Contents of the vaccine PSF
The PSF provides information on the product composition, manufacturing procedure, testing, stability, labelling, clinical experience and available post-marketing safety information.That is, it consolidates and communicates information relating to the manufacturing company and to the product that is required for evaluation for prequalification.
The contents of the PSF must include:
- 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.
See below for further information and guidance on the information to be provided.
The PSF must be written entirely in English and provided in either Microsoft Word or as a PDF.
Liaising with the national regulatory authority
Since reliance on effective regulatory oversight by the national regulatory authority (NRA) of the country of manufacture plays a critical role in the system, manufacturers are required to engage with NRAs from the beginning of the prequalification application process and to complete the following steps:
- inform the NRA of their application to WHO for the vaccine prequalification by sending to the NRA a copy of the application letter sent to WHO
- request the NRA to participate/collaborate in the process
- provide the NRA with the necessary authorization to discuss the relevant files with WHO representatives.
Before submitting a product summary file (or common technical document) in application for WHO prequalification, manufacturers must also obtain a marketing authorization from the responsible NRA. The marketing authorization demonstrates that the NRA has conducted the required regulatory oversight – review and assessment – of the product and grants it a licence to be marketed.
Submission
Deadlines for submission
WHO has established three deadlines per year for eCTD submission:
- 31 January
- 31 May and
- 30 September
Any application must arrive at WHO no later than the submission date if it is to beconsidered for the subsequent round of review. Applications received after the submission deadline will not be considered for evaluation until the following review round.
NEEDS INFORMATION ABOUT WHERE TO SEND AND TO WHOM
Transition to CTD format
As of 1 January 2021, the eCTD format will be a mandatory requirement and PSFs will no longer be accepted. WHO already accepts applications in the (electronic) common technical document (eCTD) format provided that:
- it includes a detailed cross-referencing of contents
- information required by WHO but not included in the CTD requirements are presented.
Where the PSF cross-references to the CTD format, the documentation can be submitted in electronic form only. Electronic documents should be in searchable text where possible.
PREPARATION OF CHAPTER 1 ‒ GENERAL INFORMATION ‒ OF A PRODUCT SUMMARY FILE
1.1 Provide brief information on the company (including name and address of the site, telephone, fax and 24-hour telephone numbers, and the principal contacts of the company) and its relation to other sites where steps of the process or testing activities (for both the active biological components and diluent) may be conducted.
1.2 List pharmaceutical and non-pharmaceutical manufacturing activities carried out at the site, as licensed by the national regulatory authority. This information should also be provided for contracted manufacturers.
1.3 Provide a short description of the site (size, location and immediate environment). List buildings on the site(s) or provide a site plan, identifying the manufacturing, control and storage activities in each building.
1.4 State the number of employees engaged in production, quality assurance, quality control, storage and distribution.
1.5 List outside scientific, analytical or other technical assistance in relation to manufacture and analysis, including equipment and/or other facility maintenance and validation. In the case of contract manufacturing and contract testing of part of the process, provide information on the way in which GMP compliance of the contract acceptor is assessed.
1.6 Give a short description of the quality management system of the company responsible for manufacture.
1.7 Give a short description of the internal audit system and the programme for qualifying suppliers of raw materials.
1.8 List the manufacturers supplying biological raw materials and adjuvants.
PREPARATION OF CHAPTER 2 ‒ PERSONNEL ‒ OF A PRODUCT SUMMARY FILE
2.1 Provide an organizational chart showing the relationships between different areas, including quality assurance, production and quality control, with identification by name of key personnel (heads of production, quality assurance, quality control, warehousing and engineering).
2.2 Provide curricula vitae for heads of production, quality assurance and quality control, indicating educational and experience qualifications.
2.3 Outline arrangements for basic and continuing training and how records are maintained.
2.4 Describe requirements for personnel engaged in production, particularly relating to requirements for monitoring of health status (including immune status) of production personnel, and for outside contract service personnel entering the manufacturing areas.
PREPARATION OF CHAPTER 3 ‒ PREMISES AND EQUIPMENT ‒ OF A PRODUCT SUMMARY FILE
These will be examined in depth during the site audit. However, the following preliminary information must be submitted.
3.1 Provide simple, currently-valid, floor plans and text descriptions of manufacturing and quality control areas. The floor plans should give an indication of scale, air ow and flows of materials, product, personnel and waste (architectural or engineering drawings are not required), room classification, and air handling unit identification by room.
3.2 Describe the nature of construction and finishes of manufacturing and quality control areas.
3.3 Describe ventilation systems in the manufacturing and quality control areas. More details should be given for critical areas with potential risks of airborne contamination (schematic drawings of the systems are desirable). Classification of the clean rooms used for the manufacture of sterile products should be included. A description of the environmental monitoring programme is required.
3.4 Provide information on special areas for the handling of highly toxic, hazardous and sensitizing materials.
3.5 Describe water systems (schematic drawings of the systems are desirable, showing storage tanks, loops, points of use and sampling points), including sanitation procedures and schedules. A description of quality control testing and schedules is required.
3.6 Describe the maintenance system (planned preventive maintenance programmes and recording system).
3.7 Complete a table briefly describing major production and control laboratory equipment used for the production of the vaccine (including diluent).
3.8 For products for which a separate facility is required (e.g. tetanus, bacille Calmette–Guérin vaccine), describe how separation is achieved.
3.9 Describe qualification and validation procedures, including computerized recording and controller systems. A description of the validation master plan is required.
3.10 Provide a brief description of the procedures for cleaning manufacturing areas and equipment. For multipurpose areas, briefly describe the system for cleaning and testing between campaigns.
PREPARATION OF CHAPTER 4 ‒ VACCINE COMPOSITION, PRESENTATIONS AND SCHEDULES ‒ OF A PRODUCT SUMMARY FILE
4.1 State the composition of the product (including diluents).
4.2 Describe the presentations made available to UN agencies, including diluents (if applicable), combination products, forms, dose sizes, type of containers, vaccine vial monitor used, and descriptions of application devices (e.g. autodisable syringes) to be delivered with the vaccine, if applicable.
4.3 Give the recommended schedule and route of administration.
4.4 For both the final product and diluent, provide samples of primary container, labels, boxes and package inserts to be used for UN agency supply (in English). French, Portuguese, Russian and Spanish versions need to be made available before supply to UN agencies starts. Include the calculated volume per dose in cm3 SUPERSCRIPT of the secondary packaging.
4.5 Include a sample of the lot summary protocol to be provided to UN (using the WHO-recommended format).
PREPARATION OF CHAPTER 5 ‒ PRODUCTION ‒ OF A PRODUCT SUMMARY FILE
Note: WHO recommendations or guidelines and UN agencies' tender specifications must be met. For each specific test done, the international standard met should be identified.
5.1 Provide the following:
- the manufacturing formulae for the production of each antigen in the vaccine (i.e. fermenter or culture volumes for each bulk batch size, as applicable and typical bulk volumes per production run)
- the batching formula for each batch size of final formulated bulk product
- the approximate number of vials and doses for each fill size and presentation
- the lot numbering system for intermediates and final products.
5.2 Provide a description of the manufacturing processes and the characterization of the product. is should include history of the master cell banks/virus seeds. Detailed flowcharts should be provided to indicate:
- each manufacturing step
- the location (building/room) of each step, and transfers to other
- buildings/sites, if applicable
- in-process and quality control tests performed on all intermediates and final products
- identification of any processes or tests performed by contract manufacturers or testers
- storage times and temperatures of intermediates.
For recombinant vaccines, a description of the construction and characterization of the recombinant vector, as well as of the source of master cell bank/constructs, must be provided, as well as details of the manufacture and quality control of any adjuvant and diluents.
5.3 Describe the general policy for process validation. List the process-validation activities performed.
5.4 Summarize arrangements for the handling of starting materials, packaging materials, bulk and finished products, including sampling, quarantine, release and storage.
5.5 Summarize arrangements for the handling of rejected materials and products, and procedures for their destruction.
PREPARATION OF CHAPTER 6 ‒ QUALITY CONTROL ‒ OF A PRODUCT SUMMARY FILE
6.1 Starting materials
6.1.1 List the control tests performed on raw materials, with appropriate characterization of starting materials, namely:
- list of raw materials meeting compendial specifications, indicating the pharmacopoeia
- list of raw materials meeting in-house specifications, including the tests performed and specifications
- list of biological starting materials (human or animal origin) with information on the requirements to avoid risk of transmissible spongiform encephalopathies and human diseases (HIV, hepatitis, etc.) in the final product
- list of media with ingredients, tests performed and specifications.
6.1.2 List the control tests performed on labelling and packaging material(s), including primary and secondary packaging material.
6.1.3 Describe the qualification criteria for suppliers of raw material and relevant certificates.
6.2 Intermediate products (as appropriate)
6.2.1 List the routine tests performed and specifications for intermediates. Include copies of standard operating procedures for critical quality- control tests (uncontrolled copies or concise descriptions of the method and re-test criteria are acceptable).
6.2.2 List the assay validation activities performed.
6.3 Finished product (including diluent)
6.3.1 List the routine tests performed and specifications for the final product. Concise descriptions of the method and retest criteria are acceptable but full standard operating procedures in English should be made available on request.
6.3.2 List the assay validation activities performed.
6.3.3 List the final lots internally rejected in the previous 2 years and the reasons for rejection.
PREPARATION OF CHAPTER 7 ‒ STABILITY ‒ OF A PRODUCT SUMMARY FILE
Stability studies are expected to have been designed and conducted to meet WHO guidance. See: Guidelines on stability evaluation of vaccines (2006).
7.1 Provide information on stability tests on intermediates, namely:
- information on containers for intermediate products
- assigned shelf-life and storage conditions
- quality control methods and specifications, and rationale for the choice of tests for determining stability
- identification of the dates of manufacture of the lots, the lot numbers, the vial and dose size and the scale of production.
Results of quantitative assays must be expressed as a numerical value, with the appropriate limits, and not as “pass” or “fail”.
7.2 For each presentation, provide information on stability testing of the finished product, namely:
- assigned shelf-life and storage conditions
- quality control methods and specifications and rationale for the
- choice of tests for determining stability profile
- identification of the dates of manufacture of the lots, the lot numbers, the vial and dose size and the scale of production.
Results of quantitative assays must be expressed as a numerical value, with the appropriate limits, and not as “pass” or “fail”.
In addition to data on final product stability at the recommended storage temperature, the accelerated stability data at elevated temperatures should be sufficient to justify the choice of vaccine vial monitor for use with the product. See: Vaccine vial monitor (2006).
7.3 Provide information on stability testing of diluents and reconstituted vaccine in the case of lyophilized vaccines.
7.4 Describe the policy for assigning the date of manufacture of each component, as well as the final product (e.g. combination vaccine) and diluents, as appropriate.
PREPARATION OF CHAPTER 8 ‒ CLINICAL EXPERIENCE ‒ OF A PRODUCT SUMMARY FILE
- Guidelines on clinical evaluation of vaccines: regulatory expectations (2017)
- WHO Guidelines on nonclinical evaluation of vaccines (2005)
- Guidelines for good clinical practice (GCP) for trials on pharmaceutical products (1995)
Other guidance documents are:
- Clinical considerations for evaluation of vaccines for prequalification (2010)
- Guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.
Note 2: For vaccines whose licence was originally obtained many years before the application for WHO prequalification, it is possible that many or all of the clinical trials may not have been conducted or monitored to current international standards. For these vaccines, all sections should be completed but additional emphasis should be given to information provided in sections 8.2.1, 8.2.5, 8.3.1 and 8.3.2, in order to establish sufficiently a history of safe and effective use.
Note 3: In some cases, where the information received regarding the sections detailed below is not sufficient, is not clear enough or requires further scrutiny, WHO may request the applicant to submit the raw data.
8.1 Tabulated summary
The applicant should provide a tabulated summary of the clinical development programme in one or more tables, in which critical parameters that may have changed during the clinical development should be mentioned.
8.2 Clinical trials information
8.2.1 Overview of clinical trials sponsored by the applicant: The sponsor should provide a list of all clinical trials performed in all countries that are relevant to the application for WHO prequalification. These should include all studies sponsored by the applicant, both before and at any time after initial licensure, whether or not submitted previously to the national regulatory authority(ies) (NRA) of the countries where the product is licensed. For each study on the list, the following information is required:
- final approved protocol, which should indicate the date of protocol approval by the ethics committee and the NRA
- evidence of registration in a clinical trial registry that is included in the WHO International Clinical Trials Registry platform
- indication of whether the study complied with good clinical practice.
For each such study, in a tabulation or brief summary, the following information should be provided:
- the type of study
- the rationale for its conduct
- the location(s) of study sites
- the dates of the study
- the numbers and ages of subjects
- a statement of final conclusions on safety and immunogenicity.
Copies of all publications and abstracts relating to these trials should accompany the submission in section 8.2.1.
In addition, the applicant should list any trials that are known to be currently ongoing, with a summary of details of the study plan and expected date of results.
8.2.2 Other studies with the applicant’s product: The applicant should make every e ort to provide a list of all trials and, where applicable, observational studies relevant to the application that were not sponsored by the applicant but in which the product was evaluated. is list should be compiled from publications identified using an extensive literature search (details of which should be provided) and, in the case of co-licensure agreements, from any other company that holds a licence for or a right to market the same product.
8.2.3 Clinical summary: Provide a detailed summary and interpretation of the safety and efficacy data obtained from the pre-licensure clinical studies and all studies performed in the post-licensure period that support the current prescribing information. e summary should pay particular attention to any data that are relevant to the use of the product worldwide in WHO-recommended schedules (e.g. co- administration of other vaccines). In the absence of such data, the summary should provide a preclinical and/or clinical justification for the extrapolation of the existing data to the likely circumstances of use after prequalification. This summary should complement, and not replace, the summary written by an independent clinical expert described in 8.2.5.
8.2.4 Assessment reports: Whenever possible, the applicant should provide the clinical sections of the NRA assessment reports from the country of origin and/or country where the vaccine is initially licensed. Assessment reports for both initial licensure and any subsequent variations to the licence for changes relevant to clinical data are requested.
8.2.5 Clinical expert report: Provide an independent clinical expert report on the clinical studies (evidence of expertise and independence should be provided). 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.
8.2.6 Preclinical studies sponsored by the applicant: Provide a simple list of all preclinical studies that were sponsored by the applicant in support of use in clinical trials in humans, or for significant changes to manufacture or use. Include in the list any important conclusions. For preclinical studies performed after initial licensure, indicate the reasons for these studies. Any other particularly relevant reports regarding safety aspects, whether or not generated by the applicant, should be provided.
8.3 Documentation of safety
Safety data should be submitted both in the case of the initial application for prequalification evaluation and for reassessment purposes.
8.3.1 Post-marketing pharmacovigilance: Provide an outline of the post-marketing pharmacovigilance plan for the product.
8.3.2 Initial evaluation of vaccines that have been on the market for a long time, or reassessment of already prequalified vaccines: Provide an outline of the applicant’s procedures for the collection, onward notification and assessment of adverse events. Provide a listing of all reported AEFIs for the vaccine in question in the last five years or since the last WHO reassessment. As far as is possible from the reports received, applicants should list the type of reaction, lot number, date and place of immunization, patients’ initials and age and, for immunization series, the dose number. A judgement of seriousness and whether or not the event was expected (in the light of the prescribing information) should be provided where this is possible from the information. An assessment of the relationship to the vaccine made by a clinician and, where relevant, by the applicant company or its independent clinical expert, should be included.
Whenever periodic safety updated reports (PSURs) are available, these must be submitted. The PSURs should include information following the ICH format, from all geographical areas where the vaccine is used, or the absence of such information should be defended.
8.3.3 Recently licensed vaccines: In the case of vaccines that have recently been licensed, provide information on any ongoing phase IV studies or on any active monitoring of the safety profile that is taking place.
8.3.4 Documentation of serious adverse events: For serious adverse events reported in the last five years, or as long as the vaccine has been marketed (when shorter than five years), provide the fullest possible description of each case, including any information there may be on investigations, actions, patient treatment and outcome. This information should be provided as part of the PSUR.
PREPARATION OF CHAPTER 9 ‒ PRODUCTION AND DISTRIBUTION DATA ‒ OF A PRODUCT SUMMARY FILE
9.1 Provide information on the quantity of finished product distributed domestically and exported in the previous 3 years. List the different presentations separately, and indicate whether the list gives the numbers of vials or the numbers of doses distributed. When the product is a combination vaccine, information should also be provided on the history of distribution of component vaccine(s), when applicable.
9.2 Provide a list of countries where the product is licensed (marketing authorization) and supplied.
9.3 Summarize the arrangements and recording system for distribution, including the release process performed by the manufacturer and the national regulatory authority.
9.4 Summarize he packaging procedures for international shipments (including box sizes, packing volumes, etc.). Provide the validation protocols and reports of the shipping boxes used for UN supply. Recommendations provided in the most recent version of the WHO Guidelines on the international packaging and shipping of vaccines (2005) must be followed.
9.5 Describe the arrangements for handling complaints and product recalls. Include description of the recall investigation system, procedures for corrective actions, and description of the regulatory requirements in case of recalls. Include provisions for informing WHO and the United Nations agencies.
9.6 Give the quantity of bulk vaccine destined for UN agencies that has been supplied to contract fillers/packagers for finalization (list individually).
PREPARATION OF CHAPTER 10 ‒ UPDATE ON REGULATORY ACTIONS ‒ OF A PRODUCT SUMMARY FILE
10.1 Provide a copy of regulatory documentation, namely:
- marketing authorizations for all formulations
- information on refusals, withdrawals or suspensions including those initiated by the manufacturer
- the good manufacturing practice certificate or equivalent.
10.2 Provide a list of lots rejected by the national regulatory authority (NRA), if applicable.
10.3 Describe restrictions on distribution or recalls, including manufacturer- initiated recalls.
10.4 Name clinical trial suspensions, including manufacturer-initiated suspensions.
10.5 Describe dosage or schedule modifications since the initial licensure was granted.
10.6 Provide information on changes in target populations or indications since the initial licensure was granted.
10.7 List inspections conducted by NRAs within the previous 2 years, including the scope of each inspection.
10.8 List inspections conducted by foreign authorities within the previous two years, including the scope of each inspection.