FDA Guidelines for Process Validation: Then and Now

September 17, 2015 by

Difference between the 1987 and 2011 FDA Guidelines for Process Validation – an overview

It’s been over 20 years since the guidelines for process validation were updated. The FDA’s 1987 guidance document, Guideline on General Principles of Process Validation was replaced January of 2011 when the FDA published the updated  Guidance for Industry-Process Validation: General Principles and Practices. The new guidelines introduces new concepts and principles and denotes the evolution in process validation requirements. Like other guidelines, they are not law, but adherence to them provides a good framework for building a compliance program.

computer system validation

What Changed?

The 1987 definition of process validation defined process validation as “establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics”.

The new guidelines defines 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”.

From comparison of the definitions we can clearly see that the new guidelines are asking for a lifecycle approach for process validation as it requires collection and evaluation of data from the process design stage throughout production.  In the past, process validation activities commenced at product commercialization, and involved collection of massive amount of data from typically three process validation batches. The number of batches to be evaluated was not stated in the 1987 guidelines, but most companies used the number three to establish reproducibility.

The new guidance does not have a requirements for the number of batches to be use, but does recommend the use of statistical techniques to provide impartial evidence of process capability. The acceptance criteria for results must be pre-determined and defined. As a result, statistics and statisticians are playing an increasingly important role in a company’s process validation program.

Another key difference between the old and new guidelines is the fact that the qualification “lots should be manufactured under normal conditions by personnel expected to routinely perform each step of each unit operation in the process.” The old paradigm required the verification that execution of the process within process parameter limits will not lead to process or product failure. Addressing processing and product variability is now shifted to the Design stage of validation activities.


What These Changes Mean

When we examine the main differences between the traditional way we did Process Validation and the new approach we can see that FDA is asking for more scientific arguments to support our activities and the use of a Life Cycle approach. The new approach provides opportunities for a more holistic approach to process validation and across the product lifecycle. It also provides opportunities for automation of the collection, processing, and reporting of the required information.

The lifecycle approach to process validation is described in three stages: Process Design and development (Stage 1), process verification by the manufacturing of a number of commercial scale batches (Stage 2), and maintenance of the process in a state of control during routine commercial production through continuous monitoring (Stage 3).

A systematic approach to product and process development ensures the performance of validation activities in a documented, methodical, organized, orderly fashion. An efficient process validation program within an organization can rely in automation to make the right data, available to the right people, for the right purpose.

The FDA has adopted Quality by Design (or QbD) principles in drugs discovery, product development, and commercial manufacturing. QbD can be looked at as “a risk based approach to manufacturing practices to ensure that your development and processes yield a quality product based on solid scientific and engineering principles”.

The new process validation guidelines and QbD promote better, more in depth understanding of the process and the product, allowing us to achieve higher confidence levels when it comes to tweaking our processes due to changes or desirable outcome. This is similar to the benefits obtained from Process Analytical Technologies activities, which were also designed to provide a better understanding of your processes. The previous process validation approach did not lend itself to provide the level of understanding of the manufacturing process.

Validation Packages

The Manufacturing Process

QbD is more applicable at the first stage (Process Design), but information gathered during this stage is used in the other two stages mentioned above. Information from Stage 1 is typically passed on to Stages 2 via the Technical Transfer Report. The information in this report contains key elements of the Stage 2 protocol.

The focus of the Process Qualification Stage is to evaluate if the process is capable of reproducible commercial manufacturing. The process performance qualification protocol verifies process performance within the established parameters. Collected and processed test results provide the evidence and confidence that the process is capable of yielding reproducible quality product. The protocol also covers the manufacturing facility, qualification of equipment and utilities, and sampling plans. Qualification activities for manufacturing equipment involved in the production process have not changed from the old guidelines, the required phases of installation, operation, and performance qualification still apply.

The Process Verification Stage is about monitoring the process on an ongoing basis to ensure it remains in a state of control. The Critical Quality Attributes (CQAs) are verified and controlled through testing and statistical analysis. The data that is collected while monitoring as well as throughout the lifecycle of the product allows for a more informed optimization of the process by altering any aspect of that process, operating conditions, process controls, material characteristics, etc. The impact evaluation process of changes is facilitated as such a change may have been considered during modeling activities of Critical Process Parameters (CPPs) and CQAs interaction.


What Else is New?

Other notable differences are those related to the concepts of retrospective validation and revalidation. Retrospective validation is typically performed on established products whose manufacturing processes are considered stable and when on the basis of resource limitations, prospective validation programs cannot be justified. The new guidelines clearly state that “in most cases, the PPQ study needs to be completed successfully and a high degree of assurance in the process achieved before commercial distribution of a product”.

The intent of re-validation is to provide the evidence that any intentional or unintentional changes to the process or its environment, do not adversely affect process characteristics and product quality. The new guidelines states that “manufacturers of legacy products can take advantage of the knowledge gained from the original process development and qualification work as well as manufacturing experience to continually improve their processes. Implementation of the recommendations in this guidance for legacy products and processes would likely begin with the activities described in Stage 3”.

The new guidelines recommend that the quality unit meet periodically with production staff to evaluate data, discuss possible trends or undesirable process variation, and coordinate any correction or follow-up actions by production. With the old guidelines Process Validation activities and their outcome were typically performed and assessed exclusively by process validation personnel.

The 1987 guidance document was published when process validation concepts and principles were still being developed. The 2011 guidelines are based on experiences gathered by the agency and industry alike since 1987, as well as the FDAs initiative cGMPs for the 2st century, a risk based approach. Technological advancement in support systems have made it easier to automate the collection, processing and reporting of information to comply with the new guidance. Purpose built tools that interface with key systems in the organization to allow for the processing of data are now available and allow process validation professionals to move away from inefficient traditional document management exercise to focus more on the science.


Want to know more about Process Validation and Quality by Design principles? Check out our tips on how to apply QbD principles to Process Validation.


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