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One of the key elements supporting commercial manufacturing of pharmaceutical or compounded products is the facility design. This element is captured in the Drug cGMPs as subpart C Buildings and Facilities, and codified in 21 CFR 211.42 Design and construction features.
Process Validation Guidance & Facility Design
Facility Design is also a key element of the Jan 2011 FDA Process Validation Guidance Stage 2 Facility Design. As stated:
Proper design of a manufacturing facility is required under part 211, subpart C, of the CGMP regulations on Buildings and Facilities. It is essential that activities performed to assure proper facility design and commissioning precede PPQ. Here, the term qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly. These activities necessarily precede manufacturing products at the commercial scale.
In simplistic terms – the end user must know how they intend to use the facility and ensure the design & construction will meet that intended purpose. As stated in the FDA Process validation guidance, qualification of utilities and equipment generally includes the following activities:
- Selecting utilities and equipment construction materials, operating principles, and performance characteristics based on whether they are appropriate for their specific uses.
- Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).
- Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges. This should include challenging the equipment or system functions while under load comparable to that expected during routine production. It should also include the performance of interventions, stoppage, and start-up as is expected during routine production. Operating ranges should be shown capable of being held as long as would be necessary during routine production.
This is true for large and small pharma as well as 503B Outsourcing facilities. However, a sampling of Compounding Facilities/Pharmacies from the FDA inspection citation dataset identifies 200 citations associated attributed to only this area (note: 200 citations is not an all inclusive listing):
Table 1: 503B Inspection Sample Summary – Facility Design
| Citation | Description | Frequency |
| 21 CFR 211.42(a) | Buildings of Suitable Size, Construction, Location – Buildings used in the manufacture, processing, packing, or holding of a drug product do not have the suitable construction to facilitate cleaning, maintenance, and proper operations. | 5 |
| 21 CFR 211.42(b) | Adequate space lacking to prevent mix-ups and contamination – The building lacks adequate space for the orderly placement of equipment and materials to prevent mix-ups between drug products and to prevent contamination. | 1 |
| Product flow through building is inadequate – The flow of components, drug product containers, in-process materials, and drug products though the building is not designed to prevent contamination. | 5 | |
| 21 CFR 211.42(c) | Defined areas of adequate size for operations – The separate or defined areas necessary to prevent contamination or mix-ups are deficient. | 14 |
| 21 CFR 211.42(c)(1) | Incoming material area – Separate or defined areas to prevent contamination or mix-ups are deficient regarding operations related to the receipt, identification, storage, and withholding from use of components and drug product containers pending sampling, testing, or examination by the quality control unit before release for manufacturing or packaging. | 2 |
| 21 CFR 211.42(c)(10) | Aseptic Processing Area – Separate or defined areas to prevent contamination or mix-ups are deficient regarding operations related to aseptic processing of drug products. | 17 |
| 21 CFR 211.42(c)(10)(i) | Floors, walls, ceiling surfaces – Aseptic processing areas are deficient in that floors/ceilings are not smooth and/or hard surfaces that are easily cleanable. | 2 |
| 21 CFR 211.42(c)(10)(ii) | Temperature / Humidity Controls – Aseptic processing areas are deficient regarding temperature and humidity controls. | 1 |
| 21 CFR 211.42(c)(10)(iii) | Air Supply – Aseptic processing areas are deficient regarding air supply that is filtered through high-efficiency particulate air filters under positive pressure. | 21 |
| 21 CFR 211.42(c)(10)(iv) | Environmental Monitoring System – Aseptic processing areas are deficient regarding the system for monitoring environmental conditions. | 66 |
| 21 CFR 211.42(c)(10)(v) | Cleaning System – Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the to produce aseptic conditions. | 47 |
| 21 CFR 211.42(c)(10)(vi) | Equipment to control conditions – Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions | 12 |
| 21 CFR 211.42(c)(5) | Mfg / Processing Operations Area – Separate or defined areas to prevent contamination or mix-ups are deficient regarding the manufacturing and processing operations. | 2 |
| 21 CFR 211.42(c)(7) | Quarantined Drug Products Area – Separate or defined areas to prevent contamination or mix-ups are deficient regarding operations related to the quarantine storage of drug products prior to release. | 1 |
| 21 CFR 211.42(d) | Penicillin processing area not kept separate | 4 |
| Grand Total | 200 |
If you are contemplating registering with FDA as a 503B Outsourcing Facility? Are you wondering if your facility is appropriately designed to meet its intended purpose? Have a question on the FDA Good Manufacturing Practices? Are you interested in a cGMP Compliance Audit? If any of these are YES please contact Performance Validation using our Contact Us page.
About Performance Validation: Performance Validation has been serving the life science industries since 1988, and is a nationwide leader in providing validation, commissioning, and quality services for pharmaceutical, biotechnology, and medical device manufacturers.
