Full Assessment – Multisource (Generic) FPPs

In order to be prequalified, a multisource (generic) finished pharmaceutical product (FPP) must meet the requirements relating to the active pharmaceutical ingredient(s) (APIs) it contains, the finished pharmaceutical product (FPP), and the site(s) at which the FPP is manufactured. This will include:

demonstrating the bioequivalence of the FPP
demonstrating the quality of the API(s)
demonstrating the quality of the FPP
demonstrating adherence to WHO Good Manufacturing Practices.

Additionally, if a contract research organization (CRO) performed a related study, inspection of that CRO with respect to the particular study, may also be necessary.

GUIDANCE DOCUMENT

Procedure for prequalification of pharmaceutical products (2011)

The product dossier

The product dossier must contain information attesting to the quality, safety and efficacy of the product. The prequalification guidance documents and templates follow the modular format of the Common technical document (CTD) M4, as developed by the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.

The product information must be presented following the guidance in the principle guidance documents listed below.

The dossier must also include summarized information using the templates below for the:

quality information summary (QIS)
quality overall summary – product dossier (QOS-PD)
bioequivalence trial information form (BTIF).

GUIDANCE DOCUMENTS, APPLICATION FORMS & TEMPLATES

Guidance documents

The guidance documents that follow are the primary references for requirements on quality information to be included in the product dossier for both the API(s) and FPP. Additional technical and product specific guidelines refer to Guidance documents

Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (2012)

Guidelines on submission of documentation for prequalification of a multisource (generic) finished product. Preparation of product dossiers in CTD format (2011)

Application form & templates

Quality information summary (QIS) (1 June 2020)

Quality overall summary – product dossier (QOS-PD) (14 March 2023)

Presentation of bioequivalence trial information - BTIF (13 January 2023)

Presentation of bioequivalence trial information - BTIF Appendix 1 - Template for Study Individual Concentration and PK Data (14 January 2020)

Screening checklist for generic products (13 May 2021)

Demonstrating the quality of the API(s)

Data may be supported by any of the following options:

a WHO-prequalified API
a Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP) issued by the European Directorate for the Quality of Medicines and HealthCare;
an API master file (APIMF)

or:

a complete module 3.2.S for the API as part of the FPP dossier submitted for evaluation.

Complete details on the data required in the product dossier to support each of the above options are detailed in the main quality guidelines (2012).

GUIDANCE DOCUMENT

Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for WHO prequalification: quality part (2012)

Active Pharmaceutical Ingredient Master File (APIMF) procedure

Additional guidance is available when using the APIMF option, including requirements for amendments (changes).

See API Master File Procedure section.

Stability of the FPP

The FPP manufacturer must be able to demonstrate that the FPP is stable under climatic conditions prevailing in the country or countries in which the FPP is intended to be used. This means that the manufacturer must establish ― by using an appropriate stability-testing programme ― the shelf-life of the product in relation to recommended storage conditions. The stability testing programme and conditions must themselves have followed the recommendations included in the main WHO quality guideline (2012).

GUIDANCE DOCUMENTS

Requirements for stability studies of finished pharmaceutical products (FPPs) (29 March 2010)

Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (2018)

Bioequivalence

The manufacturer must also demonstrate that the FPP submitted is bioequivalent to the PQTm comparator product upon which it is based. This means being able to demonstrate that it satisfies the same standards as those applicable to the innovator product, and providing assurance that it is clinically interchangeable with, i.e. therapeutically equivalent to, the PQTm comparator product. This may necessitate that the manufacturer carries out a bioequivalence study and presents the bioequivalence study (trial) information: the data generated should provide a bridge between the comparator product for which safety and efficacy data are available and the generic products for which such data are not available. If a CRO carried out this study, the manufacturer must be able to demonstrate that the CRO adhered to WHO Good Clinical Practices and WHO Good Laboratory Practices when it carried out the study.

Criteria used to screen product dossiers

A screening checklist is an in-house list of dossier characteristics that need to be confirmed as being acceptable before a dossier is assigned a WHO reference number and accepted for full assessment. The screening requirements provide insight into what aspects are considered the key elements of assessment. To help applicants better understand the assessment process and to enhance their ability to meet screening requirements, the screening checklist is now published.

Template

Screening checklist for generic products (13 May 2021)

The manufacturing site(s) and CRO

Additionally, the manufacturing site of any FPP submitted for prequalification must comply with WHO Good Manufacturing Practices. An inspection or inspections may be necessary to confirm the adequacy and effectiveness of technical/production processes and that these are controlled effectively. The quality management system, including the effective implementation of the manufacturer's documented and validated procedures, is of critical importance and should be demonstrably robust.

Documents and records from all levels of the quality system will therefore be reviewed and inspectors will seek evidence of their appropriateness as well as their effective and consistent implementation. Both formal and informal interviews of personnel at all levels and discussions with subject matter experts form an essential and major part of the inspection process.

Evidence of compliance and non-compliance will be collected on site through:

Additionally, evidence will be collected on site through:

examination of documents, including standard operating procedures and records
visual observation of activities
visual observation of environmental conditions
interviews to confirm statements of fact, before any observations are finalized.

If a CRO carried out a study, on behalf of the manufacturer, to generate data that demonstrates the product's bioequivalence with the originator or innovator product, an inspection of the CRO may be required to verify adherence to WHO Good Clinical Practice and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies, as well as the date generated.

INSPECTION OF FPP AND API MANUFACTURING SITES

Initial inspection

An initial or first inspection of an API or FPP manufacturing site is conducted only after the relevant API or FPP dossier has been accepted for assessment for prequalification. Such an inspection will be necessary if evidence from recent inspections conducted by other national medicines regulatory agencies operating to equivalent standards and stringency is insufficient. During the inspection, the site’s level of compliance with WHO Good Manufacturing Practices (GMP) will be assessed.

An API manufacturing site may be inspected as part of the assessment of an API for prequalification, or as part of the assessment of an FPP for prequalification.

If an initial inspection is considered necessary it will generally be scheduled within six months of acceptance for assessment of the relevant API or FPP, and announced one to two months before the inspection takes place. The procedure for an initial API or FPP manufacturing site inspection consists of:

review of the site master file submitted by the applicant at the time of dossier submission
review of product dossier for information of relevance to the inspection (such as information about the production process, sources of key starting materials, analytical methods, specifications, stability data, validation data), in preparation for on-site verification
inspection of the manufacturing site to assess compliance with WHO GMP
preparation and forwarding of the inspection report, listing all the observations and findings, to the applicant, within 30 days of the last day of the inspection
submission by the applicant, at the request of WHO, and within 30 days of receipt of the request, of no more than two rounds of proposed corrective and preventive actions (CAPAs), to correct deficiencies observed during the inspection
review by WHO of the proposed CAPAs, which may include a follow-up inspection ― within 6 months of the last day of the previous inspection if the written responses received are not considered adequate and especially if any “critical observations” were made during the inspection
- if no "critical" and less than six "major observations" were made, the inspection can normally be closed out based on acceptance of the CAPAs; for "other" observations, CAPA implementation is confirmed during the next inspection, which will generally be a routine inspection
posting on this website of a WHO Public Inspection Report (WHOPIR) once the site is considered to comply with WHO GMP.

Follow-up inspection

In some instances, a follow-up inspection may be conducted to verify CAPA implementation by the manufacturer. It will normally be carried out within six months of the previous inspection (whether initial or routine).

The follow-up inspection of an API or FPP manufacturing site inspection consists of:

review of the submitted CAPAs and the report of their assessment
inspection of the manufacturing site to assess whether CAPA implementation is satisfactory
preparation and forwarding of the inspection report, listing all the observations and findings, to the applicant, within 30 days of the last day of the inspection
posting on this website of a WHO Public Inspection Report (WHOPIR) if the site is now considered to comply with WHO GMP.

Should the follow-up inspection reveal that CAPA implementation is unsatisfactory, the site must undergo and pass a further inspection if it is to attain be considered tto be in compliance with WHO GMP.

If the follow-up inspection is conducted after six months, it will be a full, routine inspection. That is, it will not be limited only to verification of the CAPAs that were requested by WHO in response to the previous inspection.

INSPECTION OF A CRO

A study-specific inspection may be undertaken if a CRO performed a clinical study(ies) for the finished pharmaceutical product (FPP) for which prequalification is sought. WHO may stipulate that the CRO be inspected to verify that the study(ies) comply(ied) with WHO Good Clinical Practices for Trials on Pharmaceutical Products (GCP) and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies and to verify the data generated.

The decision as to whether or not to conduct an inspection of a CRO is taken using a risk-based approach, i.e. it takes into account the complexity of the relevant dosage form (e.g. with respect to solubility, polymorphism), the compliance status observed during previous WHO inspections and the corrective and preventive actions implemented, or inspections carried out by a stringent regulatory authority (SRA), and the date of any previous WHO or SRA inspections. CRO inspections are often triggered by WHO assessors' concern relating to data that is “too good to be true”, to the previous level of compliance of the CRO, or to the fact that the CRO is “new” to WHO.

A CRO inspection is generally scheduled with the CRO within six months of acceptance for assessment of the FPP dossier and announced one to two months before the inspection takes place.

A CRO inspection consists of:

review of the clinical and bioanalytical parts of the dossier submitted for the FPP concerned
request for and review of the CRO master file
inspection of the CRO to assess compliance with WHO GCP and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies
preparation and forwarding of the inspection report, listing all the observations and findings, to the applicant, within 30 days of the last day of the inspection
submission by the applicant, at the request of WHO and within 30 days of receipt of this request, of no more than two rounds of proposed corrective and preventive actions (CAPAs), to correct deficiencies observed during the inspection
review by WHO of the proposed CAPAs
posting on this website of a WHO Public Inspection Report (WHOPIR) if the site is considered to have complied with WHO GCP and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies during the study concerned.

If a CRO study-specific inspection determines that WHO GCP and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies were not adhered to when the study was carried out, and therefore do not support the application for prequalification of the product concerned, the application may be rejected. Moreover, if “critical observations” relating to the overall compliance culture of the CRO and/or data integrity were made during the inspection, all previous studies conducted at this site — when linked to other any other applications for product prequalification – may also be rejected, unless they have been specifically inspected and found individually acceptable.

MANUFACTURER/CRO RESPONSIBILITIES DURING AN INSPECTION

Following receipt of inspection observations verbally at the closing meeting, and thereafter of the inspection report, and if any observations were made, the manufacturer or CRO is responsible for:

performing both vertical and horizontal analysis of the issues raised as a result of any specific observations in order to assess the extent of the underlying deficiency, and any impact on other areas of manufacturing (in the case of a manufacturer) and control (in the case of a manufacturer, or on the different studies conducted (in the case of a CRO)
determining the root cause of all observations identified
determining the corrections and corrective actions to be taken to address the observations and to appropriately address directly-related, but also related systemic issues
submitting a corrective action plan within 30 days of receipt of the inspection report
implementing and verifying the effectiveness of the corrective actions in a timely manner
informing WHO of the completion of these actions as required
informing WHO of any subsequent significant change to the quality system (in the case of a manufacturer, CRO or QCL) or product(s) (in the case of a manufacturer).

If critical observations or a large number of major observations were made during the inspection and communicated at the closing meeting, and/or in the inspection report, the impact on products already released to market (in the case of a manufacturer), or on studies that were already performed (in the case of a CRO), should be assessed by all involved parties.

In the case of a manufacturer, timely and appropriate action should be taken for a product that has already been manufactured. This should include evaluating whether any product released to the market should be recalled.

In the case of a CRO inspection, the CRO concerned should communicate the inspection findings to the sponsor promptly. The sponsor of the relevant study(ies) performed at the CRO is expected to take appropriate action concerning the studies conducted. This may include withdrawing the data generated by a clinical study(ies) and submitted to WHO as part of a submission for prequalification of a product or products.

Clinical studies cannot be corrected retrospectively. So if submitted clinical data can no longer be considered reliable, a new study or studies, under conditions that comply with WHO Good Clinical Practices for Trials on Pharmaceutical Products and WHO Good Laboratory Practice, may have to be performed.

INSPECTION WAIVER

Where satisfactory recent, relevant and reliable evidence of compliance is available to WHO, an on-site inspection may be waived or deferred.

A waiver for inspection may be granted for an API and/or FPP manufacturing site if inspection by national medicines regulatory authorities (NMRAs) operating to equivalent standards and stringency has been performed within the past two years and a positive outcome declared. In such instances, WHO will conduct a desk review and decide whether a waiver of all or part of a site inspection can be given. During the desk review WHO will review:

the inspection reports prepared by other NMRAs operating to equivalent standards and stringency
the extent to which the scope of that inspection was applicable to operations relevant to the product undergoing prequalification; this is especially important in relation to larger sites for which inspection coverage of operations for the product under prequalification may not have been adequate
implementation and proof of acceptable implementation of any corrective action and preventive actions relating to observations made during that inspection
an updated site master or laboratory information file
a copy of the manufacturing authorization
a list of all products manufactured on site
the most recent product quality review for the product(s) concerned
the batch manufacturing and packaging record for the product concerned
the list of any recalls that have occurred during the last three years
written confirmation from the senior quality assurance representative that a full self-inspection or external audit dedicated to the product has been performed within the preceding year.