"Bracketing" during Process Validation

"Bracketing" during process validation has become common practice. In the USA, bracketing has been practiced for some time, and the topic was included in the Annex 15 revision in 2015 (Chapter 5.4.).

According to Annex 15, it is a science- and risk-based validation approach in which only batches that represent extremes of certain predetermined and justified design factors, e.g. strength, batch and/or pack size, are tested during process validation. This concept assumes that the validation of all intermediate stages is represented by the validation of the extreme values.

Bracketing concept must be well justified

This is shown by a recent Warning Letter issued by the US FDA. With reference to 21 CFR 211.100 ("written procedures for production and process control"), the FDA has criticized the lack of process validation in contract manufacturing. The validation protocol ("Process Qualification Protocol - Mixing/Formulation") of the contract manufacturer categorized all products into 3 groups according to therapeutic indication and route of administration. For each of the 3 groups, process validation was performed with one product. Here, the FDA criticizes that there is no sufficient scientific rationale for the process validation to be representative of all other products.

In response, the contract manufacturer offered to "review" the manufactured products to determine which products require validation. Products that have been newly introduced will be validated. Products that have already been launched will be validated when orders for them are received.
The FDA was not satisfied with these measures. It requires a risk assessment of all products on the market that are not validated. It also requires "interim" controls until process validation is complete. So far, so good. Furthermore, the FDA requires:

  • a commitment that a third party will undertake an independent review of all validation activities and also "oversight" of them.
  • a commitment and a proposal that in-depth release testing will take place until the process validation is complete.
  • a detailed overview of the company's internal validation program, including associated procedures. In particular, the "PPQ" and "Continued Process Verification" should be described.
  • a timeline for the PPQ, also for products that are not subject to Continued Process Verification.
  • a program for equipment and facility qualification.
  • an assessment that a data-based and scientifically justified program is available for each medicinal product that identifies and controls process variability.

In the Warning Letter, it is then pointed out that similar violations have already been detected in past FDA inspections and that a GMP consultant should therefore be hired. Interestingly, this GMP consultant should also carry out a six-system audit of all of the company's GMP activities and the CAPA system. Reference is then made to an older FDA Quality System Approach guideline in which the system is described.  

Conclusion: Brackting approaches in process validation should be justified by a sufficiently scientific rationale.

As always, you can find the complete Warning Letter on the FDA website.

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