Validation study: Why Three batch for validation study?

In this article we will try to understand the fundamental concept of three batches for Validation study; or more correctly we say Process performance qualification (PPQ). This is very important to know “what we are doing and why we are doing” to come on fruitful conclusion. So, we will continue the topic with the small background on regulatory requirements.

Fig. 01: Validation-Three batch concept

In the world of pharmaceutical manufacturing, Validation of manufacturing processes is a requirement of the Current Good Manufacturing Practice (CGMP) regulations (21 CFR 211.100 and 211.110) and is considered an enforceable element of current good manufacturing practice for active pharmaceutical ingredients (APIs) under the broader statutory CGMP provisions of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.

A validated manufacturing process has a high level of scientific assurance that it will reliably produce acceptable product. The proof of validation is obtained through rational experimental design and the evaluation of data, preferably beginning from the process development phase and continuing through the commercial production phase.

Before the commercial distribution begins, a manufacturer is expected to have accumulated enough data and knowledge about the commercial production process to support post-approval product distribution.

Normally, this is achieved after satisfactory product and process development, scale-up studies, equipment and system qualification, and the successful completion of the initial conformance batches. Conformance batches (sometimes referred to as "validation" batches and demonstration batches) are prepared to demonstrate that, under normal conditions and defined ranges of operating parameters, the commercial scale process appears to make acceptable product.

Generally it is considered; three batches are required for validation study

If we get the desired quality in the first batch, it is accidental, second batch quality is regulator and quality in the third batch is validation.

For statistically evaluation and to prove reproducibility, as two data points would not show fluctuation (if any) it will always give a straight line and no conclusive remark.

No regulatory agency defines minimum or maximum no. of batch for validation study.

If three batch meets quality requirement as per established specification or acceptance criteria;

Fig. 02: Validation-Three batch concept

Some Fact with resect to regulatory guidance

Neither the cGMP/ICH Q7 rules, nor an FDA policy requires a minimum number of runs for proving the validity of a process, in validation study. The FDA considers a reduction to 3 runs as too simple for being able to prove validity. (News Feed)

No. Neither the CGMP regulations nor FDA policy specifies a minimum number of batches to validate a manufacturing process. The current FDA guidance on APIs (see guidance for industry ICH Q7 for APIs) also does not specify a specific number of batches for process validation. The manufacturer is expected to have a sound rationale for its choices in this regard. (FDA Reference)

However, the "rule of three" batches or runs are no longer appropriate for process validation activities. FDA’s guidance for industry Process Validation: General Principles and Practices (2011) recommends that a validation protocol should include the sampling plan, including "sampling points, number of samples, and the frequency of sampling for each unit operation and attribute. (Reference)

Even those with a limited knowledge of statistics will recognize that a run of three is not statistically significant. And those who have a mastery of statistical techniques already know that a sample of three is not significant.

If a manufacturer were to use the success-run theorem to determine the number of process validation runs, using 95% confidence and 90% reliability, it would require 30 runs. However, 30 runs is neither practical nor cost effective. Additionally, some products may be produced only occasionally.

I Hope this article helped you to get an fundamental overview on the Fundamental concept of Three batches for validation study. This curious topic have many different different opinion for execution. i this series we tried to reveal the basic concept. This is not the end we will keep in touch with the consideration of topic PPQ Study and will get back with new stuff….

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