FDA seeks to reduce PAS, CBE workload through protocols.

The guidance for comparability protocols, released with the agency's Final Report "Pharmaceutical cGMPs for the 21st Century--A Risk-Based Approach," was developed to identify options for a systematic risk-based approach to the review process for post-approval manufacturing changes.

According to the guidance, "a comparability protocol is a comprehensive, detailed, written plan that describes the specific tests and studies, analytical procedures, and acceptance criteria to be achieved to demonstrate the lack of adverse effect for a specified type of CMC change that may relate to the safety or effectiveness of the drug product."

The guidance also notes that the Changes Without Prior Review Working Group determined that "a reduced reporting category can be justified when a comparability protocol provides evidence that an applicant has a scientific and technological understanding of the drug, manufacturing process, controls, proposed change and potential effect of that change on the product quality."

A comparability protocol is beneficial because it could allow an applicant to implement a CMC change without waiting for prior approval from FDA. It could therefore place a product in distribution sooner than without a protocol.

"A comparability protocol may also provide a means to facilitate process improvement and/or process optimization. In some cases, a comparability protocol may provide a means to prevent or mitigate drug supply disruptions or shortages," the guidance document states.

The draft guidance document "Comparability Protocols Protein Drug Products and Biological Products--Chemistry, Manufacturing and Controls Information," issued in September 2003, notes some instances where comparability protocols have been utilized:

* Increasing or decreasing in batch size that affects equipment size;

* Modification of production operating parameters in fermentation;

* Adding, deleting or substituting raw materials;

* Mode changes (usually associated with equipment changes such as tangential flow);

* Establishing a new working cell bank using a modified procedure;

* Reprocessing the drug substance or drug product, as appropriate;

* Addition, deletion or rearrangement of production steps;

* Facility-related changes for products with facility/establishment information provided Future changes the agency is considering in the guidance include:

* Change ICH Q8 to describe the suggested contents for the 3.2.P.2 Pharmaceutical Development section of a regulatory submission in the ICH M4 Common Technical Document format. The intent is to provide sponsors of drug applications an opportunity to present knowledge gained during development of a product.

* Under the Manufacturing Subcommittee of the Advisory Committee for Pharmaceutical Science (ACPS), form a working group to identify specific steps needed to move towards the desired state.

* Consider ACPS recommendations on regulatory flexibility for post-approval changes (e.g., reduce the need for prior review) for modifying the draft Comparability Protocol Guidance (for small molecules only).

Currently the agency is finalizing the guidance to incorporate the agency's new risk-based approach to ensure reductions in post-approval manufacturing changes and to ensure that appropriate manufacturing science is incorporated in the decision-making processes.