Process Validation

The term Process Validation refers to the requirement in medical device manufacturing (and related life science industries) to establish, through objective evidence, that a manufacturing process will consistently produce results or products that meet their predetermined specifications [59(1), 300(kk), 73(a)].

Process Validation is a formal, documented procedure that proves, with a high degree of assurance, that a specific process (especially one whose output cannot be fully verified through final inspection) reliably and repeatedly delivers a product or result that meets all quality and safety specifications [73(a)].

Process validation is a mandatory part of the FDA's Quality System Regulation (QSR), particularly under Production and Process Controls (Subpart G) [49, 73(a)]. It is essential for processes like sterilization, welding, or certain heat treatments where inspection alone is insufficient to guarantee product quality.

Regulatory Definition and Requirement

The FDA's Quality System Regulation (QSR), 21 CFR Part 820, specifically mandates process validation:

• Definition: Process validation means establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications [59(1)].
• Mandate: Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures [73(a)].
• Documentation: The manufacturer must document the validation activities and results, including the date and signature of the individual(s) approving the validation and, where appropriate, the major equipment validated [73(a)].

Validation in Specific Processes (HCT/P and Medical Devices)

The requirement for validation applies broadly to critical manufacturing processes for both medical devices and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P):

• HCT/Ps: If the results of processing HCT/Ps cannot be fully verified by subsequent inspection and tests, the process must be validated and approved according to established procedures, with documentation of the activities and results [303(a)]. Any written representation that processing methods reduce the risk of transmission of communicable disease (e.g., sterility or pathogen inactivation) must be based on a fully verified or validated process [303(b)].
• Specific Device Processes: Suppliers to medical device manufacturers are often required to have an established validation process for their processes or outsourced sub-processes that cannot be fully verified by subsequent inspection or test methods (e.g., welding, brazing, heat treating, passivation, or anodizing).

Key Components of the Validation Process

Process validation follows a structured approach, often consisting of Installation, Operational, and Performance Qualifications (IQ, OQ, PQ):

• Established Procedures: Manufacturers (and their suppliers) must have an established validation process that meets the needs of the specified quality system.
• IQ, OQ, and PQ: The validation process must minimally consist of Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).
• Monitoring and Control: Manufacturers must establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that specified requirements continue to be met [74(b)].
  • The manufacturer must ensure that validated processes are performed by qualified individual(s) [74(b)(1), 405].
  • The monitoring and control methods, data, date performed, and, where appropriate, the individual(s) performing the process or the major equipment used shall be documented [74(b)(2)].
• Sampling Strategy: Validation processes should include appropriate statistical rationale for sampling strategy.
• Computer Software: When computers or automated data processing systems are used as part of production or the quality system, the manufacturer shall validate computer software for its intended use according to an established protocol [72(i)]. All software changes must also be validated before approval and issuance, and these activities and results must be documented [72(i)].

Handling Changes and Deviations

Once a process is validated, any alteration requires formal evaluation to maintain the state of control:

• Review and Revalidation: When changes or process deviations occur, the manufacturer shall review and evaluate the process and perform revalidation where appropriate [75(c)]. These activities must be documented [75(c)].
• Process Changes in QSR: Changes to a specification, method, process, or procedure related to production and process controls must be verified or where appropriate validated according to Section 820.75 (Process validation) before implementation.
• Supplier Notification: A supplier must have a process for evaluating changes against the current validated state and a method detailing revalidation activities when required. Suppliers must also agree to notify the purchaser immediately if any validation process deviations occur.

Relationship to Design Validation

It is important to distinguish between Process Validation and Design Validation:

• Process Validation: Ensures the manufacturing method consistently produces a conforming product ("Did I make the product correctly every time?"[59

• Design Validation: Establishes by objective evidence that device specifications conform with user needs and intended use(s) ("Did I make the correct product?") [60(2), 309].

Validation is confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled [59(z)]. Design Validation must ensure that devices conform to defined user needs and intended uses and should include software validation and risk analysis, where appropriate [67(g)].

Analogy for Understanding Process Validation

If Quality Control (QC) is inspecting every cake baked to ensure it meets visual and weight standards, Process Validation is confirming that the oven itself is perfectly reliable. If the cake-baking process includes a critical step—like using a blast freezer whose temperature cannot be fully measured by inspecting the final, frozen cake—you must perform process validation. This means running the freezer multiple times (IQ, OQ, PQ) with monitoring equipment to prove that, under specified operating conditions, the freezer reliably hits and holds the target temperature every single time, guaranteeing the consistency of the output with a high degree of assurance [73(a)].

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