Buildings and equipment used in the manufacture, processing, packaging, holding or storage of drug product are subject to the regulations set forth by the FDA in 21 CFR Part 211. These regulations are considered the minimum current good manufacturing practices (cGMPs), for the manufacture of human and animal drug products. Commissioning and qualification of these buildings and equipment is essential for ensuring compliance to these regulations and confirming that the drugs manufactured within them are fit for their intended use.
As described by USFDA (2011, p. 10): During the process qualification (PQ) stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacture. This stage has two elements: (1) design of the facility and qualification of the equipment and utilities and (2) process performance qualification (PPQ).
To meet the goals identified by USFDA above, there are a number of accepted methods and/or practices that can be used. This includes consensus guides such as ASTM E2500-13, Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical manufacturing systems and Equipment, industry guidance such as ISPE’s Baseline Guide Volume 5: Commissioning & Qualification, among others. Some companies have merged elements of multiple approaches into a unique company solution. Provided the solution meets the requirements of the cGMPs any solution should be deemed adequate. The graphic below provides one possible solution to meet the intent of the 2011 process validation guidance.
Prior to starting commissioning activities, a plan should be developed. Depending on the organization the plan may be referred to as a Commissioning Plan, Commissioning and Qualification Master Plan (CQMP), or Validation Master Plan (VMP). The plan should define and provide an overview of the system, facilities, and equipment to be commissioned and/or qualified. The plan should include the scope and strategy of activities, an overview of deliverables to be completed, and the roles and responsibilities of the persons involved. Planning is addressed in ISPE Baseline Guide Volume 5: Commissioning & Qualification, FDA Guidance for Industry: Process Validation – General Principles and Practices, and ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients.
Quality Risk Management
Quality risk management tools are utilized as a means to determine which aspects of the process will have the largest effect on product quality (USFDA, 2011). Tools such as impact assessments are conducted on systems to evaluate their impact on product quality and to determine which system components are to be deemed critical (International Society of Pharmaceutical Engineering [ISPE}, 2007). Other risk management tools help to identify the critical quality parameters such as Fishbone diagrams, Failure Mode Effects Analysis (FMEA), and Design of Experiments (DoE) (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH], 2005, 2009). Utilizing quality risk management tools may also help narrow the scope of qualification to what’s most important, e.g. Critical Quality Attributes (CQAs) and Critical Process Parameters CPPs thus reducing cost (ASTM International, 2013; International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH], 2009).
Commissioning is a systematic approach to the start-up and turnover of facilities, systems, and equipment to end-users and ensuring that user requirements and design specifications are met (International Society of Pharmaceutical Engineering [ISPE}, 2007). Activities within this phase may include design reviews, factory acceptance testing, installation verification, and functional testing. Summary reports are generated at the conclusion of commissioning activities and include an overview of the results and any deviations encountered during testing. Commissioning, if well documented, may be leveraged to reduce or eliminate qualification testing.
As defined in the FDA Process Validation Guidance, qualification refers to the activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly. As discussed previously there are multiple approaches that demonstrate suitability for intended use.
- Under an ISPE Baseline Guide 5 approach, systems and equipment determined to have a direct impact on product quality are typically qualified using Installation and Operational Qualifications. While systems with an indirect impact on product quality may only be commissioned.
- Under an ASTM E2500 approach, testing typically considered as part of IQ/OQ is referred to as verification. ASTM E2500 emphasizes utilizing a science-and-risk-based approach in order to focus the verification activities on critical aspects of the system.
Commissioning activities, if performed to cGMP standards may be leveraged during the Qualification phase as they verified the system is suitable for its intended use and demonstrated proper functionality.
Multi-functional teams, which should include the Quality Unit for Direct Impact/Quality Critical systems, provide final approval of qualification or testing documentation and deem the system or equipment fit for its intended use. At this stage, a declarative statement is made on the disposition of the system or equipment and the release for operational use. Summary reports are generated at the conclusion of qualification and include an overview of the results and any deviations encountered during testing.
- Systems that have a direct impact to product quality are accepted by the organizations quality unit among other SMEs (International Society of Pharmaceutical Engineering [ISPE}, 2007).
- Systems with critical aspects are accepted by the organizations quality unit among other SMEs (ASTM International, 2013)
Process Performance Qualification
As described in (USFDA, 2011, p. 11): Process Performance Qualification (PPQ) combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected . PPQ is documented through an approved testing protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes .
The PPQ lots should be manufactured under normal conditions by the personnel routinely expected to perform each step of each unit operation in the process. Normal operating conditions should include the utility systems (e.g., air handling and water purification), material, personnel, environment, and manufacturing procedures. PPQ must be successfully completed before product can be distributed commercially (USFDA, 2011, p. 13). During PPQ, process data is collected and evaluated to ensure the manufacturing process performs as expected.
On completion of testing, a summary report is created that includes analysis of data collected, a discussion of any manufacturing nonconformance, description of corrective actions, any changes to existing procedures and controls, and a conclusion stating whether or not the process meets established acceptance criteria.
Acceptance of this report by a multi-functional team including Engineering, Area Manager, Quality Assurance, and Quality Control releases lots for distribution, provides approval of the process, and deems the process ready for Stage 3 – Continued Process Verification. Under stage 3, the organization is responsible to establish one or more systems that will monitor the manufacturing process to detect unplanned departures from the process. As defined by USFDA (2011, p. 14):
An ongoing program to collect and analyze product and process data that relate to product quality must be established (§ 211.180(e)). The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.
About Performance Validation
Performance Validation has assisted large and small pharmaceutical manufactures in providing turn-key or staff augmentation support for commissioning, qualification, and validation projects. We have successfully worked with companies that have implemented an ISPE Baseline Guide methodology, an ASTM E2500 methodology, and various combinations to achieve a compliant solution. For services offered please see the Commissioning & Qualification page of our website. For information on projects that we have successfully completed please see the Projects Summaries page of our website. Our goal is to provide our customers with peace of mind concerning their commissioning, qualification, and validation projects.
Please use our contact us page if you have a question on Commissioning, Qualification, and Validation or would like further information on Performance Validation’s capabilities.
ASTM International. (2013). E2500-13: Standard guide for specification, design, and verification of pharmaceutical and biopharmaceutical manufacturing systems and equipment. West Conshohocken, PA: ASTM International.
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH]. (2005). Quality risk management. Retrieved from https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH]. (2009). Pharmaceutial development. Retrieved from https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf
International Society of Pharmaceutical Engineering [ISPE}. (2007). Baseline guide: Volume 5 commissioning and qualification (Vol. 5). Tampa, FL: ISPE.
USFDA. (2011). Guidance for Industry. Process Validation: General Principles and Practices. Rockville, MD, USA: Government Printing Office.