The author provides a review of the concepts of design and qualification that apply to single-use systems.
By Jerold M. Martin
Single-use technologies (SUT) have made significant inroads in biopharmaceutical and vaccine manufacturing. Greater adoption in the years to come can be anticipated, given their broad use in pre-clinical and clinical manufacturing and expanding use for approved therapeutics. With increasing regulatory oversight of SUT processes, it’s worthwhile to review basic concepts of design and qualification that apply to single-use components and systems (SUS).
Equipment Design Regulations and Guidance
While drug and vaccine manufacturers are subject to regulatory review and inspection of how equipment is used, that is not the case for the manufacturers of process equipment, including SUT components and systems, even when sold for use under good manufacturing practice (GMP). Suitability of design and qualification for use must be determined by the therapeutic manufacturer. The US Code of Federal Regulations (21 CFR 211.63), Section 211.63 states, “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance” (1). While this is the responsibility of the user, equipment manufacturers need to understand and design to user requirements for what may be considered appropriate, adequate, or suitable.
US 21 CFR does provide some information for process equipment designers: Section 211.65, paragraph (a) states, “Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements” (1). While not specifying those requirements, this requirement highlights the need for SUT equipment designers to consider operational performance criteria, as well as potential chemical interactions and equipment-derived impurities or particulate contaminants that may be introduced into applicable processes and potentially impact intermediates or final dosages.
Much of SUT use occurs in therapeutic protein API production. International Council for Harmonization (ICH) Q7, European Medicines Agency (EMA) Q7, and FDA
Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients incorporate essentially the same design requirement statement: “Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications” (2-4).
Fortunately, established SUT manufacturers have significant experience working with drug and vaccine companies and have learned to adopt SUT equipment designs to meet user needs in GMP-regulated processes. Adoption of established good engineering practices for design and deployment of SUTs is crucial and requires close collaboration between users, component designers and system engineers having experience in polymer materials, device manufacturing, human interface engineering, and other related practices (5).
SUT Design Considerations
Design considerations for SUT manufacturers can be divided into six categories:
• Physico/chemico properties cover selection and performance of the materials of construction and finished component under anticipated use conditions, with reasonable safety factors. These properties can include pressure requirements (e.g., operating, burst, creep, pressure drop), max/min temperature requirements (e.g., operating, thermal sterilization, melt, cryogenic, impact of temperature on pressure performance), mechanical properties (e.g., flexibility, rigidity, and tensile strength), optical properties (e.g., clarity or opacity), cleanliness (e.g., surface or embedded particles), biocompatibility, material oxidation and radiation stability, gas barrier properties, polymer additives, transmissible spongiform encephalopathy-bovine spongiform encephalopathy (TSE-BSE) status, and other raw material supplier data, etc.
• Fluid contact properties that should be considered in product design include chemical compatibility (e.g., polymer solubility, swelling, embrittlement, etc.), chemical reactivity, extractables under appropriate solvents and extraction conditions, particle shedding, and protein binding/adsorption to contact surfaces (along with any other formulation ingredients).
• Form, fit, and function relates to the “fitness for purpose” of the physical design of the component(s) and assemblies. It includes handling and other ergonomic properties, accessibility for installation and removal, microbial barrier and physical and fitment (leak) integrity properties, sterilizability, drainability, incorporation into an automated platform as the disposable fluid path, etc.
• Manufacturability ensures that the SUT production equipment and environment are suitable to effectively produce the component or system as designed and maintain quality specifications with a high degree of assurance. Manufacturability should also include operator training and in-process and final product testing (as needed) for quality factors such as integrity (i.e., retention properties of filters, leak absence of containers, connector and hose fitments, microbial barrier, etc.) bioburden, endotoxins, and particle contamination or generation.
• Packaging and shipment containers must be designed to effectively protect the SUT component or assembly during transport from the manufacturing or assembly site, as well as ease and security of unpacking and installation at the user site.
• Documentation should also be considered as part of product design, to include support data for performance claims, design and production validation data reports, operation guides, and other information that may be requested by users or from regulatory authorities.
Qualification is the action of proving that any equipment works correctly (as designed) and can be expected to perform as intended. For the user, qualification includes confirming that the equipment is the right tool for the job. While the term validation is sometimes applied to incorporate the concept of qualification, validation means verifying (and documenting) that the equipment consistently functions within a specified range of operations to produce an intended result. Qualification studies are, therefore, done with representative samples prior to use. Validation is conducted on process equipment (or scaled-down models) under actual use conditions.
While the word qualification is not specifically mentioned in 21 CFR 211, the interpretation of these regulations by both industry and regulatory agencies has introduced terms such as design qualification (DQ) (i.e., is the design suitable for user requirements?), installation qualification (IQ) (i.e., is the equipment installed properly?), operational qualification (OQ) (i.e., does it operate according to the manufacturer’s specifications?), and performance qualification (PQ) (i.e., does it consistently perform to meet the user’s requirements?). Additional terms that combine these concepts include factory acceptance qualification (FAQ) or test (FAT) (e.g., DQ, IQ, OQ) and site acceptance qualification (SAQ) or test (SAT) (e.g., IQ, OQ, PQ).
The first step of qualification should be DQ. For SUT, this occurs in two phases: confirmation by the equipment supplier that the equipment meets its’ design and operation criteria, and evaluation by the user that the component design and performance is suitable for use in the intended application. To the degree that the equipment supplier can anticipate the user’s requirements, some portion of the manufacturer’s qualification data can also serve as the user’s evaluation and be incorporated into the user’s documentation to be presented to regulatory authorities. This is of course provided that the manufacturer/supplier procedures and data are suitable for GMP use, the user review of the data is documented, and a user audit is conducted to confirm data validity.
Conformance of the SUT design with the manufacturer’s claims and user’s process requirements should be demonstrated and documented. According to European Union GMP Annex 15, Section 3, “Qualification activities should consider all stages from initial development of the user requirements specification (URS) through to the end of use of the equipment, facility, utility or system.” Once the URS is developed, “The next element in the qualification of equipment, facilities, utilities, or systems is DQ where the compliance of the design with GMP should be demonstrated and documented. The requirements of the user requirements specification should be verified during the design qualification” (6).
Supplier Quality System and Qualification Practices
SUT and SUS are unique from traditional stainless equipment in that the user depends on the supplier’s quality system. Review of the supplier’s quality system should be part of supplier qualification. Furthermore, users cannot normally perform incoming testing prior to using SUSs intended for implementation in production, so are also more dependent on suppliers’ product qualification practices.
Supplier qualification of SUT products can be summarized in product qualification and process validation reports suitable for user documentation and submittal to regulatory authorities. Applicable test methods for pre-use qualification are detailed in Bio-Process Systems Alliance (BPSA’s) Quality Test Reference Matrices document, along with supplemental BPSA guides with specific recommendations on qualification of extractables, sterilization, and particulates testing (7). Additional tests for SUS qualification have been described by users (8-12). The United States Pharmacopeial Convention (USP) has published a draft standard on extractables testing for plastic process equipment (13). A BPSA guide on SUS leak testing is also under development. In addition, BPSA provides an industry consensus-generated Quality Agreement Template that can be used to document accountabilities (7), and audits should be used to review these under the supplier’s quality management system.
Also important for SUS users is to qualify the SUT equipment supplier’s reliability and delivery history. Potential supplier performance can be assessed by the experience of integrators and users who have previously worked with them. Attendance at industry meetings, participation on scientific association SUS committees, or trade associations such as BPSA provide important access to suppliers, integrators, and users to aid in determining appropriate supplier/integrator qualification practices.
1. FDA, US Code of Federal Regulations (21 CFR 211.63), Section 211.63, Current Good Manufacturing Practice for Finished Pharmaceuticals (FDA, April 2014).
2. ICH, Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (ICH, November 2000).
3. EMA, Note for Guidance on Good Manufacturing Practice for Active Pharmaceutical Ingredients (CPMP/ICH/4106/00), November 2000.
4. FDA, Guidance for Industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, August 2001
5. M. Botterill and B. Rawlings, BioProcess Int. (December 2008).
6. EMA, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification and Validation, February 2014.
7. BPSA, Component Quality Test Matrices, Gamma Irradiation and Sterilization, Extractables and Leachables, Particulates, Quality Agreement Template, www.bpsalliance.org
8. PDA, Technical Report No. 66, Application of Single-Use Systems in Pharmaceutical Manufacturing (PDA, 2014).
9. D. M. Stephenson, J. Val. Technol. (February 2003).
10. M. A. Petrich, Amer. Pharm. Rev. 16 (7) (November/December 2013).
11. W. Ding, BioPharm Int. 28 (9) (September 2015) pp. 32-39.
12. D. Riedman and J. Martin, BioProcess Int. 9 (S2) (2011) pp. 28-35.
13. USP, <661.3> (draft): Plastic Systems Used for Manufacturing Pharmaceutical Products, USP—Pharmacopoeal Forum 42 (3) (USP, March 2016).