When manufacturing a healthcare product, be it a drug, a biologic, or a medical device, validation activities (including that of the active pharmaceutical ingredient) are an essential component of Good Manufacturing Practice (GMP) requirements.
Validation is the documented act of demonstrating that any procedure, process or activity will consistently lead to the expected results. It includes the qualification of systems and equipment. A careful design and validation of systems and process controls can establish a high degree of confidence that all lots or batches of the healthcare product manufactured will meet their intended specifications.1
The proof of validation is obtained through experimental design and through evaluating data that is collected throughout the product and process development. Routine end-product testing alone is not considered sufficient. Quality cannot be “tested” into the finished healthcare product, but rather it should be built into the manufacturing processes―with controls established so that the end product meets all the pre-defined quality specifications.1,2
Typical validation activities
Typical validation activities include validating the process, the analytical methods, the equipment, the computer system and software, and the cleaning methods.1,3
Process validation involves documenting evidence to provide a high degree of assurance that a specific process will consistently produce a product that meets its predetermined specifications and quality.
Process validation includes identifying, monitoring and controlling any sources of variation that can contribute to changes in the healthcare product. This is achieved after satisfactory product and process development, scale-up studies, equipment and system qualification, and the successful completion of initial validation batches (also known as conformance batches). Validation batches are prepared in order to demonstrate that, under normal conditions and defined ranges of operating parameters, the commercial-scale process appears to make an acceptable product based on its predetermined specifications and quality attributes. Process validation typically includes evaluating three consecutive commercial-scale batches to demonstrate their consistency and quality.
Analytical method validation
Analytical methods are required to measure the healthcare product characteristics (for example, identity, purity, potency and safety) that support product quality, safety and effectiveness. Once developed, these analytical methods should be evaluated for the following to ensure that they are capable of producing consistent and correct results without error:
- Calibration (detection and quantitation limits)
- Assay sampling
Once a method is validated, different analyzers should be able to follow the same procedure and generate consistent results.
This is established to ensure that the processing equipment and any ancillary systems are capable of consistently operating within the established limits and tolerances. Studies include equipment specifications, installation qualification (IQ)i and operational qualification (OQ)ii of all major equipment to be used in the manufacture of commercial-scale batches. Equipment qualification should simulate actual production conditions, including “worst-case” or stressed conditions.
Computer system and software validation
Any computer system or software that is used to automate any part of the manufacturing process and its related activities should be validated for its intended use. For instance, any software used to automate any aspect of the quality system (for example, medical device design, manufacturing, testing or packaging) should be validated accordingly.4 Compliance with Code of Federal Regulations (CFR), Title 21, Part 11, regarding electronic records and electronic signatures, is expected.5
This demonstrates that the procedures for cleaning processing components and equipment are capable of reducing all residues (for example, from products or cleaning agents) to an acceptable level. This is particularly important in multi-use plants that manufacture more than one product in order to avoid any batch-to-batch carryover. Cleaning validation is also used to demonstrate that routine cleaning and storage of equipment does not allow microbial proliferation. If cleaning validation cannot be demonstrated, consider using dedicated equipment or disposable processing components instead.
Key aspects of validation
It is important to know that regulatory agencies conduct inspections to ensure manufacturing companies comply with validation activities. When implementing and conducting validation, key concerns include:1
- Make sure to follow relevant regulatory requirements and guidance documents―validation is a GMP requirement. Examples of such documents and their issuing authorities are:
- Health Canada: Validation guidelines for pharmaceutical dosage form (GUI-0029)
- International Conference on Harmonisation: CH Q2(R1), Validation of analytical procedures
- U.S. Food and Drug Administration (FDA): General principles of software validation
- US FDA: CPG Sec. 490.100, Process validation requirements for drug products and active pharmaceutical ingredients subject to pre-market approval
- U.S. FDA: Process validation: general principles and practices
- Establish a “Validation master plan” to provide an overview of the entire validation operation, its organizational structure, and its content and planning. The main elements of the plan would be a list of the items to be validated and the planning schedule. Make sure to include all validation activities concerning critical technical operations related to product and process controls.
- Validate all critical production processes.
- Conduct validation studies in accordance with pre-defined protocols. Prepare, evaluate, approve and maintain written reports that summarize the recorded results and conclusions.
- Prior to implementation, validate any changes to production processes, operating parameters, equipment or materials that may affect the product quality or the reproducibility of the process.
i IQ: Documented evidence that process equipment and ancillary systems are properly selected and correctly installed.
ii OQ: Documented evidence demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications.
The information presented in these articles is intended to outline the general processes, principles and concepts of the healthcare product development lifecycle. Since regulatory requirements are ever-changing, it is current only as of the date of publication and not intended to provide detailed instructions for product development. Every healthcare product is unique and therefore so is its associated product development lifecycle. Specific advice should be sought from a qualified healthcare or other appropriate professional.
Published: October 17, 2012
- Health Canada. (2010, January 28). Validation guidelines for pharmaceutical dosage forms (GUI-0029). Retrieved June 4, 2012, from http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/validation/gui_29-eng.php.
- U.S. Food and Drug Administration. (2010). CPG Sec. 490.100 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-market Approval. Retrieved June 4, 2012, from http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm074411.htm?utm_campaign=Google2&utm_source=fdaSearch&utm_medium=website&utm_term=process%20validation&utm_content=1.
- Lutz, H. (2005, March). Introduction to validation of biopharmaceuticals. The BioPharm International guide. 4,6.
- U.S. Food and Drug Administration. (2002, January 11). General Principles of Software Validation; Final Guidance for Industry and Staff. Retrieved June 4, 2012, from .
- drug development, healthcare, healthcare product, life sciences, medical devices, product management, regulatory submissionUnited States Code. (2012, April 1). Title 21, Part 11, Electronic records; Electronic signatures. Retrieved June 4, 2012, from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11&showFR=1.