CMC Comparability Protocols Should Allow For Broader Changes, PhRMA Says

The scope of FDA's chemistry, manufacturing & controls comparability protocols should be broader if sufficient data are available, the Pharmaceutical Research & Manufacturers of America suggests.

"The protocols should be made applicable to any change in an entire process, such as synthesis or purification of a drug substance or a process change anywhere in the manufacture of a drug product," PhRMA says in July 24 comments to an FDA draft guidance.

"The key to allowing use of a comparability protocol in such circumstances is the availability of sufficient manufacturing science data to demonstrate adequate understanding of the substance and product in the light of the proposed changes," the comments state.

FDA's draft guidance, "Comparability Protocols - Chemistry, Manufacturing & Controls Information," was released in February as part of the agency's risk-based good manufacturing practices initiative (¹ , p. 20).

An approved comparability protocol could reduce the level of the reporting category for the particular CMC change when implemented from a prior approval supplement to a changes-being-effected supplement or an annual report.

The draft document advises companies not to submit comparability protocols for "broad, nonspecific plans for CMC changes [or] a change whose adverse effect on the product cannot be definitively evaluated by pre-specified tests, studies, analytical procedures and acceptance criteria."

PhRMA maintains that use of the protocols should be based on whether there is an understanding of the "critical process parameters and controls necessary to make the substance or product" and "how robust the substance or product is in the face of changes."

"If such knowledge is available, all changes made under a comparability protocol should be made using an annual report rather than the 'one category lower' proposed in the guidance," the comments state.

"The guidance should more appropriately emphasize consideration of product/process complexity, robustness and capability in determination of single versus multiple reporting category reductions."

PhRMA requests that FDA provide an example in the final guidance for when multiple-level category reductions are possible and an explanation for how they would be guaranteed. "It is not clear how the reduced reporting category is ensured and how the agreement between the agency and the applicant is reached (i.e. discussions)," the comments state.

The draft guidance covers CMC comparability protocols that would be submitted in NDAs, ANDAs or supplemental applications and well-characterized synthetic peptides.

A January draft guidance, "Drug Product: Chemistry, Manufacturing, and Controls Information," provides recommendations for the CMC information that should be submitted in NDAs and ANDAs to ensure continued product quality (² , p. 32).

The guidance states that the "Pharmaceutical Development section should contain information on the development studies conducted to establish that the dosage form, formulation, manufacturing process, container closure system, microbiological attributes, and usage instructions are appropriate for the purpose specified in the application."

The Generic Pharmaceutical Association's July 7 comments on the guidance recommend FDA take a more flexible approach to ANDAs.

"FDA should consider identifying the types of ANDAs that may warrant submission of a pharmaceutical development report and request the reports only in those instances," the comments state.

"For many products, a simple confirmation that the formulation is essentially the same as the reference listed drug, the container closure is the same as that used by the brand product, or the product and container complies with a compendial monograph, provides assurance that there are no new issues raised in regard to the development of the proposed drug product."

FDA notes that "more detailed guidance...may be available in separate guidance documents for specific types of drug products or dosage forms."