The following chapter is an excerpt taken from The Medical Device Validation Handbook.
Process and Design Validation—Regulatory Concerns
Countless Warning Letters or FDA 483s include the following violations:
“Failure to ensure, where the results of a process cannot be fully verified by subsequent inspection and test, that the process can be validated with a high degree of assurance and approved according to established procedures, as required by 21 CFR 820.75 (a). For example, your firm has no documentation to demonstrate that the _____________process for _____________used to _____________ products, such as ___________, has been validated” or “For example, there is no documentation that process validation or revalidation activities were conducted for the following………….” or
“Failure to document when changes or process deviations occur, your firm must review and evaluate the process and perform revalidation where appropriate. These activities shall be documented as required in 820.75 (c).”
Process validation along with corrective and preventive action, complaints, production and process controls and design controls are the most frequently cited violations by the Food and Drug Administration (FDA), but process validation is the most difficult to address. Process validation actually was fourth on the list of reasons for issuing FDA Form 483s according to information posted on the agency’s website, and inadequate process validation was cited more than 600 times in 2013. The problem may lie in the definition of validation in 21 CFR Part 820. Section 820.5(z) notes validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled. The regulation also divides process and design validation into two separate entities. “Process validation means establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications.” On the other hand, “design validation means establishing by objective evidence that device specifications conform with user needs and intended use(s).” The definitions lack specificity, and companies therefore must interpret the regulations independently. Even more strange, process validation is defined differently in the 2011 Guidance for Industry: Process Validation: General Principles and Practices. In that document, process validation is defined as “the collection and evaluation of data, from the process design stage through the commercial production which establishes scientific evidence that a process is capable of consistently delivering quality product.”
The background information for the 2011 guidance document states additional experience allows the agency to update the recommendations issued in the Guidance on General Principles of Process Validation issued in 1987. Thus, the revised guidance replaces the 1987 version but only for human drugs, veterinary drugs, biological and biotechnology products, finished products and active pharmaceutical ingredients (APIs or drug substances) and the drug constituent of a combination product. It does not cover medical devices. Guidance for medical devices was provided in cooperation with the Global Harmonization Task Force (GHTF). The principles and recommendations now are available from the International Medical Device Regulators Form (IMDRF) (see: http://www.imdrf.org/docs/ghtf/final/sg3/technical-docs/ghtf-sg3-n99-10-2004-qms-process-guidance-04010.pdf (included in Annex 1)). It is important to know the principles provided in the 2011 guidance can be studied for use with process validation requirements for medical devices under circumstances where they apply.
The requirement for process validation for the European sector is stated in ISO 13485:2012, section 18.104.22.168. “The organization shall validate any processes for production and service condition where the resulting output cannot be verified by subsequent monitoring or measurement. This includes any processes where deficiencies become apparent only after the product is in use or the service has been delivered.” Design and development verification is defined in 7.3.5 as “verification shall be performed in accordance with planned arrangements to ensure that the design and development outputs have met the design and development input requirements. Records of the results of the verification and any necessary actions shall be maintained.” For design and development validation, section 7.3.6 notes “it shall be performed in accordance with planned arrangements to ensure that the resulting product is capable of meeting the requirements for the specified application or intended use. Validation shall be completed prior to the delivery or implementation of the product.” A special note included in 7.3.6 states if a medical device can be validated only following assembly and installation at point of use, delivery is not considered complete until the product has been formally transferred to the customer.
Quality System Regulations—History
Since the mid-1970s, validation considerations have played an increasingly major role in the manufacture and quality of healthcare products in the US. Beginning by recognizing the need to validate sterilization and aseptic manufacturing processes, validation principles advanced by the early 1980s to apply to all manufacturing processes. Even before 1976, the concept of validation had been applied for many years to analytical test methods. Additional requirements soon followed.
Pursuant to section 520(f) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), FDA issued a final rule in the 21 July 1978 Federal Register (43 FR 31508) prescribing current Good Manufacturing Practices (CGMPs) for the methods used in and the facilities and controls used for manufacture, packing, storage and installation of medical devices. This regulation became effective on 18 December 1978, and was codified under 21 CFR Part 820. No requirements for design controls were contained in that regulation. Design controls were added when the Safe Medical Devices Act (SMDA) of 1990 (Public Law 101-629), enacted on 28 November 1990, amended section 520(f) of the FD&C Act and provided FDA the authority to add preproduction design controls to the CGMP requirements. Process validation was included in the 1978 regulation under §820.100(a)(1) Specification Controls, §820.100(b)(1 and 2) Processing Controls and §820.101 Critical Devices, Manufacturing Specifications and Processes. Neither verification nor validation is mentioned, however. The only reference included under specification controls relates to the need for written manufacturing specifications and processing procedures (including sterilization)to be established, implemented and controlled to ensure the device conforms to its original design or any approved changes in that design. There was also a requirement that there be procedures for developing manufacturing specifications.
In November 1993, FDA issued a proposed rule to revise the CGMP requirements to include design controls; the changes were intended to make FDA’s regulations compatible with the EU’s ISO 9001. A working draft of the final rule became available in July 1995, and in March 1996, FDA issued two draft guidance documents, Design Control Guidance For Medical Device Manufacturers, which provided a general understanding of design control theory and practice, and Do It By Design—An Introduction to Human Factors in Medical Devices, which provided details on human factors theories as they related to medical device design. The proposed rule was followed by the publication of Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation in October 1996, which superseded the original 1978 GMPs. It focused on the various processes within a quality management system, with new emphasis on the design and development process. This was much closer to the approach taken by the International Organization for Standardization’s ISO 9001:2000 and subsequent ISO 13485:2003. Verification and validation are included in the design control section (820.30) and, although they are associated concepts, important differences are described in the design control guidance issued in March 1997. According to the guidance, verification is the process of checking at each stage whether the output conforms to the requirements for that stage. For example, does the air conditioning system deliver the specified cooling capacity to each room? Is the roof rated to withstand so many newtons per square meter of wind loading? Is the fire alarm located within 50 meters of each location in the building? At the same time, the architect has to keep in mind the broader question of whether the results are consistent with the ultimate user requirements: Is the facility cool? Is the roof strong enough? Is the house adequately protected against fires? These broader concerns are the essence of validation.
In the initial stages of design, verification is the key quality assurance technique. As design progresses, verification activities become more comprehensive. Validation follows successful verification and ensures each requirement for a particular use is fulfilled. Design verification and design validation thus answer the oft quoted questions: did we make the product right and, most important, was the right product produced?
Of historic interest is that the initial proposed Quality System Regulation included, under 820.75, the heading “Special Processes.” This term included processes such as sterilization, where final inspection and testing were not feasible as a means to verify the specified requirements are met. A number of comments to the proposal stated the term “special processes” was unclear. Other comments stated FDA should provide examples. In response, FDA dropped the term from the regulation and added the term “process validation.” The agency further provided examples of such processes including sterilization, aseptic processing, injection molding and welding, among others. Accordingly, processes that cannot be fully verified by subsequent inspection and test shall be validated with a high degree of assurance.
The Validation Handbook
As mentioned above, process and design verification and validation nonconformances or violations found in Form 483s and Warning Letters are quite common and may be the most difficult deficiencies for manufacturers or specification developers to address. This book is designed to help resolve such issues, and each chapter individually focuses on specific topics related to verification and validation. Each is written by an expert in the field. The initial chapter on regulatory requirements for design and process validation discusses all of the compliance concerns. Subsequent chapters cover risk-based verification and validation, sterilization, packaging, Six Sigma concepts for validation studies for medical device packaging, cleaning, software, unique device identification, equipment, sample size selection and computer modeling. For the first time, all of the essential elements of validation and verification are included in a single, readily accessible, practical and comprehensive handbook. The authors’ contributions to the book are a tribute to their dedication to the medical device industry, and the information provided should facilitate manufacturing and ensure compliance with the quality system and ISO 13485 requirements. A biographical summary of each author’s qualifications can be found at the end of every chapter. Your comments are welcome.
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