For the purpose of the draft guidance document, FDA defines the term "process validation" as the "collection and evaluation of data, from the process design stage throughout production, which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." The draft guidance document details the use of product and process development information and knowledge to create a successful validation program. Notably, FDA believes manufacturers should understand and be able to detect variation, its source(s), impact(s), and appropriate control. The draft guidance document is applicable to human drugs, veterinary drugs, biological and biotechnological products, and finished products as well as active pharmaceutical ingredients (API or drug substance), and the drug constituent of a combination drug and medical device product. It provides practices and principles that can be universally applied by these manufacturers in validating a manufacturing process.
In the draft guidance document, FDA builds on the May 1987 Guidance on General Principles of Process Validation (the 1987 guidance), incorporating concepts and understandings related to additional experience the Agency has gained since its publication. This includes the goals FDA set forth as part of the Pharmaceutical CGMPs for the 21st Century – A Risk-Based Approach, particularly in the areas of using technological advances in pharmaceutical manufacturing and implementing modern risk management and quality system tools and concepts. The practices and principles detailed in the draft guidance would supersede the 1987 guidance when finalized.
As part of the draft guidance document, FDA outlines process validation as a series of activities constituting three phases across the product lifecycle, including:
The guidance explicates and describes typical activities associated with each stage, even though some activities may overlap different stages in practice. The draft guidance document explicitly provides that "[b]efore any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process such that it will consistently produce APIs and drug product meeting those attributes relating to identity, strength, quality, purity, and potency." The recommendations provided in the draft guidance document are aimed at enhancing the degree of assurance the manufacturer has in product attributes.
Brief Summary of Draft Guidance Document Recommendations
In general, FDA recommends implementing and adhering to an integrated team approach to process validation, a concept that is discussed in greater detail in the FDA guidance document, Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations. The integrated team approach includes compiling expertise from multiple complementary disciplines, including process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance. At all points in the product lifecycle, studies planned and conducted according to sound scientific principles, appropriately documented, and approved may be undertaken to evaluate or confirm information about the product and process. FDA recommends initiation of the following activities during specific stages for process validation as follows:
With respect to stage 1, in the draft guidance document, FDA recommends building and capturing process knowledge and understanding, as well as establishing a strategy for process control. FDA opines that early process design experiments need not be conducted under CGMP conditions, but they should be conducted according to sound scientific principles. However, this general position does not apply in all circumstances. FDA points out, for example, that certain studies-namely viral and impurity clearance studies having a direct impact on drug safety-should be conducted under CGMP, even on a small-scale basis.
During product development, FDA suggests considering the functionality and limitations of commercial manufacturing equipment and how different component lots, production operators, environmental conditions, and measurement systems contribute to variability. Such considerations may be made with laboratory or pilot-scale models designed to assess variability representative of the commercial process. Design of experiment studies can also be used to enhance product process knowledge, as they reveal relationships between variable inputs.
Process controls can consist of material(s) analysis and equipment monitoring at significant processing time points to establish the process remains on target and in control. This is particularly important when the product attribute cannot be readily measured due to limitations of sampling or detectability or when intermediates and products cannot be highly characterized or well-defined quality attributes cannot be identified.
In the draft guidance document, FDA provides recommendations regarding facility design and qualification of utilities and equipment, and performance qualification approach, protocol, and execution and report for stage 2 activities. Qualification of utilities and equipment generally include activities ranging from selecting the construction materials, operating principles, and performance characteristics due to their appropriateness for the specific use to verifying the utility system and equipment operate in accordance with process requirements. According to the draft guidance document, this qualification can be managed under individual plans or as part of an overall project plan, considering the requirements of use and incorporating risk management principles.
Additionally, the draft guidance document discusses process qualification - which combines the actual facilities, utilities, equipment, and trained personnel with the commercial manufacturing process, control procedures, and components to product commercial batches - suggesting that qualification should be based on sound science and the manufacturer's overall level of product and process understanding. This includes using cumulative data from all relevant studies to determine the manufacturing conditions.
Finally, in the draft guidance document, FDA provides insights regarding continued process verification for stage 3 activities. As stated in the draft guidance document, the goal of the third stage is to "continually assure that the process remains in a state of control (the validated state) during commercial manufacture." Integral to the verification is development of system(s) to detect unplanned departures from the process. Per regulations, an ongoing program must be developed to collect and analyze product and process data related to product quality. FDA recommends that data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products.
In addition, good process design and development should anticipate significant sources of variability; to that end, the process should set forth appropriate detection, control, and/or mitigation strategies, and alert and action limits. Moreover, process variation can be detected by the timely assessment of records related to production, including: defect complaints, out-of-specification findings, process deviation reports, process yield variations, batch records, incoming raw material records, and adverse event reports. Meetings of the quality unit can facilitate the assessment of these records and to discuss possible drift(s) in the process.
The Agency prepared the draft guidance document with a view toward the product lifecycle process that links product and process development, qualification of the commercial manufacturing process, and maintenance of control during routine commercial production. It incorporates concepts instituted in guidance originating from the International Conference on Harmonisation, including Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System (when finalized). When finalized, FDA expects the draft guidance to help align with the concepts set forth with existing FDA guidance as well as promote modern manufacturing principles, process improvements, innovation, and sound science.