.7.2 List of lots rejected by the NRA, if applicable.1.7.3 Restrictions on distributions and recalls, including those initiated by the manufacturer1.7.4 Clinical trial suspensions.1.7.5 Dosage or schedule changes since the initial marketing authorization in the country of manufacture and/or the country of reference.1.7.6 Changes in target populations since the initial marketing authorization in the country of manufacture and/or the country of reference.
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Module 1 (cont.)
1.8 DISTRIBUTION INFORMATION
1.8.1 Quantity of finished product distributed in vials/doses whether domestic or export.
1.8.2 List of countries where the product has received a MA and whether supplied.
1.8.3 Lot release process by the NRA/NCL and recording system for distribution.
1.8.4 Summary of the international packaging and shipping procedures and the validation– (including box sizes, packing volumes, etc.).
WHO requirements WHO/IVB/05.23 Guidelines on the international packaging and shipping of vaccines should be followed.
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Module 1 (cont.)
Module 2
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As per ICH guidelines M4Q, M4S, M4E):
2.1 Table of Contents (Modules 2-5) 2.2 VPQD introduction2.3 Quality Overall Summary2.4 Nonclinical Overview2.5 Clinical Overview2.6 Nonclinical Written and Tabulated Summaries Pharmacology Pharmacokinetics Toxicology2.7 Clinical Summary. Studies Clinical Efficacy, Clinical Safety, Literature References. Synopses of Individual Studies.
VPQD SUMMARIES
Module 3: Quality Aspects
DRUG SUBSTANCE
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DRUG SUBSTANCE (DS) The DS is the unformulated active (immunogenic) substance
which may be subsequently formulated with excipients toproduce the drug product.
The DS may be:whole bacterial cells, viruses, or parasites (live or killed); crudeor purified antigens isolated from killed or living cells; crude orpurified antigens secreted from living cells; recombinant orsynthetic carbohydrate, protein or peptide antigens;polynucleotides (as in plasmid DNA vaccines); or conjugates.
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Module 3: Drug Substance (S)
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Module 3: Drug Substance
3.2.S DRUG SUBSTANCE1 (NAME, MANUFACTURER)
3.2.S.1 General Information (name, manufacturer)
3.2.S.2 Manufacture (name, manufacturer)
3.2.S.3 Characterization
3.2.S.4 Control of Drug Substance
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure System
3.2.S.7 Stability
3.1 Table of contentDrug substance1.General information (Information on the nomenclature of the DS; recommended INN, Biological/chemical/compendial/national names, Strain/structure details)2. Manufacture
1.Information on the manufacturer (Identification, address, activities)2. Description of Manufacturing Process and Process Controls (Flow diagram)3.Control of Materials (Source of starting & raw materials biological/chemicals/ SPFeggs/Cell and Seed Bank System, Full characterization and manufacturing processesincluding test methods and results)4.Controls of Critical Steps and Intermediates (selection and justification of criticalmanufacturing steps, process controls, and acceptance criteria – CQA & CPP)5.Process Validation and/or Evaluation (Full description of studies for critical manufacturing steps i.e. starting from Cell/Seed culture, Harvesting, Purification, Detoxification & modification and inactivation. Procedures for container closure, filling, transport & storage. Details of PV 3 Lots, lot sizes and all IPC & QC test results) – VMP
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3.2.S.2.6 Manufacturing Process Development (any major changes & optimization madethroughout the development. Conclusions from the assessment used to evaluate productconsistency. Cross-reference to the non-clinical and clinical & PV studies used batches)
3. Characterization1.Elucidation of Structure and other Characteristics (Physicochemical, Immunological and Genetic Characterization and test results)2.Impurities (Process related from manufacturing DS i.e. BSA, Trypsin, antibiotic, HCP,DNA. Product related impurities i.e. due to alteration of antigen. The impurities shouldbe identified and monitoring limits during the clinical and PV lots)
4. Control of the antigen(s) – refer to vaccine’s specific WHO TRS and Phs1. & 5 Specification & Justification of Specification
• List of validated test methods, parameters, acceptance criteria (List of specification and justification as per Ph/nonPh references/citation). i,.e. appear, identity, potency
2. & 3 Analytical Procedures & validation• Validation of analytical methods is important to ensure that the assay is fit for its
purpose. Validation depends on the type of assay & fulfilled ICH Q2A/Q6Bparameters (Accuracy, precision, LOD, LOQ. Robustness)
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3.2.S.4.4 Batch Analyses• Batch description and results of 3 lots of Drug Substance (3 Process Validation
Batches) consistent with within the specifications5. Reference standards or reference materials
• RS/RM are necessary in assuring consistency in product characteristics• Description of the preparation, characterization, and stability of primary and working
reference standards, release testing (acceptance criteria) results should be provided.6. Description and suitability of the container closure system
• compatibility of Containers with the DS including L&E should be submitted.• evidence of container and closure integrity during shelf-life
7. Stability1. Stability Summary and Conclusions (design & type of studies and protocols)2. Post-approval Stability Protocol and Stability Commitment3. Stability Data
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Module 3: Quality Aspects
DRUG PRODUCT
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DRUG PRODUCT (DP) The DP is the finished dosage form of the product. The DP
contains the drug substance(s) formulated with otheringredients in the finished dosage form ready for marketing.Other ingredients, active or inactive, may include adjuvants,preservatives, stabilizers, and/or excipients.
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For vaccine formulation, the drug substance(s) may bediluted, adsorbed, mixed with adjuvants or additives, and/or lyophilized to become the drug product.
Module 3: Drug Product (P)
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Module 3: Drug Product (P) 3.2.P DRUG PRODUCT (NAME, DOSAGE FORM)
3.2.P.1 Description and Composition of the Drug Product (name, dosage form)
3.2.P.2 Pharmaceutical Development
3.2.P.3 Manufacture
3.2.P.4 Control of Excipients
3.2.P.5 Control of Drug Product
3.2.P.6 Reference Standards or Materials
3.2.P.7 Container Closure System
3.2.P.8 Stability
3.2.A APPENDICES: Facilities, equipment; adventitious agents safety evaluation; excipients; literature.
Vaccine (name, dosage from)1.Description and composition (for all components and amounts per unit including excipients, adjuvant, preservative MD i.e Thiomersal, 2PE, Phenol)
2. Pharmaceutical development• Compatibility between active ingredients of DP with DS bulk/s, Excipients type,
adjuvant, and preservative. The formulation development as part of clinical lots/PV vs commercial lot. This should be supported by satisfactory stability studies
• Suitability and safety of container closure system• Microbial attributes (antimicrobial preservative with Multidose vial; Sterile Filtration)• Compatibility between DP and reconstitution diluent
3. Manufacture• Information on the manufacturer.• Description of the manufacturing process and the controls that are intended to
effect in the routine and consistent production. Flow diagram/s to provide• Description of the process validation and/or evaluation
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2.Batch Formula• list of all components of the dosage form and amount to be used in the
manufacturing process plus their amounts on a per batch basis3. Description of Manufacturing Process and Process Controls (Flow diagram)4.Controls of Critical Steps and Intermediates (Time, temperature, pH & QC identified tests as part of PV)5. Process Validation and/or Evaluation• critical steps or critical assays used in the manufacturing process (i.e., validation of the
sterilization process or aseptic processing or filling)4. Control of excipients (diluent, bulking agents, adsorbents/adjuvants, stabilizers)
• Specifications and justification to be identified; analytical procedures; Validation• Excipients of Human or Animal Origin with information on safety data of Adventitious
agents5. Control of the vaccine
Specification(s) & Justification; Analytical Procedures & Validation. Characteristic of impurities identified
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6.Reference standards or reference materials
7.Information on the suitability of the container closure system and integrity (Extractability and Leachability test)
8. Stability• Stability Summary and Conclusions (design & type of studies and protocols)• Post-approval Stability Protocol and Stability Commitment• Stability Data
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Module 3 - Quality Aspects – Drug ProductA. APPENDICES
1.Facilities and Equipment (name, manufacturer)2.Adventitious Agents Safety Evaluation (name, dosage form,manufacturer) – Non viral and Viral adventitious agents (Biologicalmaterials & virological testing carried out)3. Novel Excipients
3.2.R Regional information (any possible additional information on theantigen(s)/drug substance or finished product)If applicable, include subheadings where appropriate
3.3. Literature References
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Other specific aspects/ consideration
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Programmatic suitability
Cold chain / VVM
Shipping
Programmatic Suitability
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https://www.who.int/immunization_standards/vaccine_quality/ps_pq/en/
As part of the WHO vaccine prequalification process, product summary files are assessed by the WHO Prequalification (PQ) Secretariat to determine ‘the suitability of the vaccine for the immunization services where it is intended to be used’.
The emergence of unique vaccine presentations has driven the need to define the characteristics that determine programmatic suitability and the process for assessing compliance with these characteristics.
Following consultation and endorsement by the Immunization Practices Advisory Committee (IPAC) the guidance document on Assessing the Programmatic Suitability of Vaccine Candidates for WHO Prequalification has been published.
Programmatic Suitability Vaccine composition, presentations and schedules
• Label intended to detect vaccine recommended storage temperature and warning “Do Not Freeze”.
• Vaccine Vial Monitor (VVM): a label containing a heat sensitive material- color density changes indicator.
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https://www.who.int/immunization_standards/vaccine_quality/vvm_10years_index/en/
https://www.who.int/immunization_standards/vaccine_quality/vvm_specifications_e6in5.pdf
International Shipping & Validation
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https://www.who.int/immunization/documents/WHO_IVB_05.23/en/
The ''WHO guidelines on the international packaging and shipping of vaccines'' has been one of the most widely used documents in the field of immunization.
It is being used UN agencies procuring vaccines and PAHO RF in its invitations to bid for vaccine supply as well as by countries directly procuring their vaccines.
It takes into account aspects of: vaccine stability temperature monitoring information on recently prequalified vaccines Shipment information (e.g.: packed volumes; insulated packages).
Clinical requirements for prequalification
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Important Notes
Note 1 Reference documents
• TRS 978, Annex 6 (2012, PQ procedure) http://www.who.int/entity/immunization_standards/vaccine_quality/TRS_978_61st_report_Annex_6_PQ_vaccine_procedure.pdf
• TRS 850 (1995, GCP); http://apps.who.int/prequal/info_general/documents/TRS850/WHO_TRS_850-Annex3.pdf
• Guideline on clinical evaluation of vaccine-TRS 1004
https://www.who.int/biologicals/WHO_TRS_1004_web.pdf?ua=1
• TRS 927 (2005; non-clinical evaluation of vaccines) http://who.int/biologicals/vaccines/nonclinial_evaluation_of_vaccines/en/
• Points to consider for manufacturers of human vaccines: clinical considerations for evaluation of vaccines for prequalification http://www.who.int/immunization_standards/vaccine_quality/pq_vaccine_evaluation/en/
• Any specific TRS and related WHO position paper
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Important Notes
Note 2– For vaccines originally licensed many years before application
for prequalification, emphasis should be given to document history of safe and effective use.
Note 3– Provision on request of raw data
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Key Clinical Data Questions 1Key Clinical Data Questions 1
How was the data generated – GCP and sound ethical principles?
Is this vaccine safe – non clinical, clinical, procedure and duration?
Does it protect against the disease – efficacy or immune bridging?
Which age group should receive the vaccine?
What is the dose, and how was it determined?
Which comparators were used – WHO Pqed, vacc with efficacy data?
What is the duration of protection? Is a booster dose required?
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Key Clinical Data Questions 2?Key Clinical Data Questions 2?
Is there data on consistency of 3 commercial lots? If not, why?
Can the vaccine be co-administered with other vaccines?
How generalizeable is this data – other popn or WHO regions?
What is the pharmacovigilance plan – considering UN market?
What is the post marketing experience?
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Module 1
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Module 1.6 – Pre-Clin and Clin Information
1.6.1 - List of pre-clinical studies sponsored by applicant –not included in Module 2.6 and Module 4 of the application-including any conclusion(s) including preclinical studies performed after initial licensure of product (and the reasons for these studies) If none, indicate
1.6.2 - List of all clinical trials sponsored by the applicant relevant for the application – not included in Module 5.2 of the application – site, age, date, objectives, registration, GCP compliance, statement on conclusion
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1.6.3 Cross reference to the final approved protocol by ERC and NRA
1.6.4 List of any clinical trials that are known to be currently ongoing with the vaccine candidate, not relevant to the current PQ application including the summary of details of the study plan and expected date of result (for example, clinical trials being conducted for a different use indication and/or with a different age group, etc.).
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1.6.5 List of other studies with applicant product – not included in Module 5 - for which the applicant is not the sponsor.
This list should be compiled from publications
1.6.6 Complementary clinical summary supporting the use of the product worldwide by UN agencies
This applies to those cases where the vaccine will be used in a different way from the conditions in the marketing authorization.
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1.6.7 Assessment Report from the NRA(s)
The applicant should provide the reference NRA assessment reports or rationale why it cannot be provided.
1.6.8. Clinical Independent expert report
This is important especially if the application for prequalification is based on the extrapolation of the existing clinical data to the likely circumstances of use after prequalification, and if the data are old or there is a doubt regarding the ethical or regulatory oversight of the trial, the report should discuss the degree of compliance with WHO GCP recommendations and current guidance regarding preclinical and clinical trials with vaccines”. Discuss epidemiology and how the vaccine fits in the global context.
Provide the CV of Expert.
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1.6.9 Post marketing Safety documentation
1.6.9.1 Outline of the post-marketing pharmacovigilance plan for the product or Risk Management Plan – must be relevant to UN supply
1.6.9.2. Initial evaluation of vaccines that have been in the market for more than five years or reassessment of already prequalified vaccines (The latest PSUR may be provided)
• Outline of the applicant’s procedures for the collection, onward notification and assessment of adverse events.
• Listing of all reported serious AEFIs for the vaccine in question in the last five years or since the last WHO reassessment- type, lot #, date and place of vaccination, patient age and initial, seriousness criteria, causality and outcome
1.6.9.3 List of ongoing clinical studies for vaccines licensed within the last five years. Add a cross reference to Module 5 and any studies that may not be part of the CTD
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Module 2
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Module 2: Common Technical Document Summaries
2.1 Common Technical Document Table of Contents (Modules 2-5)
2.3 Nonclinical Overview
2.4 Clinical Overview
2.5 Nonclinical written and tabulated summaries
2.6 Clinical Summary
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Module 5
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Module 5: Clinical Study Reports
5.1 Table of Contents of Module 5
5.2 Tabular Listing of All Clinical Studies according to development plan [site, age, date, CT registry, objectives, GCP compliance, statement on conclusion]. This table should include any changes that has occurred over time in formulations, manufacturing scales etc.
5.4 Identification of pharmacodynamics studies (e.g.: immunogenicity to support the dose, dosage, schedule, formulation).
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5.5 Identification of completed or on going efficacy studies (e.g.: place-control; active comparator; dose-response; uncontrolled studies).
5.6 Clinical Study Reports – relevant studies
5.7 Other study reports (e.g.: interim analyses of studies, reports of studies not reported previously; ongoing studies; safety update with discussion of sAEFI).
5.8 Post-marketing studies or information (including all significant safety observations).
5.9 Literature References
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News Flash!!!! News Flash!!!!
Follow the recent guidelines rigorously
Ask questions if anything is not clear to you
Note that we are collaborators
HIS/EMP/PQT Slide 47
THANK YOU