Computer science defines validation as ensuring that software meets its specifications. But, this definition does not suit the pharmaceutical and biotechnology industry adequately. For this reason, the pharma industry developed its own definition to suit its needs. Accordingly, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) describes validation as a program that establishes and documents that a specific process, method, or system will consistently produce a result meeting pre-determined acceptance criteria [ICH Q7A]. Simply put, pharmaceutical validation is a program that confirms processes, methods, equipment, or systems operate as intended. Ultimately, validation is a program demonstrating the intended use of processes, methods, equipment, and systems. Furthermore, a sound validation program covers the following areas; process validation, cleaning validation, analytical method validation, and computerized system validation.
What does intended use mean?
Intended use describes the purpose and aim of its subject. In the life science industry, the phrase defines the purpose or aim of a drug, equipment, laboratory instrument, process, method, or system. In other words, intended use describes a motive or goal from the user’s perspective.
Examples of intended use:
Subject: XYZ High-Pressure Liquid Chromatography (‘HPLC’) laboratory instrument
- Intended Use: XYZ HPLC is used by Grand Bio Pharma Inc. (a fictious company) to support the Quality Control Protein lab by analyzing the concentration of our in-house standards used in conjugation with analytical testing.
- Intended Use: XYZ HPLC is used by Grand Bio Pharma Inc. (a fictious company) to support the Quality Control Biologics lab for identity and concentration of specific proteins associated with the manufacturing of drub substance.
The same make and model instrument and yet 2 different intended uses. Each purpose requires different needs of each system’s users. For instance, each system’s user group requires different instrument settings to properly analyze proteins or in-house standards. Now, let’s take these ideas a bit further by discussing fitness.
What does fitness mean?
Recall that validation is a program that establishes and documents that specific processes, methods, or systems will consistently produce a result meeting pre-determined acceptance criteria [ICH Q7A]. Consequently, fitness refers to the degree of assurance obtained regarding the intended use of a process, method, or system. In other words, fitness answers the question; ‘how well does this equipment/system/ process meet the intended use of its users?’ And yet, fitness is not a static accomplishment since intended use can change over time. And so, reviewing validated systems, processes, and methods periodically is equally important for a validation program.
Note, fitness, ‘fit for its intended use’, and ‘fit for purpose’ are equivalent phrases. These phrases describe the degree of assurance obtained for the intended use of a specific process, method, or system.
Why is validation important in the pharmaceutical industry?
Regulatory agencies like the U.S. Food and Drug Administration (FDA) are responsible for protecting public health which includes policing the manufacturing, marketing, and distribution of pharmaceutical drugs. Thus, agencies have specific regulations for drug manufacturing they enforce called Current Good Manufacturing Practices (CGMP) regulations. CGMP regulations require pharmaceutical drugs to be produced with a high degree of assurance. A high degree of assurance regarding the drug’s safety, identity, strength, quality, and purity attributes. To quote a section of Title 21 Code of Federal Regulations (CFR) from the FDA:
“There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess”
21 CFR 211.100(a)
In a similar fashion, the European Commission has also expressed its expectations regarding validation:
“It is a GMP requirement that manufacturers control the critical aspects of their particular operations through qualification and validation over the life cycle of the product and process. Any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assess.”
–EudraLex Volume 4 Annex 15: Qualification and Validation
Recall that in the pharmaceutical industry, validation is a program focusing on proving that processes, methods, equipment, and systems achieve their expected results. Thereby, a validation program ensures a state of control and is critical to quality assurance for drug manufacturing. This means validation applies to many aspects of drug production including drug substance and finished drug product.
Note, a state of control refers to a condition in which the set of controls consistently provides the assurance regarding [manufacturing] process performance and product quality [ICH Q10].
Approaches to Validation
Each pharmaceutical manufacturer defines its validation strategies and approaches in a policy and program. In principle, validation and qualification activities should occur using a quality risk management approach. Meaning risk to drug quality is the primary basis for performing validation and qualification. Nonetheless, validation has three established approaches; prospective, concurrent, and retrospective.
Firstly, prospective validation occurs before the routine production of a drug. Meaning, validation that occurs prior to the distribution of a new product or a product made under a revised manufacturing process. Prospective validation is the preferred approach but there are exceptions, of course.
Secondly, concurrent validation occurs in conjunction with the production of commercial drug lots. Typically, concurrent validation occurs under exceptional circumstances that are justified by the benefit to patients.
Finally, retrospective validation occurs after a product is already in distribution. Retrospective validation is based upon the accumulation of production, testing, and control data. However, retrospective validation isn’t an option anymore according to regulatory agencies.
What does pharmaceutical validation involve?
In short, validation involves a combination of planning, developing requirements & specifications, and verifying requirements. ASTM’s E2500 provides the framework of specification, design, and verification of equipment for the pharmaceutical and biopharmaceutical industry. With a validation plan developed, designing requirements and specifications can occur. Following design, verification of the requirements using validation protocols may begin. Verification also includes compliance with CGMP regulations.
How much validation should I perform?
As stated previously, validation and qualification projects require proper planning. First, a pharmaceutical manufacturer should have the site’s validation program clearly defined in a Validation Master Plan (VMP) or equivalent document. The VMP should also define the structure, roles and responsibilities, and the site’s general validation strategy. Second, approaching validation and qualification using Quality Risk Management (QRM) principles is an expectation. This means determining the scope and extent of validation or qualification for a specific project should be based on a risk assessment. A risk assessment that evaluates facilities, equipment, utilities, processes, and systems required for the validation project and impact on current operations. Completing risk assessments determine the extent of validation and inform validation protocols for a project.
What is Qualification?
Qualification is proving that equipment is properly installed, working correctly, and achieving expected results. Therefore, qualification confirms and documents the design, installation, operation, and performance of facilities, systems, laboratory instruments, and equipment perform as intended. Qualification occurs prior to process validation. Because the equipment, laboratory instruments, and systems must work correctly before confirming a process performs effectively and reproducibly. Performing qualification occurs in a stepwise manner for design, installation, operation, and performance. Each step is commonly referred to as Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).
Note, qualification is sometimes referred to as equipment validation in the pharmaceutical industry. However, confirming equipment functionality is more appropriately referred to as qualification rather than validation in the pharmaceutical industry. Qualification directly addresses equipment meanwhile validation addresses processes and/or workflows in the pharmaceutical industry.
Areas of Validation
Validation covers several areas in pharmaceutical manufacturing including:
- Process Validation
- Cleaning Validation
- Analytical Method Validation
- Computerized System Validation
What is Process Validation?
Process Validation is the documented evidence that a process when operated within established parameters, can perform effectively and reproducibly to yield an intermediate or Active Pharmaceutical Ingredient (‘API’) meeting predetermined specifications and quality attributes [ICH Q7]. To rephrase it, process validation is proving that a process works correctly within defined criteria. Thus, process validation establishes the quality attributes and process parameters for pharmaceutical drug manufacturing to ensure specific outcomes. These outcomes are product quality and consistency.
Additionally, process validation relies very heavily on the qualification of equipment. Because equipment functionality must be confirmed before a process can be validated. For example, qualifying the installation, operation, and performance of a 50-liter fermenter before validating the fermentation process would be a critical first step.
What is Cleaning Validation?
In a similar fashion to process validation, Cleaning Validation is the collection, evaluation, and reporting of data associated with cleaning procedures that meet predetermined specifications within established operating parameters to avoid contamination or carryover of materials in drug manufacturing. In other words, cleaning validation focuses on proving a cleaning procedure can repeatedly remove a previous product or cleaning agents from equipment used in production.
What is Analytical Method Validation?
Analytical Method Validation is the collection, evaluation, and reporting of data associated with analytical method execution that provides documented evidence that the method is suitable for its intended analysis. Analytical method validation focuses on the capabilities of a test method. Test method capabilities like specificity, linearity, range, accuracy, precision, limits on detection and quantitation, robustness, and system suitability. While process validation supports the establishment of production processes for a drug, analytical method validation supports quality control testing. Specifically, analytical method validation is for test methods that do not conform to a pharmacopeia standard. Pharmacopeia standards like those published in the International Pharmacopoeia by the World Health Organization (WHO) or by the United States Pharmacopoeia (USP). Examples might include validation of test methods for intermediates and API for batches of material used in support of drug production.
What is Computerized System Validation?
Computerized System Validation is the collection, evaluation, and reporting of documented evidence that the process(es) or operation integrated with a computer system performs as intended, effectively, and compliantly with applicable GxP regulations. Computerized system validation also relies on qualification. Mainly, qualification of the computer system and equipment to support validation of the whole computerized system used by a pharmaceutical manufacturer.
For more information on Computerized Systems check out these articles:
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Related Topics
References
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients https://www.ich.org/page/quality-guidelines
- PIC/S Guide to Good Manufacturing Practice for Medicinal Products Annexes July 2018 http://www.picscheme.org
- PIC/S Validation Master Plan Installation and Operational Qualification Non-Sterile Process Validation Cleaning Validation September 2007
- FDA Guidance for Industry Process Validation: General Principles and Practices, FDA (January 2011)
- FDA, Glossary of Computer System Software Development Terminology (8/95) https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/glossary-computer-system-software-development-terminology-895
- EUDRALEX Volume 4 – Good Manufacturing Practice (GMP) guidelines https://ec.europa.eu/health/medicinal-products/eudralex/eudralex-volume-4_en
- World Health Organization (WHO) International Pharmacopoeia https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/norms-and-standards-for-pharmaceuticals/pharmacopoeia
- United States Pharmacopeia (USP) https://www.usp.org/