Validation (drug manufacture)
Encyclopedia
Validation in the pharmaceutical, medical device, food, blood establishments, tissue establishments, and clinical trials industries 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:
Similarly, the activity of qualifying systems and equipment is divided into a number of subsections including the following:
(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.
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.
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.
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.
There is often overlap between Installation, Operational, and Performance Qualification and sometimes these are performed simultaneously.
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:
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 (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". 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.
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).
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, 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-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 an direct impact on GxP data (security or integrity) it may be considered "GxP critical".
- Cleaning ValidationCleaning validationCleaning validation for is the methodology used to assure that a cleaning process removes residues of the active pharmaceutical ingredients of the product manufactured in a piece of equipment, the cleaning aids utilized in the cleaning process and the microbial attributes...
- Process Validation
- Analytical Method Validation
- Computer System Validation
Similarly, the activity of qualifying systems and equipment is divided into a number of subsections including the following:
- Design qualification (DQ)
- Component qualification (CQ)
- Installation qualification (IQ)
- Operational qualification (OQ)
- Performance qualification (PQ)
History
The concept of validation was first proposed by two Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(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
Parenteral
Parenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...
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
Sanitization
Sanitization can refer to* Data sanitization, has two distinct meanings:** the use of anonymization and other techniques to "sanitize" data to purge it of personally-identifiable information in order to protect user privacy; such techniques include:*** NULLing out*** masking data*** data...
and purified water production.
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
Therac-25
The Therac-25 was a radiation therapy machine produced by Atomic Energy of Canada Limited after the Therac-6 and Therac-20 units ....
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.
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
Validation is "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." (FDA 1987). 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 specificationValidation Master Plan
The Validation Master PlanValidation master plan
The Validation Master Plan also referenced as "VMP" is one of the key documents in the GMP regulated pharmaceutical industry. Even though it is not mandatory the Food and Drug Administration inspectors will ask you for it when they inspect your facility...
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
The validation process consists of identifying and testing all aspects of a process that could affect the final test or product. Prior to the testing of a process, the system must be properly qualified. Qualification includes the following steps: (These steps are common practice for equipment (IQ, OQ and PQ).- Design Qualification (DQ)- Defines the functional and operational specification of the instrument, program, or equipment and details the rationale for choosing the supplier.
- 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 is often overlap between Installation, Operational, and Performance Qualification and sometimes these are performed simultaneously.
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' (FDA 1983). Recently both the American FDA and the UK Medicines and Healthcare products Regulatory AgencyMedicines and Healthcare products Regulatory Agency
The Medicines and Healthcare products Regulatory Agency is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe....
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 (ISO 1994), which treats "verification
Verification
The word verification may refer to:* Verification and validation, in engineering or quality management systems, it is the act of reviewing, inspecting or testing, in order to establish and document that a product, service or system meets regulatory or technical standards.* Verification , in the...
" 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
Verification
The word verification may refer to:* Verification and validation, in engineering or quality management systems, it is the act of reviewing, inspecting or testing, in order to establish and document that a product, service or system meets regulatory or technical standards.* Verification , in the...
, validation, and testing
Software testing
Software testing is an investigation conducted to provide stakeholders with information about the quality of the product or service under test. Software testing can also provide an objective, independent view of the software to allow the business to appreciate and understand the risks of software...
(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 (Smith 2001; Tracy & Nash 2002; Lucas 2003; Balogh & Corbin 2005).
Risk Based Approach To Computer Validation
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 (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
GxP
GxP is a general term for Good Practice quality guidelines and regulations. These guidelines are used in many fields, including the pharmaceutical and food industries....
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, 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-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 an direct impact on GxP data (security or integrity) it may be considered "GxP critical".
See also
- GxPGxPGxP is a general term for Good Practice quality guidelines and regulations. These guidelines are used in many fields, including the pharmaceutical and food industries....
- Good Manufacturing PracticeGood Manufacturing Practice"Good manufacturing practice" or "GMP" are practices and the systems required to be adapted in pharmaceutical manufacturing, quality control, quality system covering the manufacture and testing of pharmaceuticals or drugs including active pharmaceutical ingredients, diagnostics, foods,...
(GMP) - Good Automated Manufacturing PracticeGood Automated Manufacturing PracticeGood Automated Manufacturing Practice is a trademark of the International Society for Pharmaceutical Engineering . The ISPE's guide The Good Automated Manufacturing Practice Guide for Validation of Automated Systems in Pharmaceutical Manufacture describes a set of principles and procedures that...
(GAMP) - Verification and ValidationVerification and ValidationIn software project management, software testing, and software engineering, verification and validation is the process of checking that a software system meets specifications and that it fulfills its intended purpose...
- Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation SchemePharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation SchemeThe Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme are two international instruments between countries and pharmaceutical inspection authorities...
- Regulation of therapeutic goodsRegulation of therapeutic goodsThe regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency...
- United States PharmacopeiaUnited States PharmacopeiaThe United States Pharmacopeia is the official pharmacopeia of the United States, published dually with the National Formulary as the USP-NF. The United States Pharmacopeial Convention is the nonprofit organization that owns the trademark and copyright to the USP-NF and publishes it every year...