Verifying that the quality of prequalified active pharmaceutical ingredients (APIs), finished pharmaceutical products (FPPs), or of testing services provided by prequalified quality control laboratories (QCLs) are being maintained, is essential to the continuing value and relevance of WHO prequalification. WHO ensures ongoing quality of prequalified APIs, FPPs and QCLs through:
- monitoring and/or review of amendments to API master files and variations to FPPs: API master file amendments and variations to FPPs must be submitted to WHO for notification or approval, depending on the degree of risk that the associated change presents with respect to the ongoing quality and safety in the case of an API, or the safety, quality and efficacy in the case of an FPP
- FPP requalification: Every five years from the date of prequalification, or when requested to do so by WHO, the holder of a prequalified FPP is requested to submit data and information about that FPP, to WHO for assessment
- reinspection of API and FPP manufacturing sites, and of QCLs: either routinely or in follow up to receipt of a complaint
- quality monitoring surveys, field sampling and testing projects: carried out randomly to monitor the quality of medicines (both WHO-prequalified and non-WHO prequalified medicines) procured by UN agencies or in follow up to receipt of a complaint
- monitoring of the quality of services provided by prequalified QCLs: through review of updated Laboratory Information Files and of laboratory annual reports and evaluation of the results of participation in an appropriate proficiency testing scheme.
Relationship between variations and amendments
The procedures for handling variations to an FPP dossier and amendments to an API master file (APIMF) address instances in which a change (changes) has (have) been made to the ICH CTD1 sections 3.2.S and 3.2.P of a prequalified API or FPP dossier. They can be summarized as follows and reflect the four options for submitting API information described in the section on :
- for a prequalified API or APIMF accepted through the APIMF procedure: changes to the API details (ICH CTD section 3.2.S) should be submitted via the APIMF amendment procedure
- for a prequalified FPP: changes to the details of the ICH CTD sections 3.2.P should be submitted using the variation procedure. The way in which changes to API details (ICH CTD section 3.2.S) are submitted will depend on which of the four possible options was selected for submitting information about the API when the application for FPP prequalification was made:
- Option 1: by referring to an API that has already been prequalified. The API manufacturer first submits the API change via the APIMF amendment procedure and thereafter informs the FPP manufacturer of the change. The FPP manufacturer should submit a variation if a revised CPQ has been reissued of if any changes to API details not covered by the CPQ — such as particle size or polymorphic form — have been made.
- Option 2: by submitting a copy of the Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP) issued by the European Directorate for the Quality of Medicines and HealthCare. The API manufacturer first submits the API change to EDQM and thereafter informs the FPP manufacturer of the change. The FPP manufacturer submits a variation only if a revised CEP has been reissued. This applies only to those details covered by the CEP. Changes to API details that are not covered by the CEP ― for instance, retest period, particle size or polymorphic form ― must be made directly by the FPP manufacturer via the variation procedure.
- Option 3: through application of the APIMF procedure. The APIMF holder must first submit the API change via the APIMF amendment procedure and thereafter inform the FPP manufacturer it has done so; depending on the nature of the change, the FPP manufacturer may be required to submit the change via the variation procedure.
- Option 4: by providing a full description within the FPP dossiers part of their submission, all API changes are made using the variation procedure.
Detailed requirements for API-related changes to an FPP dossier can be found under the Variations to FPPs section.
1 ICH refers to the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. CTD refers to the assemblage of quality, safety and efficacy information in a common format (called CTD - Common Technical Document ).
Guidance on amendments to an active pharmaceutical ingredient master file (APIMF) submitted in support of a prequalified finished pharmaceutical product (FPP) or prequalified active pharmaceutical ingredient (API) (18 October 2019)