1 XXXXXXXXXXXXXXXXXXX, Malaysia, XXXXXX September, 2011 1 3.2.S.3.2 Impurities, Malaysia, 29 September 2011 Options for submitting API data to support

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XXXXXXXXXXXXXXXXXXX,Malaysia, XXXXXX September, 20111

3.2.S.3.2 Impurities,Malaysia, 29 September 2011

Options for submitting API datato support FPP prequalification

Antony Fake

WHO Prequalification of Medicines Programme

Overview

• Introduction - API assessment.

• Options for submitting API information.

• API-related changes after prequalification of the FPP.

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Copenhagen trainingJanuary 2012

API Assessment

• The assessment of the preparation, control and stability of the API is an essential part of the FPP prequalification assessment process.

• Two bodies of API information are assessed during the FPP prequalification process.

– The preparation, control and stability of the API by the API manufacturer, and

– The control of the API by the FPP manufacturer.

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FPP manufacturer’s API controls

• The assessment of the FPP manufacturer’s controls on the API always occurs as part of the FPP assessment.

• This information is always provided by the FPP applicant as part of their dossier.

• Typically it focuses on the physiochemical properties that might affect bioavailability, API specifications and test methods, and possibly stability.

• This assessment may cover more than one API manufacturer if there are multiple suppliers.

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• This type of assessment is critical. It is the FPP specifications for the API that are the official quality standard of the API.

• It is the FPP manufacture that is responsible under GMP for quality of the API.

• Almost all medicine regulators include at least this sort of API assessment.

• However, relying only on this type of assessment creates a fundamental problem.

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FPP manufacturer’s API controls

API manufacturer information

• In order to judge the acceptability of the FPP manufacturer’s controls, information on the preparation and control of the API by the API manufacturer is required.

• This assessment is specific for each API manufacturer.

• In the FPP PQ procedure this information can be supplied in one of four ways.

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Overview

• Introduction - API assessment.

• Options for submitting API information.

• API-related changes after prequalification of the FPP.

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Options for submitting API information

• Option 1: Confirmation of API Prequalification document (CPQ);

• Option 2: Certificate of suitability of the European Pharmacopoeia (CEP);

• Option 3: Active pharmaceutical ingredient master file (APIMF) procedure; or

• Option 4: Full API details in the product dossier (PD).

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Options for submitting API information

• As part of the application the FPP application indicates in the QOS what option they are using.

• If there are several API manufacturers the FPP applicant can use a mixture of options.

• Although the documentation provided by the API and FPP applicant are different for each option, the various processes ensure that ultimately all sections of the module 3.2.S are assessed.

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Option 1

Confirmation of API Prequalification document (CPQ)

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Option 1 – CPQ document

• CPQ documents are issued as part of API Prequalification.

• API prequalification (API-PQ) is a separate procedure to FPP prequalification.

• It can also of course be used to support an application for FPP prequalification.

• Prequalified APIs are recognised as manufactured in accordance with WHO quality and GMP standards.

• The API must be prequalified, not just submitted for prequalification.

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• To become prequalified the API manufacturer submits an APIMF for assessment and evidence of GMP.

Once the APIMF is accepted and the GMP found to be acceptable prequalification is granted.

• Information regarding the prequalified API is recorded in two places: the PQP website (which is public) and the CPQ document, which is provided by the API manufacturer to the FPP manufacturer.

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Website CPQ document

API name API Name

Site(s) of manufacture Site(s) of manufacture

Packaging

Retest period Retest period

Storage temperature Storage temperature

Related APIMF version API specifications

Specification version number Assay and related substance test methodology.

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• Together these documents provide important information on the controls and stability of the API that have been assessed and found to be acceptable.

• Ultimately the reliance by FPP manufacturers and regulators on the CPQ, rather than a complete module 3.2.S, is based upon confidence in the API-PQ assessment process.

• However, for an assessor in the PQ programme there is of course available both the associated APIMF assessment reports and the APIMF itself if necessary.

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Option 1 – FPP applicant requirements

• The FPP applicant submits:

– The CPQ, which represents the evaluation of the API manufacturer’s information.

– The following information and partially completed QOS, which represents the information required to assessed the FPP manufacturer’s control of the API.

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• 3.2.S.1.3 General properties

Discussions on any additional applicable physicochemical and other relevant API properties that are not controlled by the API manufacturer’s specifications e.g. solubilities and polymorphs.

• 3.2.S.2

If the sterility of the FPP is based upon the sterile manufacture of the API then data on the sterilisation process together with full validation data should be provided.

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• 3.2.S.3.1 Elucidation of structure and characteristics

Studies to identify polymorphs and particle size distribution where applicable.

• 3.2.S.4.1 Specification

Specifications of the FPP manufacturer including all tests and limits of the API manufacturer's specifications and any additional tests and acceptance criteria that are not controlled by the API manufacturer's specifications such as polymorphs and/or particle size distribution.

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• 3.2.S.4.2 / 3.2.S.4.3 Analytical procedures and validation

Any methods used by the FPP manufacturer in addition to those in the API manufacturer's specifications.

• 3.2.S.4.4 Batch analysis

Results from two batches of at least pilot scale, demonstrating compliance with the FPP manufacturer’s API specifications.

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• 3.2.S.5 Reference standards or materials

Information on the FPP manufacturer’s reference standards.

• 3.2.S.7 Stability

Data to support the retest period if either the proposed retest period is longer or the proposed storage conditions are at a higer temperature or humidity to that of the Prequalified API.

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Option 2

Certificate of Suitability (CEP)

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Option 2 – An EDQM CEP

• This is a certification procedure run by the EDQM for APIs for which there is an EP monograph.

• It is not evidence that the batches manufactured are compliant with the stated specifications.

• It is not evidence of GMP.

• The CEP certifies that the API when manufactured by the stated API manufacturer can be adequately controlled by the tests of the EP monograph, and if necessary additional tests stated within the CEP itself.

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• The API manufacturer submits their APIMF to the EDQM directly for assessment.

• API manufacturer provide such CEPs to FPP manufacturers who can then submit this as evidence that the API manufacturer controls and preparation are acceptable.

• Again the reliance by FPP manufacturers and regulators on the CEP rather than a complete module 3.2.S is based upon confidence in the EDQMs assessment process.

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• The FPP applicant submits:

– The CEP, which represents the evaluation of the API manufacturer’s information.

– The following information and partially completed QOS, which represents the information required to assess the FPP manufacturer’s control of the API.

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• 3.2.S.1.3 General properties

Discussions on any additional applicable physicochemical and other relevant API properties that are not controlled by the CEP and EP monograph, e.g. solubilities and polymorphs.

• 3.2.S.2

If the sterility of the FPP is based upon the sterile manufacture of the API then data on the sterilisation process together with full validation data should be provided.

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• 3.2.S.3.1 Elucidation of structure and characteristics

Studies to identify polymorphs (exception: where the CEP specifies a polymorphic form) and particle size distribution where applicable.

• 3.2.S.4.1 Specification

The specifications of the FPP manufacturer including all tests and limits of the CEP and Ph.Eur. monograph and any additional tests and acceptance criteria that are not controlled in the CEP and Ph.Eur. monograph, such as polymorphs and/or particle size distribution.

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• 3.2.S.4.2 / 3.2.S.4.3 Analytical procedures and validation

For any methods used by the FPP manufacturer in addition to those in the CEP and Ph.Eur. monograph.

• 3.2.S.4.4 Batch analysis

Results from two batches of at least pilot scale, demonstrating compliance with the FPP manufacturer’s API specifications.

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• 3.2.S.5 Reference standards or materials

Information on the FPP manufacturer’s reference standards.

• 3.2.S.6 Container closure system

Specifications including descriptions and identification of primary packaging components. Exception: where the CEP specifies a container closure system and the applicant declares to use the same container closure system.

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• 3.2.S.7 Stability

Where the CEP specifies a re-test period that is of a shorter duration than that proposed, or the storage conditions have a lower temperature or humidity as proposed by the applicant.

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Option 3

Active pharmaceutical ingredient master file procedure (APIMF)

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Option 3 – APIMF procedure

• The APIMF procedure allows API manufacturers to submit their APIMFs to support of an application for FPP prequalification.

• This procedure is popular because it allows the API manufacturer to support an FPP manufacturer’s application whilst keeping secret commercially sensitive information.

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• It is important that the APIMF version submitted and assessed by PQP matches that provided to the FPP manufacturer by the API manufacturer.

• The API manufacturer also issues a Letter of Access, which authorises PQP to review the APIMF in conjunction with a specific FPP or company.

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• In this procedure the API manufacturer submits both the open and closed part of their APIMF to PQP for assessment. The API manufacturer also provides the open part to the FPP applicant, who submits this with their FPP application.

• The assessment of the APIMF occurs essentially in parallel with the FPP assessment, or if you are lucky it may have been assessed already in conjunction with another application.

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• The APIMF reports are available internally and amongst other things indicate the accepted API specifications, retest period, storage conditions, sites of manufacture etc.

• The FPP manufacturer submits:

– The open part of the APIMF, which represents the API manufacturer’s information.

– A QOS completed in full, with supporting information, avoiding only those sections relating to the restricted (manufacturing sections) of the APIMF.

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Option 4

Full Module 3.2.S

provided with the dossier

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Option 4 – Full dossier

• The final option is for the FPP applicant to provide complete information on the preparation control and stability of the API by the API manufacturer (complete module 3.2.S) in the dossier.

• This of course requires the API manufacturer to reveal detailed information on the preparation of the API to the FPP applicant.

• A fully completed QOS is required to be submitted.

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Overview

• Introduction - API assessment

• Options for submitting API information

• API-related changes after prequalification of the FPP

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API-related changes post-FPP Prequalification

• The option chosen at the time of prequalification also determines how API-related changes are handled post/prequalification.

• API changes are dealt with in different ways depending on the option used to supply the API information during prequalification.

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API-related changes

• There are two sorts of API-related changes.

– Those relating to the control of the API by the FPP manufacturer, e.g. testing parameters for received batches.

– Those relating to API-manufacturers actions, e.g. change in manufacturing process.

• It is the responsibility of the FPP applicant to file variation applications for both types of changes.

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FPP manufacturer initiated changes

• If the FPP manufacturer has initiated the change, then the FPP applicant will always provide the variation application and supporting information directly to PQP, regardless of the API option chosen at the time of prequalification.

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API manufacturer initiated changes

• For API manufacturer initiated changes there are several possible processes.

• In a standard process the API manufacturer notifies the FPP applicant of the intended change and the FPP applicant seeks approval to implement the change, or use batches of API manufactured or controlled in a changed manner.

• This is the process for FPPs that use Options 3 (APIMF procedure) and Option 4 (full dossier).

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Option 4 – Full dosser

• The FPP applicant has complete knowledge of the API manufacture so there is no “sensitive information”. It could even be that the API and FPP manufacturer are the same company.

• The FPP applicant when notified of the change will check the variation guidance and then submit the appropriate variation application.

• In support of the variation application the FPP applicant will provide all supporting information, as required in the variation guidance.

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• For FPP applicants that use the APIMF procedure (option 3) a modified version of this process is used.

– Unlike the standard process not all API changes will result in the submission of a variation application by the FPP applicant.

– Typically a lower-risk category can be chosen by the FPP applicant.

– The FPP applicant does not need to provide extensive supporting data.

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• In the APIMF procedure the API manufacturer is in contact with PQP and is responsible for keeping their APIMF up-to-date.

• When the API manufacturer initiates a change the first thing that happens is that the API manufacturer submits an APIMF amendment to the PQP.

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• Having accepted the amendment a variation application may not be required, e.g. change in API starting material supplier.

• If a variation application is required the API manufacturer then informs the FPP applicant.

• The FPP applicant submits the appropriate variation applicant, but often refers to the associated amendment rather than providing supporting information.

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Options 1 (CPQ) and 2 (CEP)

• API-related changes are handled in a fundamentally different ways for FPPs supported by CPQs or CEPs .

• In both options the FPP applicant has relied upon the CEP or CPQ as evidence of the quality and control of the API and has only limited information on the API control and preparation by the API manufacturer.

• The API manufacturer is only required to inform the FPP applicant of changes if there is a change to the details of the CPQ or CEP.

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• For CPQs the API manufacturer takes responsibility for notifying the PQP of API-related changes and obtaining approval for them.

• The FPP applicant only needs to submit a variation application if there is a change to the details of the CPQ.

• Literally this means a site of manufacture, retest or storage condition, API specifications, assay or related substances test method.

• A single variation category covers all changes to CPQs.

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Option 1 - CPQ

• It is a similar for CEPs.

• Again the API manufacturer takes responsibility for seeking approval of the API-related change.

• In this case the API manufacturer notifies the EDQM of the change.

• Only if there is a change to the details of the CEP does the FPP applicant have to submit a variation application.

• A single variation category covers all changes to CEPs.

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Option 2 - CEP

Summary

• Information pertaining to the API is provided from both the API manufacturer and FPP manufacturer.

• Information relating to the control of the API by the FPP manufacturer is always provided by the FPP applicant.

• There are four options for submitting API manufacturers’ information on the API.

• The four options for submitting API-related information also affects the manner in which API changes are handled after prequalification of the FPP.

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Thank you

Any questions?

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Documents

1 XXXXXXXXXXXXXXXXXXX, Malaysia, XXXXXX September, 2011 1 3.2.S.3.2 Impurities, Malaysia, 29 September 2011 Options for submitting API data to support