Sec. 490.100 Process Validation Requirements for Drug Products Subject to Pre-Market Approval (CPG 7132c.08)

BACKGROUND:

Validation of manufacturing processes is a requirement of the current good manufacturing practice (CGMP) regulations for finished pharmaceuticals (21 CFR Part 211). Validation is based on the documented successful evaluation of multiple full scale batches (usually at least three (3)) to provide assurance that the processes will reliably meet predetermined specifications. Refer to the Guideline of General Principles of Process Validation (May 1987) (distributed by the Center for Drug Evaluation and Research (CDER)) for further details.

The pre-approval inspection compliance program (7346.832) also emphasizes the importance of process validation to ensure the safety, efficacy, and quality of drug products. Although the program does not require completion of multiple batch process validation before an application may be approved, completion of such process validation is a CGMP requirement that must be met before any shipments of the products are made.

In addition, for products intended to be sterile, applicants are required to submit data to the applications that demonstrate the effectiveness of the intended sterilization or aseptic processing procedures. The center evaluates the data as part of the application approval process. Such data may be derived prior to undertaking full-scale production. For example, the data may be obtained by conducting media fills to determine the effectiveness of the aseptic processing procedures or by running simulated product along with biological indicators through autoclave cycles to determine the effectiveness of steam sterilization procedures.

Applications for sterile and non-sterile drug products may be approved by a center prior to the firm's completion of full-scale process validation.

The purpose of the pre-approval inspection is to audit the completeness and accuracy of the submitted data. The inspection also evaluates the effectiveness of important CGMP facilities and systems that bear on sterility assurance including, but not limited to: High Efficiency Particulate Air (HEPA), Heating Ventilation Air Conditioning (HVAC), facility conditions, and water systems.

POLICY:

1. During the pre-approval inspection, any process validation data that is available should be evaluated and any process validation deficiencies reported to the firm. Based on the lack of completed process validation data, the district should monitor the firm's post-approval validation efforts, and initiate regulatory action where product has been shipped and there are deficiencies with validation that would support such action. Seizure should be considered when there are supportable deficiencies with validation or the evidence demonstrates the product does not comply with specifications. Recommendations for enforcement action due to non-compliance with the CGMP regulations should cite 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B) based on violation of 21 CFR 211.100.

The district should recommend withholding approval of an application if any completed validation efforts include data of questionable validity or demonstrate that the process is not valid and the firm has not committed to making appropriate changes.

2. Rarely, the completion of multiple batch process validation prior to product shipment may be impractical due to public health considerations. For example, the public health benefits of expediting availability of clinically important drugs with a very limited market (e.g., certain orphan drug products) may outweigh the need to await completion of full multiple batch process validation. Under such circumstances, the firm is expected to:

A. Document the reason that complete process validation is impractical prior to shipment of the product.

B. Establish and commit to following an adequate protocol to complete the validation of the manufacturing process. In this regard, successful validation of each batch of the multiple batch validation study must be completed prior to shipment of the batch.

C. Establish and follow more extensive testing and process controls to ensure batch uniformity and conformance with predetermined specifications.

The district should consult with the center before initiating regulatory action under these circumstances.

3. Process validation requirements for bulk pharmaceutical chemicals (BPC) differ somewhat from those required for dosage form products. Refer to the BPC Inspection Guide (CDER revised, September 1991) for details. Based on recent emphasis by FDA, the industry has begun to formally validate the manufacturing processes for BPCs. The district should recommend withholding approval of an application based on the lack of process validation for the BPC where:

A. The firm has not established or is not following an adequate plan to validate all BPCs; or,

B. The process is not valid, as demonstrated by repeated batch failures due to manufacturing process variability not attributable to equipment malfunction or operator error.

NOTE: This compliance policy guide (CPG) also applies to pre-market approval applications submitted to the Center for Veterinary Medicine (NADAs or ANADAs). The CPG reference may be found at 7125.38 (See Sec. 638.100).

Issued: 8/30/93