FDA: NEW Guidance for Industry Process Validation: General Principles and Practices - Issued January 2011
FDA’s new guidance aligns process validation with the product lifecycle concept and ICH Guidelines Q8 (R2) Pharmaceutical Development, Q9 (Quality Risk Management), and Q10 (Pharmaceutical Quality System).
The guidance encourages the implementation of modern development concepts of Quality by Design (QbD), such as design space, Quality Risk Management (QRM) and control strategy, throughout the product lifecycle.
The lifecycle concept links product and process development, qualification of commercial manufacturing process, and maintenance of the process in the state of control during commercial production.
The guidance supports process improvement and innovation through sound science and knowledge management.
Effective process validation contributes significantly to assurance of drug quality and that the drug produced is fit for its intended use.
The guidance defines process validation as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.
Process validation activities occur over the product and process lifecycle in 3 stages:
1 | Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.
Process knowledge and understanding are obtained and captured during this stage. Studies should be conducted with sound scientific methods and principles and documented. Design of Experiment (DOE) studies help develop process knowledge. Risk analysis can be used to screen variables to minimize number of experiments while maximizing knowledge gained. Process information from product development can be leveraged in the process design stage and used in process qualification and continued process verification stages when the process design is revised or the control strategy changed.
The process knowledge and understanding gained at this stage form the basis for establishing a process control strategy.
2 | Process Qualification: During the process qualification (PQ) stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
PQ consists of 2 elements:
1) Facility design and qualification of equipment and utilities
2) Process performance qualification (PPQ).
Facility design and commissioning precede PPQ. CGMP procedures must be followed.
Completion of this stage is necessary prior to commercial distribution. If acceptable, products can be released for distribution.
The PPQ combines the actual facility, utilities, qualified equipment, and trained personnel with the commercial process under normal operating conditions.
A successful PPQ confirms process design and demonstrates commercial manufacturing process performs as expected. PPQ is based on sound science and manufacturer’s overall level of product and process understanding and demonstrable control. Higher level of sampling, additional testing, and greater scrutiny of process performance usually occurs during PPQ. The PPQ protocol is reviewed and approved by quality unit. The PPQ protocol execution and report, also reviewed and approved by all appropriate departments and quality unit, state a clear conclusion that the process is in a state of control.
3 | Continued Process Verification: During this stage, there is continual assurance that the process remains in a state of control (validated state) during commercial manufacture.
An on-going program to collect and analyze product and process data must be established. Data collected includes process trends and quality of incoming materials or components, in process materials, and finished products. Data should be statistically trended by trained personnel Production data is collected to evaluate process capability and stability. Continued process monitoring and sampling occurs at the level established during process qualification until sufficient data are available to generate significant variability estimates. Monitoring can then be adjusted to statistically appropriate and representative levels.
Knowledge and understanding gained is the basis for establishing an approach to control the process.
Manufactures should understand the sources of variation, be able to detect the variation, understand the impact of variation on the process and product, and control the variation commensurate with the level of risk to the process and product.
Controls can consist of material analysis and equipment monitoring at significant processing points.
Manufacturers of legacy products can benefit from knowledge gained from the original process development, qualification and experience. Legacy products and processes would likely begin with Stage 3 activities for continued process verification.
Homogeneity within a batch and consistency between batches are goals of process validation activities.
FDA recommends an integrated team approach to process validation with subject matter experts from process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance. Project plans and full support of senior management are necessary for success.Published by: Jim Anthony, Enterey | Director
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