FDA on Final Process Validation Guidance: Focus on Concepts, Not Terminology

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FDA on Final Process Validation Guidance: Focus on Concepts, Not Terminology

by Rochelle Runas, ISPE Technical Writer

“Focus on the concepts and not the terminology” was a recurring directive from the FDA in a presentation on the final Guidance for Industry – Process Validation: General Principles and Practices at the ISPE 2011 Tampa Conference.

ISPE 2011 Tampa Conference attendees Thursday, 24 February, were the first to hear direct from the FDA the agency’s thinking behind the final guidance. The guidance, published 25 January 2011, replaces the 1987 guidance. Industry has been anticipating the final guidance since a draft of it was released in 2008 to mixed reviews and interpretations.

“Don’t get hung up on terminology, get hung up on the concepts,” said Grace McNally, Senior Policy Advisor, FDA CDER Office of Compliance, Division of Manufacturing and Product Quality. McNally presented “Process Validation: Lifecycle Approach” as part of the ISPE educational session, “Pharmaceutical Inspections and Compliance – Current FDA Enforcement Trends.”

The term “critical” was not defined in the guidance, said McNally. To further explain FDA’s stance on this, McNally read straight from the guidance:

The terms attribute(s) (e.g., quality, product, component) and parameters(s) (e.g., process, operating, and equipment) are not categorized with respect to criticality in this guidance. With a lifecycle approach to process validation that employs risk based decision making throughout that lifecycle, the perception of criticality as a continuum rather than a binary state is more useful. All attributes and parameters should be evaluated in terms of their roles in the process and impact on the product or in-process material, and reevaluated as new information becomes available. The degree of control over those attributes or parameters should be commensurate with their risk to the process and process output. In other words, a higher degree of control is appropriate for attributes or parameters that pose a higher risk. The Agency recognizes that terminology usage can vary and expects that each manufacturer will communicate the meaning and intent of their terminology and categorization to the agency.

The final guidance also does not include the terms: Prospective Validation, Retrospective Validation, Concurrent Validation, IQ or OQ, Tech Transfer, Critical Quality Attribute, Critical Process Parameter, and Worst Case.

The final guidance aligns process validation activities with a product lifecycle concept and with existing FDA guidance, including the FDA/International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. Although the guidance does not repeat the concepts and principles explained in those guidances, FDA encourages the use of modern pharmaceutical development concepts, quality risk management, and quality systems at all stages of the manufacturing process lifecycle.

The goals of the final guidance are: to further the goals of the cGMPs for the 21st Century Initiative, such as advancing science and technological innovation in pharmaceutical manufacturing; to put more emphasis on process design elements and maintaining process control during commercialization; communicate that process validation (PV) is an ongoing program and aligns process validation activities with product lifecycle; emphasize the role of objective measures and statistical tools and analyses in making science- and risk-based decision making; and emphasize knowledge, detection, and control of variability.

Training of field investigators on the final guidance is underway, McNally said.

McNally also addressed industry concerns regarding a perceived expectation that FDA is no longer doing three lot applications.

“What strikes me as strange is that the criteria is the number of batches,” said McNally. “It’s not about the number of batches, it’s about what are you looking for in those batches and that is your performance criteria. The onus is on you to scientifically come up with what those criteria are and how to meet those criteria. And that’s going to be based on your product and process understanding. There’s nothing wrong with three batches if you find that is the number of batches relevant to your product and process understanding. The number of lots is not appropriate for the FDA to dictate because it’s going to be different for each company and product. What we were trying to avoid was the situation of a company saying “there were three lots made because it was according to routine procedure, but there were no comparisons between lots or any real analysis of data.”

McNally also reviewed basic cGMP requirements [211.100(a), 211.110(a), 211.110(b), 211.160(b), 211.165(c), 211.165(d), 211.180(e), 211.42, 211.63, 211.68, and 211.84] that form the basis for the process validation guide. “If you’re not complying with these basic requisites, then you might as well forget about process validation.” Key GMP concepts that have been in existence for some time and McNally recommended focusing on are: process control, performance, and process and control variability.

“Design well, demonstrate it works, then monitor the process.”

For purposes of the guidance, process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.

“The key focus of the guide is on variation, understanding, detecting, responding, and controlling it from input through output,” McNally said.

Process validation involves a series of activities taking place over the lifecycle of the product and process. The guidance, focused toward the commercial process, describes the process validation activities in three stages:

  • Stage 1 – Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities.
  • Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
  • Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

The guidance describes activities typical in each stage, but in practice, some activities in different stages might overlap. McNally emphasized that although the guidance is focused on manufacturing and not product development, if approached rationally, validation must begin in the product development phase.

Regarding existing products and processes, implementation of the recommendations in the guidance for legacy products and processes would likely begin with activities described in Stage 3, McNally said.

In Stage 2, McNally said the agency did not see much of a need to clarify Facilities, Equipment, and Utilities as there is enough literature out there. (See ISPE Guidance Documents , including Baseline® as well as GAMP® Guidance.) The guidance does not specifically discuss the validation of automated process control systems (i.e., computer hardware and software interfaces), which are commonly integrated into modern drug manufacturing equipment. These topics are covered in detail in GAMP. (See the recently published GAMP Good Practice Guide: A Risk-Based Approach to GxP Process Control Systems (Second Edition.)

The principles in the guide apply to all drug types, application drugs and monograph drugs. Recommendations can apply to all types of drug manufacturing and adjusted to the technical nature of the process, e.g., batch, continuous, and PAT.

In addition, the Process Validation Workgroup did not seek to sync up all aspects of the final guidance with all other agency guidance or other guidance from other regulators that speaks to process validation. The FDA also acknowledges that there are other earlier FDA guidances or from other regulators on this subject that does not exactly match with the lifecycle model. McNally advised that readers should consider the final process validation guidance and other guidance and use best scientific rationale to support process validation choices.

Regarding submissions, different centers or offices within CDER may have different policies regarding validation information to be submitted. “The application program may not specifically mention ‘process control,’ but you have to satisfy GMPs. You have to satisfy both.”

Few audience members had questions during the QA portion of the session. When asked by an audience member whether the guidance applied to aseptic processing or sterilization, McNally suggested that the more prescriptive guide for a particular area should be followed. “This is not the only guidance out there on process validation,” she said.

McNally asked the audience if they thought there were enough good guidances out there on product and process design. An audience member responded that it would be nice to see specific examples for Stage 1 to get an idea of where exactly to start.

In summary, McNally said you should ask yourself the following questions when considering process validation:

  • Do I have confidence in my manufacturing process? Or, more specifically, what scientific evidence assures me that my process is capable of consistently delivering quality product?
  • How do I demonstrate that my process works as intended?
  • How do I know my process remains in control?

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