API documentation from the perspective of WHO-PQP

Transcription

1 API documentation from the perspective of WHO-PQP Antony Fake PhD WHO Medicines Prequalification Programme 1 API documentation 3.2.S.3.2 from Impurities, the perspective of WHO PQP Malaysia, Mumbai, 29 September

2 Abbreviations API Active Pharmaceutical Ingredient FPP Finished Pharmaceutical Product APIMF API Master File (DMF) CPQ Confirmation of Prequalification Document 2

3 Overview Technical assessment issues API Amendments Documentation issues 3

4 Technical Issues Solubility data Since early 2012, API manufacturers have been asked to provide quantitative solubility data for their APIs under specific conditions (250 ml, three phs etc). This is to assist PQ bioequivalence assessors in determining APIs that may be eligible for biowaivers. It was found that typical qualitative data was not specific enough, and historically provided quantitative values often varied, or were non-comparable. 4

5 Manufacturing block information Technical Issues For over a year PQ has been requesting that API manufacturers define the manufacturing blocks used for preparation of their specific API. This is because some manufacturers do not have the same quality standards or quality systems operating across the entire site. This information allows for a focus, in principle, of the GMP inspection to those specific blocks manufacturing for PQ. The information is not mandatory, but without this information any activities related to this API at the site may be inspected 5

6 Technical Issues Definition of the API Starting material The number of requests to redefine the API starting material to an earlier molecule in the synthesis appears to be reducing, but still the number of requests is significant. Recent WHO, EMA and ICH (Q11) guidance all identify the need to choose the API starting materials carefully. What remains clear is that the API SM almost invariably a molecule one or more synthetic steps prior to the final API. 6

7 Technical Issues Recovery of solvents Almost all manufacturers undertake some recovery of solvents. Although the general assessment approach has not varied significantly as a reminder: The limits applied to recovered solvent do not have to be the same as fresh solvent. The limits applied must be justified based upon actual experience. This is common deficiency. Either the choice of limits is not justified or the justification is not logical. Unless the limits are so strict as to be obviously acceptable, the chosen limits must be justified by the demonstrated ability to manufacture acceptable API under the worse case scenario. 7

8 Technical Issues For instance: If the proposed limits are: Assay 98% Any single impurity 1% Total impurity content 2% Then batch data for API and solvent batches should be provided where the API meets specifications and the solvents used had impurity content near 2% 8

9 Technical Issues Proposed limits Assay 92% Single impurity NMT 2% Total impurity NMT 8% 9

10 Technical Issues Proposed limits Actual solvent batches Assay 92% 98% Single impurity NMT 2% 0.8% Total impurity NMT 8% 1.7% Not justified 10

11 Technical Issues Proposed limits Actual solvent batches Justified limits Assay 92% 98% 98% Single impurity NMT 2% 0.8% NMT 1% Total impurity NMT 8% 1.7% NMT 2% 11

12 Benzene in recovered solvents Technical Issues Control may not be necessary, but a logical scientific argument is expected See also skip testing A test for non-volatile matter (0.1%) For all recovered solvents. Number of recovery cycles There is normally no requirements to state the number of cycles a solvent will be recycled. Provided the solvent remains within specification it can be used. Water or other components should be listed in the specifications 12

13 Technical Issues Impurities discussion This is often lacking. It is not acceptable to just choose the pharmacopoeial impurities without providing a discussion over whether other impurities may occur. Like residual solvents, the impurity limits chosen (if not pharmacopeial) should be justified. 13

14 Technical Issues Class I solvents and Genotoxins There should always be a comment in the impurities section on genotoxins even if this brief and concludes there are no potential genotoxins. The European clarification over requirements for the control of class I solvents and genotoxins depending on their potential to be present is being used by PQP. 14

15 Technical Issues For instance a class-1 solvent formed or introduced prior to the final step of the synthesis does not need to be present in the API specs, provided it is controlled in a suitable intermediate. The latter condition is often overlooked. 15

16 Skip testing Technical Issues PQP sees skip testing as of useful way to ensure post-acceptance integrity of the API quality. The exclusion or inclusion of tests in the API specifications is often the subject of considerable debate and internal discussion. From a practical perspective once a test is excluded from the API specifications the chances of this being considered during subsequent post-approval reduces. There is therefore an increasing preference to include marginal tests in the API specifications, but as skip tests. It is a useful risk strategy and reduces the time taken to resolve marginal issues. 16

17 Technical Issues Skip testing Some further points: It is recognized that under GMP even routine tests may be skip tested by the manufacture if justified. Regulatory notification is not required. The identification of a particular test as a skip test in the specifications by a specific statement is unnecessary but is acceptable. There is no requirements to include a statement over the frequency of the skip testing within the specifications. 17

18 Technical Issues Holding times for intermediates This is considered to be a GMP matter and unless there is a particular reason to do so, the statements or justifications of holding times is not considered necessary. It is expected that under GMP an intermediate will not be introduced in further steps unless they are known to be of adequate quality. 18

19 API-Related Changes 19

20 API related changes There are four ways in which API information can be submitted 1.Use of a Prequalified API (submission of CPQ) 2.Use of an EDQM Certification (submission of a CEP) 3.Use of an APIMF (APIMF Procedure) 4.Provision of Module 3.2.S as part of dossier (full dossier) Regardless of the manner of submission the technical information ultimately provided remains the same. 20

21 API related changes API manufacturers who have submitted an APIMF in support of: their own Prequalified API, or the prequalification of an associated FPP Have obligations to maintain their APIMF with accurate information. And To seek approval for any API related changes (APIMF amendment) 21

22 API related changes Currently, this means 1.The submission of an APIMF amendment to PQP. 2.Receipt of the amendment acceptance letter. 3.Passing of the letter to any associated FPP manufacturers. 4.The submission of an API-related variation by FPP manufacturers 22

23 New APIMF Amendment Guidance A new APIMF amendment guidance will be circulated for comment imminently. It is very closely based upon the circulated Guidance on the Submission of Variations for PQ FPPs. It features the use of self-assessable changes. It offers a reduction in the burden upon both PQP and manufacturers. When considered alongside the variation guidance, it recognizes users of the APIMF procedure and in particular PQ d APIs. 23

24 New APIMF Amendment Guidance Four types of changes classes are envisaged Annual Amendment Notifications (AAN) Immediate Amendment Notifications (IAN) Minor Amendment (Amin) Major Amendment (Amaj) 24

25 Annual Amendment Notifications (AAN) APIMF holders must satisfy themselves that they meet all of the prescribed conditions for the change. ANs and the associated documentation should be submitted to WHO PQP within 12 months of implementation of the change. APIMF holders may group several AN changes as a single submission, or coincide these notifications with the submission of an updated APIMF, or other amendment types. 25

26 Immediate Amendment Notifications (IAN) APIMF holders must satisfy themselves that they meet all of the prescribed conditions. APIMF holders must submit all required documentation with the notification application. A change can be implemented immediately at the time of submission. The change can be considered accepted if an objection is not issued by WHO PQP within 30 calendar days of the date of acknowledgement of receipt of the application. 26

27 Minor amendment (Amin) APIMF holders must satisfy themselves that they meet all of the prescribed conditions for the change and submit all required documentation with the amendment application. A minor amendment can be implemented if no objection letter has been issued within a time period indicated on the WHO PQP website. Should questions arise during the specified period, the change can only be implemented on receipt of a letter of acceptance from WHO PQP. A target assessment time will be published. 27

28 Major Amendment (Amaj) The documentation required for the change included in this reporting type should be submitted as a minimum. Prior acceptance by WHO PQP is required before the change can be implemented. A letter of acceptance will be issued for all major amendments once the amendment is considered acceptable. 28

29 APIMF Amendment Process Three phases 1.Screening 2.Audit or Assessment 3.Implementation or Acceptance 29

30 An will be sent to the applicant Amendment application Screening Rejection Rejection Acknowledgment Accepted for assessment Notification acceptable by default Notification not acceptable by default Amendment acceptable after 30 days be default Annual notifications & Immediate notification Major amendments Minor Amendments Risk based Audit process Assessmen t Assessment Issues arising? Issues arising? Issues arising? Assessment No further action No further action Acceptance letter Letter of refusal

31 Notifications are accepted by default Amendment application Screening Rejection Rejection Acknowledgment Accepted for assessment Notification acceptable by default Notification not acceptable by default Amendment acceptable after 30 days be default Annual notifications & Immediate notification Major amendments Minor Amendments Risk based Audit process Assessmen t Assessment Issues arising? Issues arising? Issues arising? Assessment No further action No further action Acceptance letter Letter of refusal

32 Notifications will be audited rather than assessed. Amendment application Screening Rejection Rejection Acknowledgment Accepted for assessment Notification acceptable by default Notification not acceptable by default Amendment acceptable after 30 days be default Annual notifications & Immediate notification Major amendments Minor Amendments Risk based Audit process Assessmen t Assessment Issues arising? Issues arising? Issues arising? Assessment No further action No further action Acceptance letter Letter of refusal

33 This could lead to questions and potentially the reversal of the change Acknowledgment Amendment application Screening Accepted for assessment Rejection Rejection Notification acceptable by default Notification not acceptable by default Amendment acceptable after 30 days be default Annual notifications & Immediate notification Major amendments Minor Amendments Risk based Audit process Assessmen t Assessment Issues arising? Issues arising? Issues arising? Assessment No further action No further action Acceptance letter Letter of refusal

34 Minor Amendments maybe implemented 30 days after acknowledgment if there are no objections raised. Acknowledgment Amendment application Screening Accepted for assessment Rejection Rejection Notification acceptable by default Notification not acceptable by default Amendment acceptable after 30 days be default Annual notifications & Immediate notification Major amendments Minor Amendments Risk based Audit process Assessmen t Assessment Issues arising? Issues arising? Issues arising? Assessment No further action No further action Acceptance letter Letter of refusal

35 If there are no objections, no further correspondence will be received Amendment application Screening Rejection Rejection Acknowledgment Accepted for assessment Notification acceptable by default Notification not acceptable by default Amendment acceptable after 30 days be default Annual notifications & Immediate notification Major amendments Minor Amendments Risk based Audit process Assessmen t Assessment Issues arising? Issues arising? Issues arising? Assessment No further action No further action Acceptance letter Letter of refusal

36 If there are questions then assessment follows the major amendment process and implementation can Acknowledgment only occur after receipt of the acceptance letter Amendment application Screening Accepted for assessment Rejection Rejection Notification acceptable by default Notification not acceptable by default Amendment acceptable after 30 days be default Annual notifications & Immediate notification Major amendments Minor Amendments Risk based Audit process Assessmen t Assessment Issues arising? Issues arising? Issues arising? Assessment No further action No further action Acceptance letter Letter of refusal

37 APIMF Amendment Process The success of the amendment process relies on three things. 1.Correct assessment of the change type by applicants 2.Correct submission of supporting documentation 3.Correct submission of replacement sections If all three do not occur the assessment burden will remain and the new guidance will not offer the benefits it should. Consequently, in order not to disadvantage others these requirements must be strictly enforced. Applications will be rejected. 37

38 Correct assessment of the change also relates to conditions and documentation 38

39 APIMF Amendment Process The success of the amendment process relies on three things 1.Correct assessment of the change type by applicants 2.Correct submission of supporting documentation 3.Correct submission of replacement sections If all three do not occur the assessment burden will remain. Consequently, in order not to disadvantage others these requirements must be strictly enforced. Applications will be rejected. 39

40 For each amendment supporting data will be specified minimum data 40

41 APIMF Amendment Process The success of the amendment process relies on three things 1.Correct assessment of the change type by applicants 2.Correct submission of supporting documentation 3.Correct submission of replacement sections If all three do not occur the assessment burden will remain. Consequently, in order not to disadvantage others these requirements must be strictly enforced. Applications will be rejected. 41

42 Replacement sections for the APIMF are critical to ensure accurate documentation. Even if a small changes are made replacement sections are required. An updated APIMF would also be acceptable. 42

43 APIMF Documentation The new Amendment guidance highlights the need for good documentation identification and maintenance. Traceability of documentation over time has become an increasing burden for PQ as the number of APIMFs increases, restricting the amount of assessment that occurs. Traceability of amendments is particularly important. APIMF traceability is a critical feature of API Prequalification since the APIMF version number is published. A move to electronic-only submissions can only occur if good quality documentation and traceability exists. 43

44 APIMF Documentation PQ documentation requirements have been published for sometime. As part of the amendment guidance consultation, comments on documentation requirements will also be sought. Consultation is being undertaken because these requirements will then be strictly enforced. 44

45 APIMF Documentation The submitted APIMF, or amendment should: be prepared in CTD format be separated into open (applicant) and closed (restricted) sections be paginated throughout the entire document. Restarting page numbers for each subsection section is not permitted include a contents page with page number references to each of the CTD subsections be assigned a manufacturer's version number that should be present in the footer or header of each page of the APIMF. 45

46 APIMF Documentation The electronic version of the APIMF should also meet: Separate files should be provided for the open and closed sections. Single files should not exceed 30MB in size. The document should be provided in text-selectable PDF format. Document bookmarks for each of the CTD subsections should be added for each of the CTD subsections. In additional the use of hyperlinks within the body of the text is encouraged. A scanned copy of the paper version will not be accepted. The inclusion of scanned copies of supporting documents such as Certificates of Analysis, authorized specifications, signed protocols, etc are permitted. 46

47 APIMF version numbers Each APIMF should be assigned a unique version number. FPP manufacturers and PQP should hold APIMFs with the same version numbers. Amendments should be numbered to reflect the parent APIMF version they below to. Whereas an updated APIMF should be given a new version number. For instance: WHO/Lam/AP01/Amendment August

48 APIMF Documentation These requirements should not be beyond the abilities of current manufacturers. If good quality electronic documents, with systematic version control are routinely submitted by the majority of manufacturers, we will be able to: Dispense with sending paper copies to Copenhagen. Consider the submission of applications via a web-based system. 48

49 Further information The PQ website is a good source of information, please read. AND, ALSO Please me (or visit) if you have any questions. Fakea@who.int One could save you a lot of time.

50 Thank you 50