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What does Process Validation mean in the world of Pharmaceutical Excipients?

January 2017 by Jennifer Goodman

What is Process Validation?

Validation for ExcipientsThe concept of validating pharmaceutical processes or, in FDA’s definition, “the establishment of scientific evidence that a process is capable of consistently delivering quality product across its lifecycle”, was first introduced to the FDA in the 1970s.  The idea behind pharmaceutical
validation was to build quality into pharmaceutical products by ensuring that processes are robust and will routinely meet specification and customer expectation.  When processes are considered validated they are designed to perform reliably and routinely to produce conforming product.  When quality processes are built into the manufacturing process and the final testing performed on the drug product is done only as confirmation, the final product is not “tested into compliance”.    When patients take medicines, they expect that there is little to no variability with how their medicine was made and they rely on the manufacturers to validate critical processes to ensure process reliability and reproducibility.  From batch to batch, or, from the patient’s perspective, from prescription refill to refill, the product should always be produced the same way and have the same efficacy.

Three Types of Validations

There are three generally accepted types of process validations currently being conducted in the pharmaceutical industry.

  1. The first, and most preferred, is called Prospective Validation. Prospective validations will typically consist of three back-to-back production runs utilizing the approved procedures and testing protocols.  These batches are produced prior to the distribution of the product and are held under Quality oversight while the quality control testing is performed and additional process control data is analyzed, summarized and approved.
  2. The second type is called Concurrent Validation where the validation batches are produced and subsequently released for sale after quality control testing is completed, but where the evaluation of the process control data is ongoing and the formal report is approved after the products have been released.
  3. The last type of validation is called Retrospective Validation and it is validation of a process for a product already in distribution based upon accumulated production, testing and control data.

Nowadays, validation is required per the cGMPs (current Good Manufacturing Practices) and is expected for pharmaceutical processes, instruments, utilities, computer systems, packaging, analytical methods, cleaning, etc.  However, the expectations for the excipient manufacturer are not as clearly defined.

What are Excipients and how are they Validated?

cGMP Salt Solution Manufacturing Equipment

cGMP Salt Solution Manufacturing

Excipients are used in pharmaceutical processes in a variety of ways.  Some excipients are used solely for cleaning reactors or chromatography columns.  Some excipients are used to adjust pH and still others are used as flavors, colors or sweeteners.  There are no official regulations for when, how, or if to conduct validation studies on pharmaceutical excipients.  Excipient manufacturers rely on organizations such as the International Pharmaceutical Excipients Council (IPEC) to engage with regulators to develop suitable guidelines to provide direction.  The guidelines in the Excipient GMPs are flexible enough to allow sound judgment and permit innovation yet they inevitably leave room for interpretation.  The IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients states in Section 7.5.2 that a “full validation program that is typically performed in the pharmaceutical industry may not always be carried out by the excipient manufacturer.  However, the excipient manufacturer should demonstrate the consistent operations of each manufacturing process, for example, through process capability studies, development and scale-up reports, etc.”  Utilizing statistical process controls (SPC) can ensure that processes are monitored and in control.

In terms of process validations, a Retrospective Validation is suitable for most excipients and that is generally what is seen especially with stable excipient salts which have been on the market for decades.


About the Author

Jennifer Goodman, Senior Director of Quality and Regulatory Affairs at Avantor, has over seventeen years of experience in the pharmaceutical and medical device industries. Jennifer holds an MS in Pharmaceutical Manufacturing Engineering from Stevens Institute of Technology and a BS in Chemistry and BA in Psychology from Muhlenberg College.