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Process Validation: Maintaining Quality Consistency

The basic principle of pharmaceutical quality assurance is that a drug should be safe and effective for its intended use – and process validation plays a pivotal role in ensuring a drug’s quality. The basic principle of pharmaceutical quality assurance is that a drug should be safe and effective for its intended use – and process validation plays a pivotal role in ensuring a drug’s quality.

Why? Because literally everything rests upon it and builds from it. Process validation establishes evidence that manufacturing processes consistently fall within acceptable limits. It’s the foundation upon which confidence in drug manufacturing rests.

We’ve discussed at length the importance of developing comprehensive process knowledge. In a post on the Importance of Understanding Critical Reaction Parameters, we noted that therapeutics in general – both biologics and synthetic drugs – have become more complex. “Some APIs require double-digit production steps, meaning understanding and controlling reaction parameters is essential to avoid failures or out-of-spec outcomes.”

This body of process knowledge which drug and API manufacturers must develop is the mainstay of process validation. Critical to the success of process validation is the use of analytical methods which provide reliable, and consistently repeatable, results.

Defining Process Validation
First proposed by FDA officials in the 1970’s as a one-time event to improve pharmaceutical quality, process validation evolved to encompass more proactive measures (“lifecycle process validation”).

Jennifer Walsh captured this sentiment in the title of an article at Pharmaceutical Engineering in 2019: “The Evolution of Process Validation: From Box-Checking to Lifecycle Approach to Biologics Continuous Manufacturing.”

The title isn’t an overstatement – and most quality assurance professionals would (perhaps begrudgingly) admit to the once-simplistic ‘box-checking’ aspect of process validation. Back in 1987, the FDA defined it as “documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.

Our understanding of process validation differs today, since it isn’t considered a ‘once-and-done ‘event but rather an ongoing practice. Here’s a definition of process validation from

“Process validation is defined 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.”

What Does Regulatory Guidance Say?
Process validation is a legal requirement in the drug industry (among others). Governing regulations include current good manufacturing practices (cGMP) for finished pharmaceuticals, as described in 21 CFR parts 210 and 211.

GMPs require drugmakers to determine that manufacturing processes can consistently meet finished product quality requirements, including those characteristics impacting the quality, purity and potency of a compound. This means your CMO must understand:

  • when variation occurs in a process
  • what the source of the variation is
  • how the variation impacts both processes and products
  • how variation can be controlled.

As the FDA makes clear in their Guideline on Process Validation: General Principles and Practices, this typically involves teams with “expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance).”

What are the Three Key Process Validation Stages?
Process validation is broken down into stages, as follows:

Stage 1: Process Design
In this first stage, the manufacturing process is designed to ensure a consistent ability to meet target quality attributes. The key to sound process design is thorough documentation, which becomes essential in subsequent stages. Process design often includes Design of Experiment (DoE) studies, risk analysis tools and the results of verification runs at lab or pilot scale. This collective information can help predict performance of commercial scale processes.

Stage 2: Process Qualification
Process qualification refers to the qualification of both facility, equipment & utilities and the manufacturing processes themselves. Once the facilities and equipment have been individually qualified, the process performance qualification (PPQ) can occur. Process qualification assesses the data gathered from all relevant studies, including experiments, lab-, pilot- and commercial batches. Successful qualification demonstrates that commercial manufacturing processes will perform as expected.

Stage 3: Continued Process Verification
Stage 3 relates to the ongoing activities that occur, reflecting the ‘lifecycle process validation’ approach in use today rather than the one-time approach common years ago. The objective of continued process verification is to ensure the process remains validated, that it is still in a “state of control.” To confirm this, drug and API manufacturers need systems in place to detect nonconformities in processes. One outcome of this stage is often process improvement or optimization strategies, though these are often subject to additional regulatory approval or further process validation.

Are you interested in learning more about process validation? Check out the U.S. FDA’s Guideline on Process Validation: General Principles and Practices or contact Neuland Labs today.

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