FDA clarifies reporting post-approval changes for disposable manufacturing materials

Regulatory NewsRegulatory News | 01 August 2022 |  By 

The US Food and Drug Administration (FDA) on Friday issued a question-and-answer guidance  to provide clarity to manufacturers on reporting post-approval changes to disposable manufacturing material.
The guidance covers changes made to new drug applications (NDAs), biologics license applications (BLAs) or abbreviated new drug applications (ANDAs) and applies to all manufacturing establishments, including those that perform functions under contract.
During the COVID-19 public health emergency, FDA has fielded questions about changing materials and equipment due to the limited availability of disposable manufacturing materials during periods of increased demand. “Limited availability of disposable manufacturing materials can affect sterile drugs and biological products,” according to the guidance.
Post-approval changes are differentiated into four categories: major changes requiring the submission of a prior approval supplement (PAS); moderate, requiring the filing of changes being effected-30 days supplement (CBE-30), or a CBE-0 supplement; or minor changes requiring only the filing of an annual report. Annual reports do not need to be submitted as supplements.
The document addresses questions on changes an applicant can make to disposable manufacturing materials, whether there are mechanisms to lower reporting categories, and when applicants should contact FDA for feedback on proposed changes. The guidance also offers examples of changes and corresponding reporting categories for NDAs, ANDAs, and BLAs.
Changes to disposable manufacturing materials can include changing suppliers; reducing the number of materials used or extending the use of materials to increase throughput; and reusing disposable manufacturing material.
Manufacturers can use a comparability protocol (CP) to lower the reporting category of the change, says FDA, and advised industry to consult its April 2016  draft guidance on CPs if they are to be used. FDA defines CPs as a “comprehensive, prospectively written plan for assessing the effect of a proposed CMC post approval change on the identity, strength, quality, purity, or potency of a drug product or a biological product.”
The guidance also advised manufacturers to contact the agency before making a postapproval change, especially before submitting a supplement with a lower reporting category. FDA in turn will “provide timely assessment” on these changes.
Appendices to the guidance offers some examples of changes that fall in the PAS, CBE-30, CBE-0 category, and annual reports.
For NDAs and ANDAs, changing from a sterile filtration to most heat sterilization for product cotans heat-stable active pharmaceutical ingredients (APIs) would be deemed PAS; increasing the flow rate filtration parameters for aseptic processing without a changing the filter materials would be considered a CBE-30. Eliminating an in-process filtration step for a terminally sterilized drug products would be considered a CBE-0 and changing the filtration volume for a sterile product would be considered an annual reportable change.
For BLAs, changing from a stainless-steel to a disposable bioreactor for a drug substance would require the filing of a PAS; while adding, deleting or substituting a unit operation would be considered a PAS.
Changing the filter or resin suppler without changing the resin materials to the drug substance would be considered a CBE-30 change while adding or replacing equipment of the same size and materials of construction without changing the process parameters in the approved BLA would be considered an annual reportable change.
Comments will be accepted on the guide at any time.
Final guidance


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