사용자:서진선/연습장

밸리데이션(Validation)이란 '특정 공정이 기 설정된 규격과 품질 요소들을 만족하고 있는 제품을 지속적으로 생산하고 있음을 보증하기 위한 증거를 문서화 하는 것' 또는 '특정 공정, 방법 또는 시스템이 사전 설정된 허용 기준에 부합하는 결과를 일관되게 만들어낸다는 점을 상당한 정도로 보증하는 문서화된 프로그램'으로 정의된다. 즉, 제약업계에서 중요한 것은 최종 제품의 품질을 보장하는 것뿐만 아니라 해당 공정이 매번 공정에서 설정했던 결과물을 만들어 내도록 보장하는 것이다. 원하는 결과가 나왔는지 여부는 공정 산출물에 대한 규격(specifications)을 비교함으로써 확인할 수 있다. 따라서 밸리데이션에는 시스템과 장비에 대한 적격성평가가 포함된다. 밸리데이션은 식품과 의약품을 규율하는 기관에서 요구하는 필수과정이며, 한국에서는 식품의약품안전처가 규제를 담당한다. 밸리데이션이 필요한 절차, 공정 및 활동 등이 다양하기 때문에 밸리데이션은 하기와 같이 다양한 하위 목록으로 분류되고 있다.

• 설비 밸리데이션 (Equipment validation)
• 시설 밸리데이션 (Facilities validation)
• 공조 시스템 밸리데이션 (HVAC system validation)
• 세척 밸리데이션 (Cleaning validation)
• 공정 밸리데이션 (Process Validation)
• 분석법 밸리데이션 (Analytical method validation
• 컴퓨터 시스템 밸리데이션 (Computer system validation)

이와 유사하게, 시스템과 설비를 평가하는 활동은 하기와 같다.

• 설계적격성평가 (Design qualification:DQ)
• 설치적격성평가 (Installation qualification:IQ)
• 운전적격성평가 (Operational qualification:OQ)
• 성능적격성평가 (Performance qualification:PQ)

History

밸리데이션이라는 개념은 1979년 미국 식품의약국(FDA) 관리인 테드 바이어스와 버드 로프터스가 제약업의 품질을 개선하기 위해 고안하였다. 이는 대용량 비경구제제 제품의 무균성 문제에 대해 대응하기 위해 제안되었다. 최초의 밸리데이션 활동은 이 제품을 생산하는 공정에 초첨을 맞췄으나, 이내 환경관리, 배지 충전, 설비 위생처리 및 정제수 제조 공정으로 확대되었다. 밸리데이션의 사용은 The use of validation spread to other areas of industry after several large-scale problems highlighted the potential risks in the design of products. The most notable is the Therac-25 incident. Here, the software for a large radiotherapy device was poorly designed and tested. In use, several interconnected problems led to several devices giving doses of radiation several thousands of times higher than intended, which resulted in the death of three patients and several more being permanently injured.

In 2005 an individual wrote a standard by which the transportation process could be validated for cold chain products. This standard was written for a biological manufacturing company and was then written into the PDA's Technical Report # 39,thus establishing the industry standard for cold chain validation. This was critical for the industry due to the sensitivity of drug substances, biologics and vaccines to various temperature conditions. The FDA has also been very focused on this final area of distribution and the potential for a drug substances quality to be impacted by extreme temperature exposure.

Reasons for validation

FDA, or any other food and drugs regulatory agency around the globe not only ask for a product that meets its specification but also require a process, procedures, intermediate stages of inspections, and testing adopted during manufacturing are designed such that when they are adopted they produce consistently similar, reproducible, desired results which meet the quality standard of product being manufactured and complies the Regulatory and Security Aspects. Such procedures are developed through the process of validation. This is to maintain and assure a higher degree of quality of food and drug products. "Process validation is defined 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 involves a series of activities taking place over the lifecycle of the product and process.". A properly designed system will provide a high degree of assurance that every step, process, and change has been properly evaluated before its implementation. Testing a sample of a final product is not considered sufficient evidence that every product within a batch meets the required specification.

Validation Master Plan

The Validation Master Plan is a document that describes how and when the validation program will be executed in a facility. Even though it is not mandatory, it is the document that outlines the principles involved in the qualification of a facility, defines the areas and systems to be validated and provides a written program for achieving and maintaining a qualified facility with validated processes. It is the foundation for the validation program and should include process validation, facility and utility qualification and validation, equipment qualification, cleaning and computer validation. The regulations also set out an expectation that the different parts of the production process are well defined and controlled, such that the results of that production will not substantially change over time.

The validation process

Figure 1: Traditional Qualification Process (adapted from the typical V-Model)

The validation scope, boundaries and responsibilities for each process or groups of similar processes or similar equipment's must be documented and approved in a validation plan. These documents, terms and references for the protocol authors are for use in setting the scope of their protocols. It must be based on a Validation Risk Assessment (VRA) to ensure that the scope of validation being authorised is appropriate for the complexity and importance of the equipment or process under validation. Within the references given in the VP the protocol authors must ensure that all aspects of the process or equipment under qualification; that may affect the efficacy, quality and or records of the product are properly qualified. Qualification includes the following steps:

• Design qualification (DQ)- Demonstrates that the proposed design (or the existing design for an off-the-shelf item) will satisfy all the requirements that are defined and detailed in the User Requirements Specification (URS). Satisfactory execution of the DQ is a mandatory requirement before construction (or procurement) of the new design can be authorised.
• Installation qualification (IQ) – Demonstrates that the process or equipment meets all specifications, is installed correctly, and all required components and documentation needed for continued operation are installed and in place.
• Operational qualification (OQ) – Demonstrates that all facets of the process or equipment are operating correctly.
• Performance qualification (PQ) – Demonstrates that the process or equipment performs as intended in a consistent manner over time.
• Component qualification (CQ) – is a relatively new term developed in 2005. This term refers to the manufacturing of auxiliary components to ensure that they are manufactured to the correct design criteria. This could include packaging components such as folding cartons, shipping cases, labels or even phase change material. All of these components must have some type of random inspection to ensure that the third party manufacturer's process is consistently producing components that are used in the world of GMP at drug or biologic manufacturer.

There are instances when it is more expedient and efficient to transfer some tests or inspections from the IQ to the OQ, or from the OQ to the PQ. This is allowed for in the regulations, provided that a clear and approved justification is documented in the Validation Plan (VP).

Figure 2: OPQ Validation Process (adapted from the typical V-Model)

This combined testing of OQ and PQ phases is sanctioned by the European Commission Enterprise Directorate-General within ‘Annex 15 to the EU Guide to Good Manufacturing Practice guide’ (2001, p. 6) which states that:

"Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ."

Computer System Validation

This requirement has naturally expanded to encompass computer systems used both in the development and production of, and as a part of pharmaceutical products, medical devices, food, blood establishments, tissue establishments, and clinical trials. In 1983 the FDA published a guide to the inspection of Computerized Systems in Pharmaceutical Processing, also known as the 'bluebook'. Recently both the American FDA and the UK Medicines and Healthcare products Regulatory Agency have added sections to the regulations specifically for the use of computer systems. In the UK, computer validation is covered in Annex 11 of the EU GMP regulations (EMEA 2011). The FDA introduced 21 CFR Part 11 for rules on the use of electronic records, electronic signatures (FDA 1997). The FDA regulation is harmonized with ISO 8402:1994, which treats "verification" and "validation" as separate and distinct terms. On the other hand, many software engineering journal articles and textbooks use the terms "verification" and "validation" interchangeably, or in some cases refer to software "verification, validation, and testing (VV&T)" as if it is a single concept, with no distinction among the three terms. The General Principles of Software Validation (FDA 2002) defines verification as "Software verification provides objective evidence that the design outputs of a particular phase of the software development life cycle meet all of the specified requirements for that phase." It also defines Validation as "Confirmation by examination and provision of objective evidence that software specifications conform to user needs and intended uses, and that the particular requirements implemented through software can be consistently fulfilled". The software validation guideline states: “The software development process should be sufficiently well planned, controlled, and documented to detect and correct unexpected results from software changes." Annex 11 states "The validation documentation and reports should cover the relevant steps of the life cycle."

Weichel (2004) recently found that over twenty warning letters issued by the FDA to pharmaceutical companies specifically cited problems in Computer System Validation between 1997 and 2001.

Probably the best known industry guidance available is the GAMP Guide, now in its fifth edition and known as GAMP5 published by ISPE (2008). This guidance gives practical advice on how to satisfy regulatory requirements.

Scope of Computer Validation

The definition of validation above discusses production of evidence that a system will meet its specification. This definition does not refer to a computer application or a computer system but to a process. The main implications in this are that validation should cover all aspects of the process including the application, any hardware that the application uses, any interfaces to other systems, the users, training and documentation as well as the management of the system and the validation itself after the system is put into use. The PIC/S guideline (PIC/S 2004) defines this as a 'computer related system'. Much effort is expended within the industry upon validation activities, and several journals are dedicated to both the process and methodology around validation, and the science behind it.

Risk Based Approach To Computer Validation

In the recent years, a risk-based approach has been adopted within the industry, where the testing of computer systems (emphasis on finding problems) is wide-ranging and documented but not heavily evidenced (i.e. hundreds of screen prints are not gathered during testing). Annex 11 states "Risk management should be applied throughout the lifecycle of the computerised system taking into account patient safety, data integrity and product quality. As part of a risk management system, decisions on the extent of validation and data integrity controls should be based on a justified and documented risk assessment of the computerised system."

The subsequent validation or verification of computer systems targets only the "GxP critical" requirements of computer systems. Evidence (e.g. screen prints) is gathered to document the validation exercise. In this way it is assured that systems are thoroughly tested, and that validation and documentation of the "GxP critical" aspects is performed in a risk-based manner, optimizing effort and ensuring that computer system's fitness for purpose is demonstrated.

The overall risk posed by a computer system is now generally considered to be a function of system complexity, patient/product impact, and pedigree (Configurable-Off-The-Shelf or Custom-written for a certain purpose). A lower risk system should merit a less in-depth specification/testing/validation approach. (e.g. The documentation surrounding a spreadsheet containing a simple but "GxP" critical calculation should not match that of a Chromatography Data System with 20 Instruments)

Determination of a "GxP critical" requirement for a computer system is subjective, and the definition needs to be tailored to the organisation involved. However, in general a "GxP" requirement may be considered to be a requirement which leads to the development/configuration of a computer function which has a direct impact on patient safety, the pharmaceutical product being processed, or has been developed/configured to meet a regulatory requirement. In addition if a function has a direct impact on GxP data (security or integrity) it may be considered "GxP critical".

Product life cycle approach in validation

Validation process efforts must account for the complete product life cycle, including developmental procedures adapted for qualification of a drug product commencing with its research and development phase, rationale for adapting a best fit formula which represents the relationship between required outputs and specified inputs, and procedure for manufacturing. Each step is required to be justified and monitored in order to provide a good quality food and drug product. The FDA emphasizes the product life cycle approach in its evaluation of manufacturer regulatory compliance as well.

See also

• Good Automated Manufacturing Practice (GAMP)
• Verification and Validation
• Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme
• Regulation of therapeutic goods
• United States Pharmacopeia

References

Bibliography

• Health Canada Validation Guidelines
• Akers, J. (1993), 'Simplifying and improving Process Validation', Journal of Parenteral Science and Technology, vol. 47, no. 6, pp. 281–284.
• ASTM E2537 Guide for Application of Continuous Quality Verification for Pharmaceutical and Biopharmaceutical Manufacturing
• EMEA (1998), EUDRALEX Volume 4 – Medicinal Products for Human and Veterinary Use : Good Manufacturing Practice, European Medicines Agency, London
• European Commission Enterprise Directorate-General (2001), Final Version of Annex 15 to the EU Guide to Good Manufacturing Practice, Qualification and Validation, Brussels. European Commission Enterprise Directorate-General.
• US FDA: Guideline on general principles of Process Validation
• Part 11: Electronic Records; Electronic Signatures,Code of Federal Regulations
• Garston Smith, H. (2001), 'Considerations for Improving Software Validation', Journal of Validation Technology, vol. 7, no. 2, pp. 150–157.
• IT Pharma Validation Europe: News and Updates on Computer System Validation and Infrastructure Qualification – e.g. EudraLex Volume 4 – Annex 11 computerised systems – revision January 2011
• Lopez, Orlando (2002), “21 CFR Part 11 – A Complete Guide to International Compliance,” published by Sue Horwood Publishing Limited.
• McDowall, R. D. (2005), 'Effective and practical risk management options for computerised system validation', The Quality Assurance Journal, vol. 9, no. 3, pp. 196–227.
• Parker G, (2005) ‘Developing Appropriate Validation and Testing Strategies’ Presented for Scimcon Ltd at the Thermo Informatics World Conference. North America.
• Powell-Evans, K. (1998), 'Streamlining Validation', Pharmaceutical Technology Europe, vol. 10, no. 12, pp. 48–52.
• Segalstad, S.H (2008), ‘International IT Regulations and Compliance: Quality Standards in the Pharmaceutical and Regulated Industries, John Wiley & Sons , pp. 157 – 178.
• Swartz, M. (2006) ‘Analytical Instrument Qualification’, Avanstar [online], available at: http://www.advanstar.com/test/pharmascience/pha-sci_supp-promos/phasci_reg_guidance/articles/Instrumentation1_Swartz_rv.pdf (Accessed 29 March 2009).
• Validating Software used for the Pharmaceutical Industry. (2007). Retrieved July 6, 2009, from http://www.plainsite.net/validation/validation.htm
• WHO Technical Report Series, No. 937, 2006. Annex 4. Appendix 5. 2006
• Wingate, G.A.S. (2004), 'Computer Systems Validation: Quality Assurance, Risk Management, and Regulatory Compliance for the Pharmaceutical and Healthcare Industry', Interpharm Press.

Sources

• Pharma Validation Guidelines