Validation (drug manufacture)

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The process of establishing documentary evidence demonstrating that a procedure, process, or activity carried out in testing and then production maintains the desired level of compliance at all stages. In the pharmaceutical industry, it is very important that in addition to final testing and compliance of products, it is also assured that the process will consistently produce the expected results. The desired results are established in terms of specifications for outcome of the process. Qualification of systems and equipment is therefore a part of the process of validation. Validation is a requirement of food, drug and pharmaceutical regulating agencies such as the US FDA and their good manufacturing practices guidelines. 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:

Contents

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

History

The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in 1979 in USA, to improve the quality of pharmaceuticals. [1] 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 [2] 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. [3] 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.[ citation needed ] 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. 4.6. Accuracy: Accuracy of an analytical procedure is the closeness of test results obtained by that procedure to the true value. The accuracy of an analytical procedure shall be established across its range. 4.7. Precision: The precision of an analytical procedure expresses the closeness of agreement between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. 4.8. Method precision (Repeatability): Method precision carried out on different test preparation of a homogenous sample within short interval of time under same experimental conditions. 4.9. Intermediate precision (Ruggedness): Intermediate precision (Ruggedness) expresses within-laboratories variations i.e. different days, different analysts, different equipment etc. 4.10. Range: The range of an analytical procedure is the interval between the upper and lower concentration of analyte in the sample for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity

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.". [4] 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) Traditional2.png
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:

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) OPQ Adaptation of V-Model.png
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'. [5] 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, [6] 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." [7] 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. [8]

Probably the best known industry guidance available is the GAMP Guide, now in its fifth edition and known as GAMP5 published by ISPE (2008). [9] 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'. [10] 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. [11] [12] [13] [14]

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

Related Research Articles

<span class="mw-page-title-main">Food and Drug Administration</span> United States federal agency

The United States Food and Drug Administration is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, caffeine products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), cosmetics, animal foods & feed and veterinary products.

A quality management system (QMS) is a collection of business processes focused on consistently meeting customer requirements and enhancing their satisfaction. It is aligned with an organization's purpose and strategic direction. It is expressed as the organizational goals and aspirations, policies, processes, documented information, and resources needed to implement and maintain it. Early quality management systems emphasized predictable outcomes of an industrial product production line, using simple statistics and random sampling. By the 20th century, labor inputs were typically the most costly inputs in most industrialized societies, so focus shifted to team cooperation and dynamics, especially the early signaling of problems via a continual improvement cycle. In the 21st century, QMS has tended to converge with sustainability and transparency initiatives, as both investor and customer satisfaction and perceived quality are increasingly tied to these factors. Of QMS regimes, the ISO 9000 family of standards is probably the most widely implemented worldwide – the ISO 19011 audit regime applies to both and deals with quality and sustainability and their integration.

<span class="mw-page-title-main">Good manufacturing practice</span> Manufacturing quality standards

Current good manufacturing practices (cGMP) are those conforming to the guidelines recommended by relevant agencies. Those agencies control the authorization and licensing of the manufacture and sale of food and beverages, cosmetics, pharmaceutical products, dietary supplements, and medical devices. These guidelines provide minimum requirements that a manufacturer must meet to assure that their products are consistently high in quality, from batch to batch, for their intended use. The rules that govern each industry may differ significantly; however, the main purpose of GMP is always to prevent harm from occurring to the end user. Additional tenets include ensuring the end product is free from contamination, that it is consistent in its manufacture, that its manufacture has been well documented, that personnel are well trained, and that the product has been checked for quality more than just at the end phase. GMP is typically ensured through the effective use of a quality management system (QMS).

In software project management, software testing, and software engineering, verification and validation (V&V) is the process of checking that a software system meets specifications and requirements so that it fulfills its intended purpose. It may also be referred to as software quality control. It is normally the responsibility of software testers as part of the software development lifecycle. In simple terms, software verification is: "Assuming we should build X, does our software achieve its goals without any bugs or gaps?" On the other hand, software validation is: "Was X what we should have built? Does X meet the high-level requirements?"

Computerized system validation (CSV) is the process of testing/validating/qualifying a regulated computerized system to ensure that it does exactly what it is designed to do in a consistent and reproducible manner that is as safe, secure and reliable as paper-based records. This is widely used in the Pharmaceutical, Life Sciences and BioTech industries and is a cousin of Software Testing but with a more formal and documented approach. The validation process begins with validation planning, system requirements definition, testing and verification activities, and validation reporting. The system lifecycle then enters the operational phase and continues until system retirement and retention of system data based on regulatory rules.

GxP is a general abbreviation for the "good practice" quality guidelines and regulations. The "x" stands for the various fields, including the pharmaceutical and food industries, for example good agricultural practice, or GAP.

<span class="mw-page-title-main">Medical device</span> Device to be used for medical purposes

A medical device is any device intended to be used for medical purposes. Significant potential for hazards are inherent when using a device for medical purposes and thus medical devices must be proved safe and effective with reasonable assurance before regulating governments allow marketing of the device in their country. As a general rule, as the associated risk of the device increases the amount of testing required to establish safety and efficacy also increases. Further, as associated risk increases the potential benefit to the patient must also increase.

A test plan is a document detailing the objectives, resources, and processes for a specific test session for a software or hardware product. The plan typically contains a detailed understanding of the eventual workflow.

An electronic lab notebook is a computer program designed to replace paper laboratory notebooks. Lab notebooks in general are used by scientists, engineers, and technicians to document research, experiments, and procedures performed in a laboratory. A lab notebook is often maintained to be a legal document and may be used in a court of law as evidence. Similar to an inventor's notebook, the lab notebook is also often referred to in patent prosecution and intellectual property litigation.

In the experimental (non-clinical) research arena, good laboratory practice or GLP is a quality system of management controls for research laboratories and organizations to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of products in development for human or animal health through non-clinical safety tests; from physio-chemical properties through acute to chronic toxicity tests.

Process analytical technology (PAT) has been defined by the United States Food and Drug Administration (FDA) as a mechanism to design, analyze, and control pharmaceutical manufacturing processes through the measurement of critical process parameters (CPP) which affect the critical quality attributes (CQA).

A design history file is a compilation of documentation that describes the design history of a finished medical device. The design history file, or DHF, is part of regulation introduced in 1990 when the U.S. Congress passed the Safe Medical Devices Act, which established new standards for medical devices that can cause or contribute to the death, serious illness, or injury of a patient. Prior to this legislation, U.S. Food and Drug Administration (FDA) auditors were limited to examining the production and quality control records of the device.

Good engineering practice (GEP) is engineering and technical activities that ensure that a company manufactures products of the required quality as expected. Good engineering practices are to ensure that the development and/or manufacturing effort consistently generates deliverables that support the requirements for qualification or validation. Good engineering practices are applied to all industries that require engineering.

Good automated manufacturing practice (GAMP) is both a technical subcommittee of the International Society for Pharmaceutical Engineering (ISPE) and a set of guidelines for manufacturers and users of automated systems in the pharmaceutical industry. More specifically, the ISPE's guide The Good Automated Manufacturing Practice (GAMP) Guide for Validation of Automated Systems in Pharmaceutical Manufacture describes a set of principles and procedures that help ensure that pharmaceutical products have the required quality. One of the core principles of GAMP is that quality cannot be tested into a batch of product but must be built into each stage of the manufacturing process. As a result, GAMP covers all aspects of production; from the raw materials, facility and equipment to the training and hygiene of staff. Standard operating procedures (SOPs) are essential for processes that can affect the quality of the finished product.

Cleaning validation is the methodology used to assure that a cleaning process removes chemical and microbial residues of the active, inactive or detergent ingredients of the product manufactured in a piece of equipment, the cleaning aids utilized in the cleaning process and the microbial attributes. All residues are removed to predetermined levels to ensure the quality of the next product manufactured is not compromised by residues from the previous product and the quality of future products using the equipment, to prevent cross-contamination and as a good manufacturing practice requirement.

Verification and validation are independent procedures that are used together for checking that a product, service, or system meets requirements and specifications and that it fulfills its intended purpose. These are critical components of a quality management system such as ISO 9000. The words "verification" and "validation" are sometimes preceded with "independent", indicating that the verification and validation is to be performed by a disinterested third party. "Integration verification and validation" can be abbreviated as "IV&V".

Aseptic processing is a processing technique wherein commercially thermally sterilized liquid products are packaged into previously sterilized containers under sterile conditions to produce shelf-stable products that do not need refrigeration. Aseptic processing has almost completely replaced in-container sterilization of liquid foods, including milk, fruit juices and concentrates, cream, yogurt, salad dressing, liquid egg, and ice cream mix. There has been an increasing popularity for foods that contain small discrete particles, such as cottage cheese, baby foods, tomato products, fruit and vegetables, soups, and rice desserts.

A specification often refers to a set of documented requirements to be satisfied by a material, design, product, or service. A specification is often a type of technical standard.

Quality by design (QbD) is a concept first outlined by quality expert Joseph M. Juran in publications, most notably Juran on Quality by Design. Designing for quality and innovation is one of the three universal processes of the Juran Trilogy, in which Juran describes what is required to achieve breakthroughs in new products, services, and processes. Juran believed that quality could be planned, and that most quality crises and problems relate to the way in which quality was planned.

Process validation is the analysis of data gathered throughout the design and manufacturing of a product in order to confirm that the process can reliably output products of a determined standard. Regulatory authorities like EMA and FDA have published guidelines relating to process validation. The purpose of process validation is to ensure varied inputs lead to consistent and high quality outputs. Process validation is an ongoing process that must be frequently adapted as manufacturing feedback is gathered. End-to-end validation of production processes is essential in determining product quality because quality cannot always be determined by finished-product inspection. Process validation can be broken down into 3 steps: process design, process qualification, and continued process verification.

References

  1. ↑ Agalloco, J. (1995). "Validation: An unconventional review and reinvention". Pda Journal of Pharmaceutical Science and Technology. 49 (4): 175–179. PMID   7552236.
  2. ↑ 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.
  3. ↑ Leveson, N. G. & Turner, C. S. (1993), 'An investigation of the Therac-25 accidents', Computer, vol. 26, no. 7, pp. 18–41.
  4. ↑ FDA (1987). "Guidelines on General Principles of Process Validation".{{cite journal}}: Cite journal requires |journal= (help)
  5. ↑ FDA (1983). "Guide to Inspection of Computerised Systems (The Blue Book)". US Food and Drug Administration, Maryland, USA.
  6. ↑ International Organization for Standardization, Geneva, Switzerland (1994). "ISO 8402:1994: Quality management and quality assurance—Vocabulary".{{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  7. ↑ "General Principles of Software Validation; Final Guidance for Industry and FDA Staff" (PDF). US FDA. 2002. Retrieved February 27, 2013.
  8. ↑ Weichel, P. (2004). "Survey of Published FDA Warning Letters with Comment on Part 11 (21 CFR Part 11)". Journal of Validation Technology. 11 (1): 62–66.
  9. ↑ ISPE (2008). "GAMP5: Risk Based Approach to Computer Compliance". International Society for Pharmaceutical Engineers, Tampa, FL.
  10. ↑ PIC/S (2004). "Good Practices for Computerised Systems in Regulated "GXP" Environments, Report PI 011-2". Pharmaceutical Inspection Convention, Geneva.
  11. ↑ Smith, H. G. (2001). "Considerations for Improving Software Validation, Securing better assurance for less cost". Journal of Validation Technology. 7 (2): 150–157.
  12. ↑ Tracy, D. S. & Nash, R. A. (2002). "A Validation Approach for Laboratory Information Management Systems". Journal of Validation Technology. 9 (1): 6–14.
  13. ↑ Lucas, I. (2003). "Testing Times in Computer Validation". Journal of Validation Technology. 9 (2): 153–161.
  14. ↑ Balogh, M. & Corbin, V. (2005). "Taming the Regulatory Beast: Regulation vs Functionalism". Pharmaceutical Technology Europe. 17 (3): 55–58.
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