Cleanrooms in pharmaceutical facilities have two functions: to protect the product, and therefore the patient, from particulate or microbiological cross-contamination; and to protect the operators from potentially hazardous compounds. In Europe, air quality in accordance with EN ISO 14644-1 is defined in the appropriate Good Manufacturing Guidelines1. For non-sterile manufacturing (e.g. tablets or capsules), the limits are not as stringent, but cleanroom design is still important. Arguably, there is also a difference between commercial manufacturing and development. In pharmaceutical development the turnover and variety of molecules is higher and the toxicity is often less understood, particularly in early stages of development and with an increasing number of highly potent drugs. In this situation, cross-contamination between different molecules needs to be considered.
Patheon’s facility in Milton Park, U.K. is an early phase pharmaceutical development center. The facility contains three GMP processing rooms capable of manufacturing a wide variety of non-sterile oral dosage forms for Phase I and II. Therefore, the facility must be flexible in order to maintain a suitable environment. The cleanrooms in this facility are required to be maintained to at least Grade D or ISO 8 standards1. This is achieved by a combination of facility design, pressure cascades, single pass HEPA filtered air, 40 air changes per hour, and personnel controls. In addition, flexible containment is used as an added layer of protection for both the product and operators, particularly when potent compounds are being processed. This is in contrast with later phases of manufacturing performed at facilities such as Patheon’s Bourgoin site, a Phase III and commercial facility. The moment it becomes pilot scale and batch size increases, more permanent containment options are required and installed at this site to accommodate the larger batch size for these potent compounds.
Flexible containment consists of using polyurethane glove bags designed to fit around the pharmaceutical development equipment. Such gloves completely enclose the equipment to form an additional sealed environment. They can be customized to have pass in or pass out chambers and HEPA filers to control air movement. For example, Patheon’s Milton Park facility has recently installed and validated an Xcelodose capsule filling system capable of automatically filling small amounts of active ingredients into capsules. This equipment is ideal for early phase testing of medicines and is used for many projects because it takes minimal formulation effort and reduces the amount of testing needed. The equipment can be operated within a flexible containment bag, allowing the operator easy access to the parts which need to be controlled (e.g. hopper refills) through glove ports, fulfilling cleanroom process protocol. The control module outside the containment bag allows the operator to optimize the process without disturbing the containment and reduces the potential for cross-contamination. For example, by flushing the bag with dry air or nitrogen, a hygroscopic drug substance can be manipulated, reducing the risk of instability. At the end of the manufacturing campaign, the equipment is cleaned and removed and the bag is disposed of, removing the need for costly and time consuming cleaning validation. This concept can be used for a wide variety of equipment ranging from encapsulation, fluid bed granulation, high shear granulation and even tablet compression.
The concept of facility design and the use of flexible containment has successfully been used to manufacture many different compounds for human use. In addition, validation work is performed using a “worst case” active ingredient from a solubility
point of view. This validation involved complete processing in one manufacturing room, followed by swabbing hot spots inside the processing room and in key traffic areas such as the main corridor outside the room. Tight parameters based on the dose and potency are set on the amount of active ingredient that could be recovered per swab. The validation data clearly demonstrated the effectiveness of containment as all swabs passed inspection.
This combination of facility design and tailored flexible containment in early phase development ensures fast and flexible turnaround of projects, providing the speed that clients demand without major cost.
1. EudraLex Volume 4, Annex 1 (2008)
Dr. Jonathan Sutch is Formulation Manager with Patheon in Milton Park, U.K. www.patheon.com
This article appeared in the April 2015 issue of Controlled Environments.