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Presentation for GADA: MCSR Incomplete Comments. Karen Finnegan (HFV-145) Amy Simms (HFV-146) Karen Wheless (HFV-145). Purpose. To investigate if there has been an increase in the number of incomplete letters sent for MCSRs and provide recommendations for future submissions. Approach.

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Presentation for gada mcsr incomplete comments

Presentation for GADA:MCSR Incomplete Comments

Karen Finnegan (HFV-145)

Amy Simms (HFV-146)

Karen Wheless (HFV-145)


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


  • 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

Factors influencing the metrics
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.


  • Inclusion of labels

  • Inclusion of new facilities (i.e. contract testing laboratories, API suppliers)

  • Incomplete Master Files


  • 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


  • 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

Finished product specifications
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.


Master Batch Record (MBR)

  • MBR has significant changes unsuitable for reporting in a MCSR


    • Changes in formulation

    • Changes in mixing parameters (if not a true solution)

    • Validation data not provided (or referenced) for increasing hold times


Master Batch Record (MBR)

  • Calculation errors

  • Unclear procedure or unclear description of the required equipment


  • Reporting new primary packaging/ delivery systems

  • USP <661> compliance for applicable containers

Raw materials
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)

Sterility assurance
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


  • 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


  • 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


  • 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)


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


  • 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

Suggestions for mcsr formatting
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

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

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