US FDA Updates Draft Guidance on Comparability Protocols for Human Drugs and Biologics (Chemistry, Manufacturing, and Controls Information)

Vivek Padalalu

The United States Food and Drug Administration (FDA) has released a draft Guidance on “Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information”, Revision 1, dated 19 April 2016. This guidance provides human drugs and biologics application holders with recommendations on implementing chemistry, manufacturing, and controls (CMC) post approval changes using a comparability protocol (CP). It replaces the draft guidance published in February 2003, titled Comparability Protocols: Chemistry, Manufacturing, and Controls Information and most of the content is new or has been updated.

Submitting a post approval CMC change:
NDA (New Drug Application), ANDA (Abbreviated New Drug Application), or BLA (Biologics License Application) holders are responsible for validating the effects of any CMC changes on the identity, strength, quality, purity, and potency of the drug, as these factors relate to the safety or effectiveness of the drug. They must notify FDA of any change to an approved application in accordance with the regulatory requirements outlined in 21 CFR 314.70 and 601.12. In those regulations, the post approval CMC changes to established conditions are categorized into one of three reporting categories. The categorization is dependent on whether the change has a substantial, moderate, or minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug or biological product. Depending on the degree of changes, the applicant may notify the FDA by submitting: a prior approval supplemental (PAS) application (for substantial changes), a change being effected in 30 days [CBE-30] supplement (for moderate changes), or an annual report (for minimal changes).

The updated guidance also provide for CPs as an optional way to manage all categories of post approval changes. A CP can be submitted in an original application or as a PAS as provided for in 21 97 CFR 314.70(e) or 601.12(e).

Comparability Protocols to document post approval CMC changes:
A CP is a comprehensive, prospectively written plan for assessing the effect of a proposed CMC post approval change on product quality. It describes the specific tests and studies to be performed and the acceptance criteria to demonstrate the lack of adverse effects of one or more proposed CMC changes on product quality.

The supplement containing the CP must be approved before distribution of a drug product produced with the change as outlined in the protocol (see 21 CFR 314.70(e) and 601.12(e)). A CP, once approved, can be used for a one-time change, or used repeatedly over the life cycle of a product. A CP can also cover identical changes that affect multiple applications (grouped supplements, trans-BLA).

Seeking approval for a CP as part of the original application may facilitate the applicant’s ability to prospectively optimize the manufacturing process or otherwise adjust the control strategy rapidly and predictably in the immediate post approval period as manufacturing experience is gained.

The purpose of a CP is to allow for a more expedient distribution of product by permitting applicant to submit a protocol for a change during original application or PAS, which if approved, may justify a reduced reporting category for the particular change at the time the change is implemented.

Examples of changes for which a CP might be useful include:

  1. Manufacturing site changes
  2. Acquisition of facilities operating under one manufacturer’s license by another licensee
    Single change in the manufacture of a product that will be implemented in multiple facilities under a single license
  3. The FDA recommends that companies consider a CP submission that proposes a reduced reporting category for particular changes only if a company has a sufficient understanding of the product and manufacturing process to assess the associated risks.

Developing a CP:
The CP submission provides a plan for the implementing proposed changes and includes:

  1. A summary, including tabular, narrative, or graphic representations
  2. A detailed description of and rationale for the proposed change (based on complexity of the change and the specific associated risks to product quality)
  3. Supporting Information and Analysis demonstrating a company’s understanding of the product, manufacturing process and control strategy
  4. Any proposed reduced reporting category

When not to use a CP:
Certain changes may be too critical, complex, or of a magnitude that a CP cannot adequately evaluate the effect of the change on the safety and effectiveness of the product. In such cases, a PAS submission is the way to implement the change. Also, use of CP would add little value to the changes already reported as CBE or in the annual report.

CPs together with ‘established conditions’ may be effective tools for the overall product life cycle management. They can also facilitate the management of post-approval CMC changes in a more predictable and efficient manner.