FDA’s New Process Validation Guidance: Its as easy as 1, 2, 3

The US FDA’s Guidance on general principles of Process validation, first published in 1987 had many shortcomings. These were addressed in a subsequent publication, Pharmaceutical cGMPs for the 21st Century- A risk based Approach. While the new guidance states that FDA’s current thinking on process validation is consistent with the principles first introduced in 1987, the new document redefines process validation, John Hyde, Chairman and founder, Dr. Peter Walter, Chief Technology officer, and Karan Manocha, Regional Manager, Asia Pacific, Hyde Engineering + Consulting present some highlights of this new guidance.

In 1987, FDA published guidance on general principles of Process Validation, based upon the request of several firms for clarification of FDA expectations. The guidance cites regulatory requirements related to process validation from the US code of federal regulations and it defines Process Validation as follows:
Process Validation is 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. In time since the guidance was published in 1987, industry and regulators have generally interpreted this definition as:

Establishing highly defined and controlled procedures for manufacture of the product. Verifying the efficacy of the process at commercial scale through the production of a certain number of successful consecutive demonstration or conformance lots, typically three. Assuring the consistency of production by putting controls in place, often SOP based, that confirms that the production of subsequent lots is done identically to the demonstration lots. Using time based criteria, periodically “re-validate” the process to show consistency of production operations and to confirm that the process has not “drifted” from the demonstration lots initially tested.

The main problem with this approach to process validation is that it relies heavily on the ability of the manufacturer to consistently and identically duplicate the process that was used for the production of the demonstration lots without necessarily defining, understanding or controlling critical process parameters and this approach does not account for inherent variability of process inputs. Time based re-validation is another significant problem with this approach as if failures result during re-validation, an entire timeframe of production may be called into question. With these shortcomings in mind and with a view toward more progressive approaches to manufacturing as discussed in FDA’s publication titled Pharmaceutical cGMPs for the 21st Century – A risk based approach and process development, Risk management and Quality Systems tools outlined in ICH Q8, Q9 and Q10, a new process validation guidance draft has been developed and issued for comment.

Highlights of the new FDA Process Validation Guidance
While the new guidance states the FDA’s current thinking on process validation is consistent with the principles first introduced in 1987, the new document redefines process validation as follows:

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

This new definition characterizes process validation as a lifecycle rather than a discrete event, as implied in the definition in the 1987 guidance. The new guidance goes on to say that “Process Validation involves a series of activities taking place over the lifecycle of the product and process” and the new guidance describes process validation activities in three stages including process design, process qualification and continued process verification. Or stated another way, process validation may be defined as:
Process Validation = Lab Studies + Development History + Commercial Scale Manufacturing @ Target Values + Ongoing Monitoring.

The following is a brief discussion of each stage and typically the activities of which they are compromised.

Stage-1: Process design-
As stated in the guidance, the commercial process is defined during this stage based on scientific knowledge gained through development and scale-up. Process knowledge is established and the process is defined through lab laboratory and pilot scale studies. Sources of variability are identified and understood, and their impact on product quality is defined. The degree of management of the sources of variability is commensurate with the risks to product and patient safety that the variability poses. Potential critical process parameters are identified and and evaluated through multivariate analyses and effects of scale are assessed. Process controls are established to manage critical process parameters and variability to process inputs. Design of Experiment (DOE) methodologies are used to perform mechanistic modeling to establish process design and operating spaces. As a part of the establishment to design and operating spaces, “worst case” conditions and parameters are evaluated. The primary objective of the stage 1 work is to define the process in enough detail so that the control of critical parameters and sources of variability is effective at commercial scale.

Stage-2: Process Qualification-
The purpose of the work in this stage is to confirm that the process design is capable of commercial manufacturing. Prerequisites to these activities include completion of activities in stage 1, qualification of the facility and critical utilities, qualification of process systems and equipment, validation of sampling and analytical methods, and performance of manufacturing operations by trained staff using approved manufacturing instructions and records. The process qualification (PQ) work is documented in a protocol which defines manufacturing condition, operating parameters, processing limits and raw material inputs; the data to be collected and how it will be evaluated; the tests to be performed for each significant process step and acceptance criteria for those tests; a sampling plans including sampling points, number of samples, and frequency of sampling based upon statistical rationale; and criteria to provide rationale to conclude that the process produces a constant product including statistical methods to be used in the evaluation of data and a pre-addressed plan for addressing deviations and non-conformances. The work is documented in a report summarizing the testing and results and their conformance with expectations that confirm the consistence of manufacturing operations. Additional in-process material and product testing beyond that for routine manufacturing operations is expected.

Stage-3: Continued Process Verification –
The object of this stage is to continuously verify that the process is in a state of control and is performing consistently and in accordance with the process that was tested during the process qualification stage. Detection of deviations or excursions from the operation of the qualified process is essential to effectively perform continued process verification. This is done by collecting and analyzing process information in real time, especially critical process parameter data, to assess process performance and to make process corrections to assure that a consistent product is produced from each manufacturing run. The guidance recommends that a person or persons trained in statistical process control establish sampling plan and methods for statistical evaluation of real time process data for purposes of trend analysis and real time process correction. These statistical data may also be used as a basis for process improvement and assessment of process variability. These analyses are essential elements in the evaluation of process “drift” and they may provide a basis for the need to perform process re-qualification activities.

Summary
FDA’s new process validation guidance modernizes concepts of process validation to reflect a lifecycle approach that is based upon principles of risk assessment and management. It formally include process development activities which define the scientific bases for the process, characterize and evaluate sources of variability, establish design and operating spaces that can be scaled, and identify critical control parameters and key quality attributes. The guidance also addresses qualification of the process at commercial scale based upon process knowledge established during the process development stage, and it provides a pathway to consistent process performance through continued process verification by collection and statistical evaluation of critical process data coupled with trained analysis and real time process correction. The principles outlined in this new guidance will provide the basis for a much higher level of process consistency, product quality and patient safety through better process development and more comprehensive process understanding and monitoring, while potentially resulting in lower cost of goods through fewer process deviations, excursions and failures.