Industry reaction and challenges
The industry reaction to the 2011 process validation guidance, in general, has been favorable. The document is nonprescriptive.
It is relatively flexible. It leaves much to the companies to decide how they wish to meet its expectations. But, as the authors
discovered through a series of industry workshops and seminars, there still is a need for further explanation and clarification
regarding the guidance as well as a real need for detailed implementation suggestions. Although there are many questions to
be answered, this paper is limited to three of the most frequently asked questions about implementing the new guidance.
The classic and most frequently asked question about the new guidance is, How many batches do I have to run to validate my processes under the new guidance? The answer does not delight many people: "It depends."
The number of batches needed to validate a process depends on how much data are required to provide a company with an appropriate
level of statistical confidence and scientific justification to begin commercial production. There is nothing wrong with a
company choosing to run three batches for validation, but that company has to be prepared to explain why the data obtained
from three batches is sufficient to determine that the process is ready to move into commercial manufacturing. Likewise, if
a company chooses to run fewer than three batches, it has to be able justify the amount of data created by those batches.
In short, there is no longer a uniform number of validation batches that can be applied globally to the industry. The approach
is now process- and product-specific, depending on a company's ability to test critical parameters, conditions, and attributes.
Overall, the batches are a means to an end, and in this case, that end is data (9).
The discussion of the number of batches required invariably leads to a second frequently asked question, How do we determine the amount of data we need in our validations? The question revolves around the amount of data needed in Stage 2–Process Qualification. FDA has been quite clear that statistical
justification for sampling is required. Specifically, the guidance states that:
- The number of samples should be adequate to provide sufficient statistical confidence of quality both within a batch and between
- The confidence level selected can be based on risk analysis as it relates to the particular attribute under examination.
- Sampling during this stage should be more extensive than is typical during routine production (1).
A key to success here will be appropriate use of risk analysis to assist in selection of appropriate confidence levels for
a product's critical quality attributes (CQAs). All CQAs are not alike, the higher the risk for a given CQA, the higher the
confidence level required during validation. The amount of data required might then increase for those CQAs that require higher
confidence levels. This decision will depend on the test methods used and the type of data collected. Test methods that create
dichotomous data (pass/fail, go/no go) will require many more samples than those that produce continuous (i.e., variable)
data. This difference needs to be taken into consideration early in the validation life-cycle process becaues it also impacts
how data will be trended in Stage 3.
Another question brought up frequently is, Do the requirements in the guidance conflict with existing global regulatory requirements? This question has two components to it.
First, there is a specific concern that validation terms within the document do not align with EMA terms, specifically Annex
15 of the European Union Guidelines to Good Manufacturing Practice, or those in ICH Q7 (10, 11). Examples of misalignment would be traditional terms such as installation qualification and operational qualification. These terms are not included in the new FDA process validation guidance, but the concept described in Stage 2 of the guidance
does state that, "qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for
their intended use and perform properly." This language is similar in nature to Sections 9–13 of the EU GMP Annex and Section
12.3 of ICH Q7 (1, 10, 11).
Second, there is a concern that certain concepts within the EU GMPs conflict with the new FDA guidance, specifically regarding
the three-batch validation approach. Section 25 of the EU GMP Annex 15 states, "It is generally considered acceptable that
three consecutive batches/runs within the finally agreed parameters, would constitute a validation of the process" (10). On
the surface, this language would seem to conflict with the FDA's new focus on data rather than the number of batches. However,
Section 25 of the EU GMP Annex 15 also states that, "...the number of process runs carried out and observations made should
be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation."
So, while the three-batch approach to validation is embedded in Annex 15, Section 25 also provides for a more flexible approach
based upon data (10).
Related to the question above are general questions regarding terminology. The most notable new term in the FDA guidance is
process performance qualification (PPQ), described earlier in this paper. The guidance defines PPQ as "the second element of Stage 2, process qualification.
The PPQ combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial
manufacturing process, control procedures, and components to produce commercial batches. A successful PPQ will confirm the
process design and demonstrate that the commercial manufacturing process performs as expected" (1). PPQ is what most companies
call their process validation (PV) and should not be confused with individual equipment process qualifications. Here again,
FDA has stated that the concepts are important, not the terms (9). Companies are free to call these activities what they wish
as long as the two parts of Stage 2 as outlined in the guidance are met.