Presentation for GADA: MCSR Incomplete Comments

1. Presentation for GADA:MCSR Incomplete Comments Karen Finnegan (HFV-145) Amy Simms (HFV-146) Karen Wheless (HFV-145)

2. Purpose To investigate if there has been an increase in the number of incomplete letters sent for MCSRs and provide recommendations for future submissions

3. Approach • Determine the number of MCSRs reviewed from January 2005 to present • Determine the number of incomplete MCSRs per year • Analyze incomplete comments sent in 2011/2012 • Categorized comments and noted trends

4. MCSR review metrics – January 2005 to June 2012

5. Factors influencing the metrics • The revised USP chapter <467> Residual Solvents became official July 1, 2008. • As a result of AGDUFA, the number of generic reviewers increased from 4 to 12 in 2008 – 2009.

6. Analysis of 2011 Incomplete Comments

7. Administrative • Inclusion of labels • Inclusion of new facilities (i.e. contract testing laboratories, API suppliers) • Incomplete Master Files

8. Analytical • Inclusion of new methods • New methods should be reported in a supplement, not an MCSR. • For revised methods (or new methods in supplements) • Not providing a comparison between your method and the USP method • Making changes to a USP method that are not within the allowable variations listed in USP <621> without revalidation

9. Analytical • For revised methods (or new methods in supplements) • Not providing justification for changes to a method • Not providing representative chromatograms and acceptance criteria • Not using all of the organisms listed in USP <61> for micro methods

10. Finished Product Specifications • Finished product specifications that do not comply with the current USP monograph • Removing tests from your finished product specifications • This should be reported in a supplement, not an MCSR. • Not providing a re-evaluation of your test method when changing your finished product specifications (e.g. changes to assay, impurities, endotoxin limits). • Depending on the change, this could require the change to be reported in a supplement, not an MCSR. Consult with CVM if needed.

11. Manufacturing Master Batch Record (MBR) • MBR has significant changes unsuitable for reporting in a MCSR Examples: • Changes in formulation • Changes in mixing parameters (if not a true solution) • Validation data not provided (or referenced) for increasing hold times

12. Manufacturing Master Batch Record (MBR) • Calculation errors • Unclear procedure or unclear description of the required equipment

13. Miscellaneous • Reporting new primary packaging/ delivery systems • USP <661> compliance for applicable containers

14. Raw materials • Specifications and test methods not updated to current USP/ NF • No justification provided for changes made to specifications (most often for tests deleted)

15. Sterility Assurance • Incomplete information provided for deviations or out of specification readings during a product fill or media fill, including any actions that were taken to address the problem • Switching to a product-wet filter integrity test from a water-wet test without supporting data from three production lots

16. Stability • No stability data reported, yet it appears from the DER that product was manufactured that year • Stability testing intervals or tests missed • Stability specifications do not meet current USP monograph • Testing not performed per the approved stability commitment

17. Stability • OOS stability data • Data is not addressed • No investigation provided • Not stated if a 3-day field alert is filed or if batches are recalled • Incomplete investigations or root cause not identified

18. Stability • Stability Commitment/Protocol • Incomplete commitments- not specifying annual reporting/actions to be taken with OOS batches • Unacceptable revisions, per GFI 5/83 • Sections Removed (such as provision to withdraw OOS batches)

19. Conclusions • The percentage of MCSR incomplete letters sent has decreased from 2009 to 2011.

20. Conclusions • Factors that may positively influence the number of incomplete letters: • Most products are now in compliance with USP <467> • Master files are referenced more consistently in MCSRs and reviewed regularly • Improved communication with sponsors regarding expectations in an MCSR

21. Suggestions for MCSR Formatting For Paper Submissions • Use CTD formatting to organize sections • All pages should be numbered • Only sections with reportable changes should be included • Insert colored pages between sections • Clearly state where previous versions of documents are located if they are not included in the submission • Only include documents that have been changed • Highlight changes within documents • Any photocopies or figures should be very clear to help with the scanning process

22. Suggestions for MCSR Formatting • Use eSubmitter – formatting is automatic • For eSubmitter Submissions • We prefer one attached file if possible • If more than one file is needed, the files should be clearly labeled (both within eSubmitter and the attached file name) • The files should be divided at a logical point (i.e. between sections) • All files should contain bookmarks and page numbers and should be OCR’d

23. More Suggestions for eSubmitter • Update eSubmitter regularly • All images and scanned documents should be as clear as possible • For originals and reactivations: • Check the eSubmitter report before packaging for formatting errors (in the Output menu) • When copying and pasting into eSubmitter, use one font size • For supplements: • Include all relevant information in the Proposed Changes section

24. Questions?