Post-Notice of Compliance (NOC) Changes

Outline Background Post-NOC Changes Guidances Future Revisions to Post-NOC Changes Quality Document How to use Quality Appendix Tables -Examples FAQs Quality NC Screening Clarification - Example

Background Underlying Principles: Any change to a drug may impact the quality, safety and/or efficacy of that drug product Any change to the drug product information (labelling) may impact the safe and effective use of that drug product

Background Available tools (prior to development of the Post-NOC Changes guidances) to manage this risk: Legislative Instruments Food and Drugs Act and Food and Drug Regulations Non-Legislative Instruments Policies and Guidances, most notably the Changes to Marketed New Drug Products policy (1994)

Background Regulatory basis in Part C of the Food and Drug Regulations Division 1: C.01.014.5 - annual notification confirming that “information previously supplied…is correct” Compilation of all Level 3 changes to be filed with the annual DIN notification Division 8: C.08.003 - “if any of the matters specified….are significantly different..” Significant changes require a supplement to the New Drug Submission

Background Changes to Marketed New Drug Products policy (1994): reflected “the regulatory amendments to C.08.003 proposed in Schedule 733”. introduced to “reduce the number of instances where a SNDS must be filed, and to provide an updated interpretation of the requirements of C.08.003.” Defined 4 levels of change based on the potential impact on safety and efficacy

Background Proposed Regulatory Amendment - Schedule 733 (1997, 1998): published in Canada Gazette Part I (March 1997) intended to introduce a graduated system of regulatory requirements for changes to new drugs marketed in Canada into the F&DRs withdrawn (Oct. 1998) because better conveyed to stakeholders in the form of policies and guidance documents, rather than embedded in the Regulations

Background Objectives of new guidance: consistent with modern principles of risk management improves international harmonization replaces out-dated policies and guidances supported by the Food and Drug Regulations increases the transparency and consistency of the review process incorporates contemporary concepts such as “design space” of ICH Q8

Background Key elements of new guidance: Revised criteria by which to categorize changes to drugs or drug products Provision of more comprehensive guidance as to information required in support of change

Background Revised criteria result in two main types of change: those that require prior review and approval by Health Canada those that may be implemented without prior review and approval by Health Canada

Background Post-NOC Changes Guidances First draft – March 16, 2007 Second draft – December 5, 2008 Finalized Guidances posted on Health Canada website with effective date of September 30, 2009.

Post-NOC Changes Guidances Framework Document that provides overarching authorities, general description of the proposed reporting categories, drug submission filing and contact information Safety and Efficacy Guidance Document (criteria and examples) Quality Guidance Document Appendix Tables 1- Pharmaceuticals 2 - Veterinary Drugs – (supplementary to Appendix 1) 3 - Biologics 4 - Radiopharmaceuticals

Post-NOC Changes Guidances Scope and Application: changes to new drugs that have received an NOC pursuant to section C.08.004 of the Food and Drug Regulations pharmaceuticals, biologics, and radiopharmaceuticals for human use pharmaceutical, radiopharmaceutical and certain biotechnological products for veterinary use applies to those submissions for which a NOC has been recommended but issuance of the NOC has been placed on hold

Post-NOC Changes Guidances Oversight Required prior to implementation: Level I (300 days*) –Safety and Efficacy & Quality Level II (90 days) Safety and Efficacy & Quality Level II (120 days) Safety and Efficacy Oversight not required prior to implementation: Level III - Annual Notification Level IV - No notification req’d –Quality only

Post-NOC Changes Guidances Guidance documents supersede: New Drug: Sufficient Time policy (1991) Extension of Expiration Dates (1991) Changes to Marketed New Drug Products policy (1994) Stability Requirements for Changes to Marketed New Drugs (1994) Changes in Product-Specific Facility Information (revised in 2004) New Drug: Sufficient Time Notice (2005) Changes in Product Colours and Markings (2005)

Future Revisions to Post-NOC Changes Review every 2 years as per Good Guidance Practices; Review would consider any stakeholder comments received during this period; Certain revisions such as for consistency and typographic errors can be made without consultation; Extensive revisions that include changes to approach in risk classification would require external consultation.

Quality Document Appendix 3: post-NOC changes (Biologics) 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

Quality Document Quality Appendices 1-4: Based on format of EU Variations guideline specific change examples, conditions, supporting data and submission type) Follows CTD progression Attempted to minimize supporting documentation to that considered necessary

Quality Document

FAQs - How to use the Quality Appendix tables 27. Replacement or addition of a drug product manufacturer / manufacturing site, involving: b. production of an immediate release product (e.g., tablet, capsule, liquids, sterile liquids, semi-solids) For an Notifiable Change (Level 2) the following conditions apply: 1.No change in the Batch Formula, Description of Manufacturing Process , Equipment Class and Process Controls, Controls of Critical Steps and Intermediates, or Drug Product Specifications. 2.No change in the container closure system. Would still be a Notifiable Change if any other associated changes are Level 2 or 3. Check any corresponding change examples: 17. Change in the composition of an immediate release solid oral dosage form (other than colours, flavours) 29. Change in the drug product manufacturing process 30. Change in the controls (in-process tests and/or acceptance criteria) applied during the manufacturing process or on intermediates 35. Change in the specification for the drug product tests and acceptance criteria, involving: 37. Replacement or addition of a primary container closure system.... ...and so on.

FAQs – DMFs for Level 3 Changes When a Drug Master File/Letter of Access is required in support of a Level 3 change this information should be filed separately with SIPD- DMF Unit and not included with the Annual Notification. The DMF may be reviewed as part of the auditing of Level 3 changes.

FAQs - Content in DMF to Assess Conditions 2. Replacement or addition of a manufacturing site and/or manufacturer involving: a. production of the starting material, intermediate, or drug substance For an Annual Notification (Level 3) one of the conditions that applies is: 2.No change in the route of synthesis, physical characteristics, and impurity profile of the drug substance (that is [i.e.] no new impurity above 0.10%, no change in the approved total impurity limit and residual solvents within ICH limits). Can a sponsor file this change as a Level 3 if the information to answer condition 2 is contained in a DMF? No. The drug submission sponsor must have sufficient information available to allow the condition to be assessed.

Quality NC Screening Clarification - Example

OTHER QUESTIONS ????

Acknowledgements Joyce Pon – Post NOC Changes Project Lead Krishnan Tirunellai Satish Mallya Joseph Benoliel Kian Mazaheri Hugo Hamel Neil Barkat Gary Condran

Thank You Randy Duhaime Contact Information: Randy Duhaime Senior Policy Analyst Bureau of Policy, Science and International Programs, TPD randy.duhaime@hc-sc.gc.ca

Post-NOC Changes on Health Canada Website http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/postnoc_change_apresac/index-eng.php