Managing Complex Considerations with Pharmaceutical Facility Design

Delivering safe and effective therapies starts in facilities that are built and maintained with safety and compliance in mind. US Food and Drug Administration (FDA) and European Commission (EC) regulations often are presented as broad guidelines that describe what manufacturers need to account for, but they are not always prescriptive because facilities have unique needs. In a September “Ask the Expert” webinar, Gerardo Gomez and Patrick Nieuwenhuizen of PharmaLex Solutions demystified the guidelines that bioprocessing companies should follow.

The Presentation
Gomez explained that facility design is a crucial step to ensuring compliance with FDA regulations. In accordance with FDA 21 CFR Part 211, building size, construction, and location all influence a company’s ability to clean, maintain and properly operate a facility (1). Each operation must be performed within predefined areas of adequate size to prevent mixing up and contaminating drug components, product containers, closures, and labels. Many factors determine compliance in bioprocessing. The agency has high standards for lighting, ventilation, air filtration, heating, sewage, washing and toilet facilities, sanitation, and maintenance.

Aseptic processing requires floors, walls, and ceilings to be hard and smooth to enable easy cleaning. Temperature and humidity controls are important, as is maintaining high-efficiency particulate air (HEPA) filters and ultra-low particulate air (ULPA) under positive pressure regardless of laminar or nonlaminar flow. Companies should have systems in place to monitor environmental conditions for cleaning and disinfecting rooms and equipment.

Nieuwenhuizen explained that EudraLex Volume 4 discusses how companies can prevent cross-contamination through attention to design (2). The guidelines explicitly state that microbiology laboratories should be arranged to minimize the risk of cross contamination. Quality risk management (QRM) also should be implemented to assess cross-contamination controls, accounting for personnel, material flow, and facility equipment design and use. QRM can help to justify facility-design risks and define steps to mitigate them. Annex 1 emphasizes processing and monitoring systems that are needed for sterile products and the QRM priorities that should be included in facility design.

Gomez said that designing a cleanroom for aseptic processing differs by product. For example, high-potency manufacturing has specific airflow requirements for protecting people and products. Drug-substance requirements differ by expression system.

Nieuwenhuizen emphasized that the flow diagrams of products, personnel, materials, and waste are key to identifying potential ingress points and mitigating problems. Solutions may include installing closed systems and air locks and tailoring heating, ventilation, and air conditioning (HVAC) to the needs of both products and personnel, accounting for pressure regime, temperature, and humidity.

Gomez said that process validation is conducted in three stages. Stage 1 involves process design. Stage 2 is divided into two parts: facility/equipment design, qualification, commissioning, and validation followed by process performance qualification (PPQ) based on three successive batches made with the validated process. Stage 3 is continued process verification, which includes routine monitoring and maintenance.

Nieuwenhuizen confirmed that EC and FDA guidelines are similar. EudraLex Volume 4, Annex 15 describes the principles of qualification and validation applicable to facilities, equipment, utilities, and processes used for manufacturing medicinal products (2). Facility qualification is done following the same model as Gomez described in stage 2 above, with user requirement specifications (URS) through equipment installation, operation, and performance qualification.

Question and Answer
For cleanroom qualification, are airflow visualization studies required for areas with classification grades lower than A or B? Yes, especially when you manufacture sterile products or those that require bioburden control. You must demonstrate that there is no ingress from lower to higher classified areas. Results from air visualization studies should be considered when developing your EM program as per Annex 1, so those studies serve two purposes.

References
1 21 CFR 211. Current Good Manufacturing Practice for Finished Pharmaceuticals. US Food and Drug Administration: Silver Spring, MD, 7 October 2023; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211.

2 EudraLex – Volume 4 – Good Manufacturing Practice (GMP) Guidelines. European Commission: Brussels, Belgium, 2019; https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en.

Find the full webinar online at www.bioprocessintl.com/category/webinars.