FDA's 2011 Process Validation: General Principles and Practices guidance created a systemic shift in industry's approaches to validation programs. The authors describe the three-stage approach
to validation that is outlined in the new guidance and discuss questions surrounding implementation.
In January 2011, FDA published its long-awaited guidance for industry on Process Validation: General Principles and Practices (1). For many in the pharmaceutical industry, the guidance created a systemic shift in the expectations of their validation programs.
Although the new guidance aligns process-validation activities with the product life-cycle concept and with existing harmonized
guidelines such as the Internatioanl Confernce on Harmonization's Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System, it may have created as many questions for the industry as it has answered. In this article, the authors briefly describe
the three-stage approach to validation that is outlined in the new guidance as well as implications for manufacturers regarding
their current approaches to process validation. Specific emphasis is placed on questions surrounding industry implementation.
Design for assurance
The regulatory basis for process validation is contained in a number of places. Process validation is legally enforceable
per the Federal Food, Drug, and Cosmetics Act. The requirements are called out in 21 CFR Parts 210 and 211 of the CGMP regulations, more specifically in Part 211.100 (a). This section is what the FDA describes
as the regulatory "foundation for process validation" (1). Here, manufacturers are required to have production and process-controls
procedures in place that are "designed to assure" drug products have a certain level of quality and that their products are
manufactured safely, effectively, and purely.
How is that assurance to be provided, however? How can industry design to assure these qualities? One way is through direct
observation; another is through prediction. Direct observation may require the destruction of the products, meaning that industry
generally must use predictive methods to determine, with a certain level of confidence, that its processes and controls are
designed to assure quality. Validation is the predictive method for providing this assurance.
A brief history of validation
In the 1970s, there was a series of contamination issues in large-volume parenteral bottles that, with a handful of other
significant adverse events, led regulatory authorities and manufacturers to focus more on process understanding and quality
assurance. The idea that finished product testing was not enough to assure product quality began to grow. Industry needed
a better system to determine whether a product was "good" (2).
In the mid-1970s, FDA's Ted Byers and Bud Loftus began to promote the idea that a focus on process design and an evaluation
of support processes and functions would assist in assuring that processes were under control (rather than just " testing
quality into the product"). At a 1974 conference, Byers called this new predictive approach "Design for Quality" (3).
In 1987, at the request of industry, FDA published its original guideline on General Principles of Validation (4). The agency established a more formal approach to process validation and created the assertion that multiple batches
need to be run. This concept eventually translated into the three-batch approach, where the successful running of three consecutive
product batches represents a validated process. Herein are fundamental questions that still exist 20 years after the publication
of the guidance:
- If companies were following the guidance, why would companies continue to see processes fail during commercial manufacture?
- Were companies really providing high degrees of assurance their processes worked reliably?
- Did companies understand how or why running three batches proved that their processes were adequately controlled and capable
of consistently providing required results?
When these questions are asked of people in the industry, the answers, in the authors' experience, are invariably, "Well,
stuff happens. Things happen. Things we didn't anticipate." "Stuff happens" tends to refer to "process variation," a key term
and a key reason why the 1987 guidance was updated.