Comparability protocols may reduce application submission and filing requirements.

FDA's draft guidance, "Comparability Protocols--Protein Drug Products and Biological Product, Chemistry, Manufacturing, and Controls Information," released Sept. 3, describes recommendations for implementing post-approval manufacturing changes using the comparability protocol approach, which was pioneered for biologics.

Once finalized, the guidance will apply to protein-based human and veterinary drug products and biological products, FDA said.

In some instances, manufacturers using approved comparability protocols will be able to implement some changes without submitting a prior approval supplement. Having information and data in the protocol will enable FDA to ensure that regulatory requirements appropriately target the risk that a manufacturing change will adversely affect product quality.

A comparability protocol is a comprehensive plan that describes the specific tests and validation studies and acceptable limits to demonstrate the lack of adverse effect for specified types of manufacturing changes on the identity, strength, quality, purity, or potency of the product, the guidance states.

FDA announced it will evaluate existing data on prior approval changes with the goal of identifying opportunities for reducing application submission and filing requirements.

"Comparability protocols offer an optional regulatory mechanism for manufacturers to use for an approved product, provided it covers comprehensive, specific tests and studies with acceptable limits," John Taylor, associate commissioner for regulatory affairs, said during a Sept. 3 press briefing. Having information in the protocol allows the manufacturer to implement chemistry, manufacturing and controls (CMC) changes sooner, he said.

The guidance applies to comparability protocols for BLAs, BLA supplements, for therapeutic recombinant DNA derived protein products, naturally derived protein products, plasma derivatives, vaccines, allergenics and therapeutic DNA plasmids.

It also applies to NDAs, ANDAs, new animal drug applications (NADAs), abbreviated new animal drug applications (ANADAs), or supplements to these applications for protein drug products, and not sufficiently characterizable peptide products.

The guidance does not pertain to comparability protocols for human blood and blood components intended for transfusion and for further manufacture, somatic cell therapy, or gene therapy vectors (except therapeutic DNA plasmids).

Comparability protocols may be submitted in the following formats:

* Annual Report (AR)

* Change-Being-Effected Supplement (CBE)

* Change-Being-Effected-in-30-Days Supplement (CBE-30).

* Prior Approval Supplement (PAS)

The guidance describes the basic elements of a comparability protocol and specific issues to consider when developing comparability protocols for changes in:

1. the manufacturing process,

2. analytical procedures,

3. manufacturing equipment,

4. manufacturing facilities,

5. container closure systems, and

6. PAT.

FDA recommends that manufacturers consider product-specific and process-specific attributes when determining whether to develop a comparability protocol. Attributes can include:

1. Complexity of the product structure,

2. Ability to characterize the physicochemical, biochemical, immunological microbiological, and biological properties of the product,

3. Degree to which differences in product characteristics (e.g., product structure and physical properties) can be detected,

4. Degree of product heterogeneity,

5. The effect of potential changes in the impurities on product safety,

6. The robustness of the product (i.e., the ability of product to remain unaffected by process changes), and

7. Rigorousness of the manufacturing process controls (i.e., the ability of the manufacturing process controls to ensure that the product remains unaffected by changes).

The guidance offers some specific examples of changes in the manufacturing process where a comparability protocol has been used:

* Increase or decrease in batch size that affects equipment size.

* Modification of production operating parameters in fermentation [e.g., time, temperature, pH, d[O.sub.2] (dissolved oxygen)].

* Adding, deleting, or substituting raw materials (e.g., buffer or media components).

* Mode changes (usually associated with equipment changes such as tangential flow filtration to centrifugation).

* 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 in a BLA, or post-approval supplement to a BLA (see examples provided in Section V. E.).

To view the guidance, visit www.fda.gov/cder/guidance/protcmc.doc