The New FDA Process Validation Guideline

Pharmaceutical Technology
From its onset in 2008, the US Food and Drug Administration’s draft guidance on process validation has fueled international debate. Not only has the regulatory agency suggested significant changes in process-validation strategy, but also has urged a paradigm shift. In its draft guidance, FDA announced the implementation of a continuous improvement and validation process, shifting from its current practice of restrictive adherence to initially established operating procedures (1).
The following article reviews the potential consequences these changes may have on European companies and elaborates on the current similarities and differences between the regulatory environment in the European Union and United States. [Note: A final version of the FDA guidance was due in 2009; however, at press time, it remained in a draft version. Nevertheless, FDA representatives say that the guideline's basic principles will not change in the final version.]
There are four key aspects to the good manufacturing practice (GMP) environment in Europe, as outlined below.
Legal requirements All requirements in the FDA draft guidance can be achieved within the European framework. Some of the regulations in the EU’s GMP guide, Annex 1, have corresponding paragraphs to the FDA draft document. For example, section §25 details the requirements for scientific verification of the number of validation batches:
“Using this defined process (including specified components) a series of batches of the final product may be produced under routine conditions. In theory, 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. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters would constitute a validation of the process. "(2)
Similarly, section §1.4 of the EU Guide to GMP outlines the requirements of a product quality review (PQR). The PQR must document deviation, in-process-controls, finished product results and changes on an annual basis. In other words, there is already a continuous review in place for screening all relevant data streams.
The EU guide also addresses risk management. According to sections §1.5 and §1.6: "Quality risk-management is a systematic process for the assessment, control, communication, and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively." (2) The quality risk-management system should ensure that: 1) the evaluation of the risk to quality is based on scientific knowledge and experience with the process, and ultimately protects patients; and 2) the level of effort, formality, and documentation of the quality risk-management process is commensurate with the level of risk.
These two elements highlight the obligation to improve scientific knowledge and understanding of company processes. Process capability is also portrayed as a significant requirement in the proposed FDA guidance and in the EU GMP guide. In the latter, section § 1.2 states that: (I) "All manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications."(3)
There are many topics in the FDA draft guidance already covered by EU regulations. However, one of the most important topics—variation—is not reflected in EU regulations. Although there are some references to the phenomenon of variation, there is no stated need to concentrate on different kinds of variations. Accordingly, the issue of variation control deserves additional attention. For example, for a product that contains herbal components with active ingredients of varying strengths, the process must be able to adjust to these variations. This presents a formidable challenge.
Compatibility with European regulationsAs outlined above, the key aspects of the FDA draft guidance are compatible with EU regulations; in fact, many are already European requirements. Most procedures recommended in the FDA proposed guidance are in line with current EU guidelines as well, except for one notable difference: European companies are expected to be the drivers of new guidance by using methods that improve quality and manufacturing within the company. The framework for that approach is already in place in Europe. In the US, however, often, the regulatory authority forces the use of new methods by issuing guidance.
Life-cycle approach
The life-cycle approach focuses on the regulatory framework as an overall structure aimed at improving the process throughout the life cycle. Despite this knowledge, companies attempting to implement a life-cycle approach are faced with many challenges. In the past, for example, quality assurance was the overriding principle to avoid changes in manufacturing of drug products. In contrast, today we understand that this is a basic conflict that needs to be continually addressed. Thus, it is critical to change the awareness and mindset of those involved. Currently, pharmaceutical companies are aware of, and follow, strict operating procedures. Although this is important, it may conflict with the need and ability to improve. Further, it might take years to change the mindset of those involved. FDA representatives are well aware of this challenge. When asked about transition periods for the guidelines at the PDA/FDA Joint Regulatory Conference 2009 in Washington, DC, they stated that there was no need for a transition period as they were “only” talking about guidelines and not laws.
Performance qualification
In the past, FDA and EU regulators shared the same standards regarding performance qualification. However, conflict may arise over the timing and content of performance qualification (PQ) in the project design and performance. This is where a real difference between FDA and EU interpretations exists.
FDA: “The PQ is the second element of stage 2, process qualification." (1) EU: "Performance qualification (PQ) should follow successful completion of installation qualification and operational qualification." (4) It was state of the art to perform PQ test runs with placebos or with water. After this technical test run, real products, APIs, etc. were used for the process validation runs. The FDA draft guidance characterizes this differently, calling this new PQ test “the process validation test.”
At first glance, it seems that the new process-validation procedure is an enhanced equipment qualification. In fact, FDA determines process validation as "the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products" (1). This implies that the entire process is continuously undergoing validation and does not end. What should be a typical answer to an FDA inspector asking for the process-validation report? "There is no process validation report at all! We still produce the product and for that reason we are still validating the process." Is this really what the FDA wants to hear? For an EU inspector, it will be insufficient. Let's wait for the final version of the process validation guidance. The results may be surprising.
  1. FDA, Draft Guidance for Industry—Process Validation: General Principles and Practices (Rockville, MD, Nov. 2008).
  2. EU, Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products (Brussels, Belgium, Oct. 2005).
  3. EU, Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Chapter 1 (Brussels, Belgium, Dec. 2005).
  4. EU, Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 15, Manufacture of Sterile Medicinal Products (Brussels, Belgium, July 2001).

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