Monday, July 6, 2009

Validation (drug manufacture)

Validation in the pharmaceutical and medical device industry is defined as the documented act of demonstrating that a procedure, process, and activity will consistently lead to the expected results. It often includes the qualification of systems and equipment. It is a requirement for Good Manufacturing Practices and other regulatory requirements. Since a wide variety of procedures, processes, and activities need to be validated, the field of validation is divided into a number of subsections including the following:

  • Cleaning Validation
  • Process Validation
  • Analytical Validation
  • Computer Validation

Similiarily, the activity of qualifying systems and equipment is divided into a number of subsections including the following:

  • Design qualification
  • Installation qualification
  • Operational qualification
  • Process qualification


  • 1 History
  • 2 Computer System Validation
  • 3 Goal of Validation
  • 4 Why Validate
  • 5 Validation Master Plan
  • 6 The Validation Process
  • 7 Scope of Computer Validation
  • 8 Risk Based Approach for Computer Systems
  • 9 Industry Guidance
  • 10 Problems in Validation
    • 10.1 Problems of Self Regulation
    • 10.2 Problems in Testing
    • 10.3 Changing Terminology
  • 11 See also
  • 12 References

[edit] History

The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the quality of pharmaceuticals (Agalloco 1995). It was proposed in direct response to several problems in the sterility of large volume parenteral market. The first validation activities were focused on the processes involved in making these products, but quickly spread to associated processes including environmental control, media fill, equipment sanitization and purified water production. In a guideline on process validation the FDA define (FDA 1987) Validation as: "Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes."

[edit] 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 and medical devices, as computer systems have entered more and more into the main stream of drug and medical device production. In 1983 the FDA published a guide to the inspection of Computerized Systems in Pharmaceutical Processing, also known as the ‘bluebook’ (FDA 1983). Recently both the American FDA and the UK MHRA have added sections to the regulations specifically for the use of computer systems, for the MHRA this is Annex 11 of the EU GMP regulations (EMEA 1998), and 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 (ISO 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”

[edit] Goal of Validation

The goal for the regulators is to ensure that quality is built into the system at every step, and not just tested for at the end, as such validation activities will commonly include training on production material and operating procedures, training of people involved and monitoring of the system whilst in production. In general, an entire process is validated; a particular object within that process is verified. 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. This also extends to include the development and implementation as well as the use and maintenance of computer systems. 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.”

[edit] Why Validate

The concept of validation was first developed for equipment and processes and derived from the engineering practices used in delivery of large pieces of equipment that would be manufactured, tested, delivered and accepted according to a contract (Hoffmann et al. 1998). 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, (Leveson & Turner 1993). 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. 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. Validation is intended to provide assurance of the quality of a system or process through a quality methodology for the design, manufacture and use of that system or process, that cannot be found by simple testing alone (McDowall 2005).

[edit] Validation Master Plan

The Validation Master Plan is a document that describes how 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 to 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.

[edit] The Validation Process

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

In general the validation process constitutes the testing stream of the typical V-Model – a recognised industry standard – that is performed on completion of the system design qualification (DQ) process, see Figure 1.

The process consists of three major phases:

  • Installation Qualification (IQ) - Demonstrates that the process or equipment to be qualified 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.

Traditionally, OQ meets the system requirements (FRS) and PQ meets the initial user requirements (URS) and there is considerable overlap in addressing the two areas separately. For this reason there is a growing trend within the industry to adopt a pragmatic OPQ approach i.e. a single test exercise that addresses both OQ and PQ testing requirements (Parker, 2005), see Figure 2.

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".

The OPQ validation approach has also gained some recognition in published works such as 'Validation of IT Systems' (Segalstad, 2008) and 'Analytical Instrument Qualification' (Swartz, 2006).

[edit] 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 (Smith 2001;Tracy & Nash 2002;Lucas 2003;Balogh & Corbin 2005).

[edit] Risk Based Approach for Computer Systems

In 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 (e.g. 100's of screen prints are not gathered during testing). The subsequent validation or verification of computer systems targets only the "GxP critical" requirements of computer systems, and in this case 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 optimising 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-Of-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 an direct impact on GxP data (security or integrity) it may be considered "GxP critical".

[edit] Industry Guidance

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 practice advice on how to satisfy regulatory requirements. Case studies for a range of computer applications applying GAMP guidance can be found in Wingate (2004).

[edit] Problems in Validation

Many practitioners within pharmaceutical validation have commented on the increasing requirement for documentation and testing, which does not give extra assurance of the safety or quality of the product. Akers (1993) said: “QA and Regulatory Affairs departments within industry and Regulatory Agencies are obstacles to reduced testing since each group has their own interests to protect. Clearly, reduced auditing and testing and therefore reduced staffing is an unwelcome notion to many middle managers.” And “From the FDA perspective, it has always been safer to have more tests even if they provide no additional statistical confidence in product safety. The result of this has been that even those creative validation people who could have made validation a real process control tool have been thwarted by other special interest groups.” Powell-Evans (1998) said that “…in its Quasi-form, validation is expensive, inefficient, ineffective and awkward. It hinders progress and clogs up otherwise creditable systems for good drug production. GMP now, as we all know, should stand for ‘great mounds of paper’. These mounds are produced in a desperate attempt to ensure that every nook and cranny, every nut and bolt, and every roll and shake of an operators lab coat is signed, sealed and delivered to the regulators cold eye. It should be asked whether all this is necessary and / or beneficial, and whether a better method can be found? Or maybe we should try and understand how validation really works, moreover applied, maybe then we can move away from the Quasi approach industry has adopted, towards the view of those in the know...validation works...if you do it right!!” This has led some practitioners to search for better ways to perform development and validation. This includes moves towards measures of Cost of Quality and Risk Assesement to provide systems that perform the job with enough assurance of quality and safety without the burden of un-necessary documentation and planning (Garston Smith 2001).

[edit] Problems of Self Regulation

In general, the regulatory agencies, through laws and guidelines provide a broad overview of what they want pharmaceutical companies to provide, but not how to do it. They will audit the system and list any areas where they feel the approach is not satisfactory, but generally do not provide help on how to fix the situation. This often leads to companies performing more work than is necessary ‘just in case’ or doing less than what is necessary. It is critical that the company has a good understanding of the equipment and the intended use so that the right amount of validation is performed.

[edit] Problems in Testing

Testing, metrology, and documentation requirements for validation are challenging. For even relatively simple computer programs, it quickly becomes impossible to test every permutation and route through the program. This was described by Boehm (1970).

[edit] Changing Terminology

Given the wide range of the pharmaceutical industry from Research and development to Production, Delivery and Sales and the different regulations like GMP and GLP enacted in different ways in different countries the basic terminology used can be different. This may be solved one day by the International Conferences on Harmonisation (ICH) but until then this will continue to be a problem.

[edit] See also

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

[edit] References

  • Health Canada Validation Guidelines
  • Agalloco, J. (1995), 'Validation: an unconventional review and reinvention', PDA J Pharm Sci Technol., vol. 49, no. 4, pp. 175–179.
  • Akers, J. (1993), 'Simplifiying 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
  • Balogh, M. & Corbin, V. (2005), 'Taming the Regulatory Beast: Regulation vs Functionalism', Pharmaceutical Technology Europe, vol. 17, no. 3, pp. 55–58.
  • Boehm, B. W. (1970), Some information processing implications of air force missions 1970-1980, The Rand Corporation, Santa Monica
  • 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.
  • FDA (1983), Guide to Inspection of Computerised Systems (The Blue Book), US Food and Drug Administration, Maryland, USA.
  • FDA (1987), Guideline on general principles of Process Validation, US Food and Drug Administration, Maryland, USA
  • FDA (2002), General Principles of Software Validation; Final Guidance for Industry and FDA Staff, US Food and Drug Administration, Maryland, USA
  • FDA (2004), Part 11: Electronic Records; Electronic Signatures,Code of Federal Regulations, Title 21 - Food and Drugs, Chapter I - Food and Drug administration, Office of the Federal Register, Maryland, USA
  • Garston Smith, H. (2001), 'Considerations for Improving Software Validation', Journal of Validation Technology, vol. 7, no. 2, pp. 150–157.
  • Hoffmann, A., Kahny-Simonius, J., Plattner, M., Schmidli-Vckovski, V., & Kronseder, C. (1998), 'Computer system validation: An overview of official requirements and standards', Pharmaceutica Acta Helvetiae, vol. 72, no. 6, pp. 317–325.
  • ISO (1994), ISO 8402:1994: Quality management and quality assurance -- Vocabulary, International Organization for Standardization, Geneva, Switzerland
  • ISPE (2008), GAMP5: Risk Based Approach to Computer Compliance, International Society for Phamraceutical Engineers, Tampa, FL.*Leveson, N. G. & Turner, C. S. (1993), 'An investigation of the Therac-25 accidents', Computer, vol. 26, no. 7, pp. 18–41.
  • Lucas, I. (2003), 'Testing Times in Computer Validation', Journal of Validation Technology, vol. 9, no. 2, pp. 153–161.
  • 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.
  • PIC/S (2004), Good Practices for Computerised Systems in Regulated "GXP" Environments, Report PI 011-2, Pharmaceutical Inspection Convention, Geneva
  • 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.
  • Smith, H. G. (2001), 'Considerations for Improving Software Validation, Securing better assurance for less cost', Journal of Validation Technology, vol. 7, no. 2, pp. 150–157.
  • Swartz, M. (2006) ‘Analytical Instrument Qualification’, Avanstar [online], available at: (Accessed 29 March 2009).
  • Tracy, D. S. & Nash, R. A. (2002), 'A Validation Approach for Laboratory Information Management Systems', Journal of Validation Technology, vol. 9, no. 1, pp. 6–14.
  • Weichel, P. (2004), 'Survey of Published FDA Warning Letters with Comment on Part 11 (21 CFR Part 11)', Journal of Validation Technology, vol. 11, no. 1, pp. 62–66.
  • Wingate, G.A.S. (2004), 'Computer Systems Validation: Quality Assurance, Risk Management, and Regulatory Compliance for the Pharmaceutical and Healthcare Industry', Interpharm Press.

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