Regulatory Expectations for Method Transfers: Health Canada's Perspective CMC Strategy Forum Methods on the move January 23, 2017

Transcription

1 Regulatory Expectations for Method Transfers: Health Canada's Perspective CMC Strategy Forum Methods on the move January 23, 2017 Hugo Hamel, Senior Biologist/Evaluator, BGTD

2 Overview of the Post-NOC Changes Quality Guidance (PNOCC) Scope & Application Structure Reporting categories Outline Regulatory expectations for method transfers Pharmacopoeial vs non pharmacopoeial Same building, different rooms Different building, same licence number (DEL#) Different building, different licence number Examples of issues with method transfers

3

4 Post-NOC Changes Quality Guidance (PNOCC) Overview PNOCC guidance documents originally posted in September, 2009 Framework document Safety & Efficacy (S&E) document Quality document Revised in 2013 and 2016 Based on the experience from the industry and BGTD Addition of new example of changes Increased clarity (correction of the conditions and supporting data)

5 PNOCC Quality guidance document Objectives To assist with the classification of quality changes made to a new drug that has received a Notice of Compliance (NOC). To provide sponsors with recommendations on the minimum data to support a change which would be considered sufficient to allow a determination of the impact of the change on the quality of the new drug as it relates to safety, efficacy and/or effective use of the new drug.

6 PNOCC Quality guidance document Scope & Application This guidance document applies to sponsors intending to make changes to new drugs that have received a NOC pursuant to Section C of the Food and Drug Regulations. This guidance applies to the following products: Pharmaceuticals Veterinary drugs Biologics Radiopharmaceuticals

7 Structure of the Quality guidance Introduction Appendix 1: post-noc changes (Pharmaceuticals) Appendix 2: post-noc changes (Veterinary Drugs) Appendix 3: post-noc changes (Biologics) Appendix 4: post-noc changes (Schedule C drugs) Appendix 5: Recommendation for comparative Dissolution profile Appendix 6: Changes to Excipients Appendix 7: Examples of Level IV Changes Appendix 8: Glossary

8 PNOCC Quality guidance document Reporting Categories Quality changes are assessed based on their potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. Level I Supplements (Major Quality Changes) Level II Notifiable Changes (Moderate Quality Changes) Level III Annual Notification (Minor Quality Changes) Level IV Record of Changes (Changes with no impact)

9 Comparative table on how post-approval changes are regulated among major NRAs

10 PNOCC Quality guidance document Risk-based approach Conditions: All conditions must be met in order to file the change at the proposed Level of filing If any of the conditions outlined for a given change are not fulfilled, the change is considered at the next higher level Supporting data: Detailed rationale must be provided when recommended supporting data cannot be provided

11 Transfer of QC testing activities Drug Substance Facility : A building in which a specific manufacturing operation or multiple operations take place.

12 Transfer of QC testing activities Drug Product Facility : A building in which a specific manufacturing operation or multiple operations take place.

13 Appendix 7: Examples of Level IV changes (on-site records) Introduction of additional laboratory facility in a facility to perform drug substance or drug product testing. For biologics and radiopharmaceuticals, with the exception of a potency assay or a bioassay, transfer of the QC testing responsibilities for a pharmacopoeial assay to a different facility within the same company. For biologics and radiopharmaceuticals, with the exception of a potency assay or a bioassay, transfer of the QC testing responsibilities for a pharmacopoeial assay to a different company listed on the sponsor s establishment licence.

14 Filing requirements for the following method transfer scenarios DEL: Drug Establishment Licence Contact the Office of Regulatory Affairs (ORA) to discuss your situation ( Potential paths: Written comments Teleconference Face-to-face meeting

15 Supporting data recommended for the different method transfer scenarios (S.2.5/P.3.5) Information demonstrating technology transfer qualification The purpose is to ensure that the receiving laboratory is capable to perform a particular analytical test that has been developed in another laboratory The extent of data required to demonstrate technology transfer qualification depends on different factors: Whether the methods are pharmacopoeial or non-pharmacopoeial Relative complexity of the assay (protein concentration vs HPLC vs Potency) Difficulty of assay transfer Whether same or similar equipment is used If different equipment is used, revalidation may be required Whether changes have been made to the test procedures Change in formulation (different excipients) Risk assessment tools may be used to determine the potential risk associated with the moving of the analytical methods to another lab (ICH Q9). Technical transfer only Partial or full revalidation

16 Supporting data recommended for the different method transfer scenarios (cont d) Different approaches may be considered acceptable if scientifically justified. In general, the expectation is that concurrent testing at the donor and receiving sites be performed to demonstrate that similar/comparable results are obtained: The acceptance criteria by which the receiving laboratory is deemed to be qualified to use the methods being transferred should be clearly described in the transfer protocol. Should include defined ranges of linearity, accuracy and precision (repeatability) Adequate statistical analysis should be used to compare the means and the variability of the results at both sites. 3 batches (in triplicate) with quantifiable amount of impurities should be tested. If not the same, samples should be of similar age, have same homogeneity and stored in the same container closure system and storage condition (should be clearly indicated) Spiked samples should be used when samples do not contain impurities above LOQ

17 Supporting data recommended for the different method transfer scenarios (cont d) Evidence that the new company/facility is GMP compliant The new testing facility should have current evidence of GMP compliance GMP evidence must be based on inspection by Health Canada or a trusted regulatory partner (MRA, PIC/S, EDQM, WHO, others who inspect against ICH Q7 Guidelines) The Regulatory Operations and Regions Branch (RORB) of Health Canada is the organization responsible for performing inspection and for issuing evidence of GMP compliance. A drug tested at the new site cannot be released in Canada until the new testing site is listed on the sponsor s Establishment Licence. The RORB is also the organization responsible for performing Drug Establishment Licencing The timeline for processing amendment request is 250 calendar days. Drug Establishment Licences del_questions_leppp@hc-sc.gc.ca

18 Supporting data recommended for the different method transfer scenarios (cont d) Defined in a guidance document Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in the guidance document may be acceptable provided they are supported by adequate justification. Supporting data are required for Level 2 and Level 3 changes Must be provided only for Level 2 changes (Notifiable Change) Must be provided upon request for Level 3 changes (Annual Notification)

19 Examples of issues with method transfers 1. No concurrent testing was performed: Transfer of a potency assay for a new strength to a company approved for the original strength Original technical transfer data were provided in support of the transfer of the potency assay for the new strength When results from concurrent testing were requested, the data showed that the potency results were systematically different at the new site 2. Lack of details in the transfer protocol with respect to sample preparation, equipment setting and technical operations Transfer of HPLC quantity assay Variance in results between labs, day-to-day and analyst-to-analyst was observed Lack of details regarding sample preparation Different devices were used for reconstitution, which resulted in difference in amount of diluent added and thereby, resulting in differences in concentration.

20 Examples of issues with method transfers (cont d) 3. Lack of suitable acceptance criteria relevant to the tests For simple assay (e.g. protein concentration by UV), the acceptance criteria are based on the release specifications (+/- 10%), which is considered too wide to demonstrate comparability. For moderately complex assay (e.g. HPLC), the acceptance criteria for the difference between the mean and for the intermediate precision should not be too wide Suitable acceptance criteria are critical element of the method transfer Criteria that are too tight could lead to rejection of acceptable results With criteria that are too loose, the receiving laboratory could pass the transfer but be unable to appropriately test the products

21 Conclusion Purpose of the technical transfer activities is to maintain the validated state of the method at the receiving site. Regulatory expectations with respect to method transfer are defined in the post-noc changes quality guidance document. Transfer of non-pharmacopoeial methods must be pre-approved (requires the filing of a Level 2 Notifiable Change) except for a transfer in the same building, different room. Transfer of pharmacopoeial methods can be implemented without prior approval (Level 3 or Level 4 changes). In term of supporting data, the fact that the requirements are defined in a guidance document provides some flexibility. Different approaches may be considered acceptable if scientifically justified. Appropriate statistical analysis should be performed to demonstrate equivalence of the data set at the sending and receiving sites. Contact the Office of Regulatory Affairs to discuss your situation.

22 Thank You!!!

23