Chapter 27: Facilities

Introduction

Good manufacturing practices (GMP) were invoked to maintain the quality of pharmaceutical and biopharmaceutical products manufactured for human consumption. The predicate regulatory documents, 21 CFR 210 and 211, outline the minimum GMP for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the Act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess. Failure to comply with the regulations renders a drug adulterated, and the drug, as well as the person(s) and company responsible for the failure to comply, are subject to regulatory action. In GMP, buildings and facilities are the second major topic addressed, indicating their importance in the overall manufacturing of quality products.

Design and Construction Features (21 CFR 211.42)

Building design is the first imperative to ensure that products are manufactured safely. Buildings should facilitate cleaning, maintenance, and proper operations, and therefore need to be large enough and constructed in a manner to accommodate these processes. They should have adequate space for the orderly placement of equipment and materials to prevent cross-contamination between different components, drug product containers, closures, labeling, in-process materials, or drug products. They should also be designed to prevent contamination through the unidirectional flow of components, drug product containers, closures, labeling, in-process materials, and drug products from minimally controlled areas to those in which control is greater. As these materials move through the production area, each area is subject to higher scrutiny and control. For example, the loading dock where raw materials and components are received will have fewer environmental controls than the area where bulk product is filled into containers.

Specifically defined areas of adequate size are required for each operation and are designed to prevent contamination or mix-ups. Specific areas are typically demarcated for:

• Receipt, identification, storage, and holding of components, drug product containers, closures, and labeling pending the appropriate sampling, testing, or examination by the quality control unit before release for manufacturing or packaging

• Holding rejected components, drug product containers, closures, and labeling before disposition

• Storage of released components, drug product containers, closures, and labeling

• Storage of in-process materials

• Manufacturing and processing operations

• Packaging and labeling operations

• Quarantine storage before release of drug products

• Storage of drug products after release

• Control and laboratory operations

• Aseptic processing, including floors, walls, and ceilings with smooth, hard surfaces that are easily cleanable; temperature and humidity controls; air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or not laminar; system for monitoring environmental conditions; system for cleaning and disinfecting the room and equipment to produce aseptic conditions; and system for maintaining any equipment used to control the aseptic conditions

Lighting (21 CFR 211.44)

The GMP are very specific and succinct regarding lighting. The facilities must have sufficient lighting to ensure that all work can be easily viewed by personnel to allow them to conduct their activities properly. Most companies provide fluorescent lighting, which produces bright, nonglaring light, facilitating visual assessment of each operation.

One area of lighting that overlaps with design and construction is cleaning and maintenance of the lighting fixtures. Since lights are placed above the working area, any particles and/or microorganisms that accumulate on them are potential contaminates that could lead to an adulterated product. Therefore, companies should design lighting systems that facilitate cleaning and maintenance to prevent unwanted contamination, such as lights that are enclosed in metal housings with removable bottom panels. Additionally, cleaning schedules should be generated and implemented. Operators and supervisors should conduct daily visual inspections of the lighting fixtures to ensure that insects or other visible contaminants have not infiltrated the lighting fixtures. An insect finding its way into a fixture before the scheduled cleaning or maintenance is indicative that the frequency of cleaning is too long and should be modified.

Ventilation, Air Filtration, Air Heating and Cooling (21 CFR 211.46)

The GMP requirements stipulate that adequate ventilation shall be provided, and equipment for adequate control over air pressure, microorganisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product. The GMP also require air filtration systems, including prefilters and particulate matter air filters, to be used when appropriate on air supplies to production areas. If air is recirculated to production areas, measures are to be taken to control recirculation of dust from production. In areas where air contamination occurs during production, exhaust systems or other systems adequate to control contaminants are required. Air-handling systems for the manufacture, processing, and packing of penicillin are to be completely separate from those for other drug products for human use.

Ventilation, air filtration, and air heating and cooling are areas that may contribute to contamination, both particulate and microbiological, and these systems should be closely monitored and controlled. Similarly to lighting, a company should generate a schedule for cleaning and maintaining air vents, ducts, and cooling systems, but human observation on a daily basis should also be practiced. For example, visual observation of blackened areas on vents is evidence that the frequency of cleaning and maintenance needs to be increased to avoid unwanted contaminants from entering the area.

Plumbing (21 CFR 211.48)

The GMP requirements for water state that potable water shall be supplied under continuous positive pressure in a plumbing system free of defects that could contribute contamination to any drug product. Potable water must meet the standards prescribed in the Environmental Protection Agency’s (EPA) National Primary Drinking Water Regulations set forth in 40 CFR 141. Water not meeting such standards is not permitted in the potable water system. Drains must be of adequate size and, where connected directly to a sewer, must be provided with an air break or other mechanical device to prevent back-siphonage.

Supply of water to the facility may significantly contribute to the overall quality of the manufacturing operation. Although a facility can not control the type of water it receives from a municipality, it should monitor the water on a scheduled basis and take appropriate actions to ensure that the water meets the current EPA regulations. The EPA specifies specific levels of organic, inorganic, and microbial agents that are allowed in municipal water supplies, and typically the municipality reports these levels annually. Pharmaceutical manufacturing facilities should exert increased diligence regarding the requirements, and may adopt a practice of testing the water more frequently than annually to ensure that the incoming supply does not overwhelm its water purification system that removes these agents. This process is critical in assessing the life-span of the filters, carbon beds, resins, and ozone or other components used to reduce the amount of agents in the water supply.

Most facilities have installed plumbing that diverts sewage, including liquids used in manufacturing, directly to a closed drain equipped with air breaks downstream from the point of entry. It is good practice to ensure that all drains are capped, even those used for discharging washing solutions after a room is cleaned. In this instance, the drains should remain capped until the room is cleaned and subsequently recapped when cleaning is concluded.

Sewage and Refuse (21 CFR 211.50)

The GMP for sewage and refuse state that sewage, trash, and other refuse in and from the building and immediate premises must be disposed of in a safe and sanitary manner. Firms should have written procedures to ensure that sewage and refuse are properly removed and disposed of. Medical waste should be removed by qualified vendors who provide complete documentation of removal and ultimate disposal, be it by incineration or other means. Liquid medical waste should be removed by the same vendors, or the firm should have written procedures documenting its inactivation before disposing of it into the municipal waste or the sewage system. They must also be in compliance with all EPA regulations before disposal. Nonmedical and nontoxic waste should be removed by general waste haulers, and the firm should have written procedures to document the details of the process.

Washing and Toilet Facilities (21 CFR 211.52)

The GMP for washing and toilet facilities require that adequate washing facilities be provided, including hot and cold water, soap or detergent, air driers or single-service towels, and clean toilet facilities easily accessible to working areas. The firm is responsible not only for providing washing and toilet facilities but also for cleaning and sanitizing them on a regular basis, as described in written procedures. The firm’s training program should include a section devoted to teaching proper washing techniques for all employees after they visit a washroom.

Sanitation (21 CFR 211.56)

The GMP for sanitization are:

• Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a clean and sanitary condition. Any such building shall be free of infestation by rodents, birds, insects, and other vermin (other than laboratory animals). Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner.

• Written procedures are needed to assign responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed.

• There shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product containers, closures, packaging, labeling materials, or drug products, and shall be followed. Rodenticides, insecticides, and fungicides shall not be used unless registered, and used in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act.

• Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations.

These regulations provide enough specificity such that a firm can follow them verbatim. Whatever written programs the firm establishes to assure adequate sanitization should be supplemented with proper training of all affected employees.

Maintenance (21 CFR 211.58)

The GMP for maintenance state that any building used in the manufacture, processing, packing, or holding of a drug product must be maintained in a good state of repair. Firms must have written procedures that describe the frequency and type of maintenance they will conduct in the facility. Typically, the more critical areas, such as the aseptic core, will be more frequently maintained, and the type of maintenance will be more highly scrutinized. In many cases, the batch records will include a section for line clearance and maintenance before the run and after the run. It may include a section for cleaning and for specific areas that require maintenance. For example, many more areas in an aseptic filling suite will be scrutinized as compared to a bulk processing area. Again, training is an essential component of maintaining a facility, and individuals should be continuously trained to ensure they are vigilant in keeping the facility as impeccable as possible.