Download (direct link):
The transfer of processing materials, or entry of personnel into clean areas, carries with it the risk of reintroduction of microorganisms and particulate matter. The principles of GMP minimizes such risks by stipulating that entry of all substances/personnel into a clean room must occur via air-lock systems (Figure 3.2). Such air-locks, with separate doors opening into the clean room and the outside environment, act as a buffer zone. All materials/process equipment entering the clean area are cleaned, sanitized, (or autoclaved if practicable) outside this area, and then passed directly into the transfer lock, from where it is transferred into the clean room by clean room personnel.
An interlocking system ensures that both doors of the transfer lock are never simultaneously open, thus precluding formation of a direct corridor between the uncontrolled area and the clean area. Transfer locks are also positioned between adjacent clean rooms of different grades of cleanliness.
Personnel represent a major potential source of process contaminants (e.g. microorganisms, particulates, etc.), hence they are required to wear specialized protective clothing when working in clean areas. Operators enter the clean area via a separate air lock, which serves as a changing area. They remove their outer clothing at one end of the area, and put on (usually pre-sterilized) gowns, face masks and gloves at the other end of the changing area. Clean room clothing is made from non-shedding material, and covers most of the operator’s body (Figure 3.3).
THE DRUG MANUFACTURING PROCESS 101
Figure 3.3. Operator wearing clean room clothing suitable for working under aseptic conditions. Note that his entire body is covered. This precludes the possibility of the operator shedding skin, microorganisms or other particulate matter into the product. Photo courtesy of SmithKline Beecham Biological Services s.a., Belgium
A high standard of operator personal hygiene is also of critical importance, and all personnel should receive appropriate training in this regard. Only the minimum number of personnel required should be present in the clean area at any given time. This is facilitated by a high degree of process automation. The installation in clean room walls of windows that serve as observational decks, coupled with intercom systems, also helps by facilitating a certain degree of supervision from outside the clean area.
Cleaning, decontamination and sanitation (CDS)
Essential to the production of a safe, effective product is the application of an effective cleaning, decontamination and sanitation (CDS) regime in the manufacturing facility. Cleaning involves the removal of‘dirt’, i.e. miscellaneous organic and inorganic material which may accumulate in process areas or equipment during production. Decontamination refers to the inactivation and removal of undesirable substances, which generally exhibit some specific biological activity likely to be detrimental to the health of patients receiving the drug. Examples include endotoxins, viruses, or prions. Sanitation refers specifically to the destruction and removal of viable microorganisms (i.e. bioburden).
Effective CDS procedures are routinely applied to:
• surfaces in the immediate manufacturing area which do not come into direct contact with the product (e.g. clean room walls and floors, work tops, ancillary equipment);
• surfaces coming into direct contact with the product (e.g. manufacturing vessels, chromatographic columns, product filters, etc.).
102 BIOPHARMACEUTICALS CDS of the general manufacturing area
Primary cleaning generally entails scrubbing/rinsing the target surface with water or a detergent solution. Subsequent decontamination/sanitation procedures vary, often involving application of disinfectants or other bacteriocidal agents. Thorough cleaning prior to disinfectant application is essential, as dirt can inactivate many disinfectants or shield microorganisms from disinfectant action. A range of suitable disinfectants are commercially available, containing active ingredients including alcohols, phenol, chlorine and iodine. Different disinfectants are often employed on a rotating basis, to minimize the likelihood of the development of disinfectant-resistant microbial strains.
CDS of clean room walls, floors and accessible surfaces of clean room equipment is routinely undertaken between production runs. The final CDS step often entails ‘fogging’ the room. This is achieved by placing some of the disinfectant in an aerosol-generating device (a ‘fogging machine’). This generates a fine disinfectant mist, or fog, within the clean room, capable of penetrating areas difficult to reach in any other manner.
CDS of process equipment
CDS of surfaces/equipment coming into direct contact with the product requires special consideration. While CDS procedures of guaranteed efficiency must be applied, it is imperative that no trace of the CDS agents subsequently remain on such surfaces, as this would result in automatic product contamination. The final stage of most CDS procedures, as applied to such process equipment, involves exhaustive rinsing with highly pure water (water for injections; WFI). This is followed if at all possible by autoclaving.