1. Post-Notice of Compliance (NOC) Changes

2. 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

3. 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

4. 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)

5. Background Regulatory basis in Part C of the Food and Drug Regulations
Division 1: C 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 “if any of the matters specified….are significantly different..”
Significant changes require a supplement to the New Drug Submission

6. Background Changes to Marketed New Drug Products policy (1994):
reflected “the regulatory amendments to C 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 ”
Defined 4 levels of change based on the potential impact on safety and efficacy

7. 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withdrawn (Oct. 1998) because better conveyed to stakeholders in the form of policies and guidance documents, rather than embedded in the Regulations

8. 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

9. 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

10. 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

11. 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.

12. 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

13. Post-NOC Changes Guidances
Scope and Application:
changes to new drugs that have received an NOC pursuant to section C 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

14. 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

15. 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)

16. 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.

17. 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

18. 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

19. Quality Document

20. 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.

21. 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.

22. 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.

23. Quality NC Screening Clarification - Example

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

26. Thank You Randy Duhaime
Contact Information:
Randy Duhaime
Senior Policy Analyst
Bureau of Policy, Science and International Programs, TPD

27. Post-NOC Changes on Health Canada Website