GMP Buildings and Facilities

Design and Construction Features:

(a)    Any building or buildings used in the manufacture, processing, packing or holding of drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.
  
 Regarding buildings and facilities, there are two major areas of concern: the external environment and the internal environment. The external environment must be amenable to the location of well-designed and constructed buildings. It is insufficient that the building in which the production operations are to occur are clean and orderly and of suitable size and construction. If the land, air, or water resources that surround the plant offer the potential for water damage, infestation, or contamination of any type, the facilities are in jeopardy of being judged unsuitable.

Pertinent consideration prior to purchase, construction, or alteration of existing facilities includes the following:
1.    Adequate space for future expansion.
2.    Zoning laws to allow anticipated development while restricting undesirable developments in the vicinity.
3.    Availability of water (quality and quantity), power, fuel, sewage and waste-stream removal.
4.    Accessibility for employees (availability of public transportation), materials, and visitors (customers, suppliers).
5.    Environmental issues such as site history; soil, water, and air quality; and geological and topological issues (potential for flooding,
       earthquakes, foundation instability).
6.    Proximity of undesirable activities likely to pollute or act as a source of vermin, insects, odor, or microorganisms-such as other
       industries, disposal sites, or open mining.
7.    Availability of a suitable labor force (people, skills, wage expectation, labor relations and attitudes, access to further education sources).
8.    Ability to provide adequate security arrangements.
9.    Proximity or accessibility to interrelated operations of the company – R&D, marketing, internally produced intermediates or
        components.
10.    Political situation – government stability, trade policies and taxation (for foreign-based operations), financial incentives.

Having identified a suitable location for the facility, the site development plan is prepared and will include:
1.    Compliance with appropriate laws and regulations and any additional company standards.
2.    Site resources and infrastructure such as amenities, green spaces, parking (employees, delivery and distribution vehicles, visitors), road
      and rail access, recreation areas, site utilities, tank farms and other external storage, and protection of wetlands and other restricted
       environments.
3.    Storm water and waste management.
4.    Site security and access – fences, guard posts, cameras.
5.    Buildings – siting, layout, usage, function interrelations for efficiency, possible expansion, surface finishes.
6.    Utilities – design, layout, backup (especially for critical utilities as electricity and nitrogen for some chemical operations).
7.    Equipment – design, layout, spares, capacity.
8.    Traffic flow – pedestrian and vehicular (internal and external).
9.    Safety – for personnel and equipment, containment for hazardous materials, sprinkler system, emergency egress, and emergency
       services access.
10.    External architecture to take into account local environmental conditions (wind, snow, humidity) and aesthetic appearance blending
        local atmosphere, comparative image, and functionality.
11.    Ease of maintenance accessibility to services (service ducts), ease of cleaning, access for equipment.
12.    Selection and use of experience contractors.
13.    Identification of project management responsibility.
14.    Validation plans and an effective change control procedure. Provision of design and "as-built" drawings.
15.    Construction materials.

a.    Walls. Walls in manufacturing areas, corridors, and packaging areas should be of plaster finish on high-quality concrete blocks or  
       gypsum board. The finish should be smooth, usually with enamel or epoxy paint.

b.    Floors. Floor covering should be selected for durability as well as clean ability and resistance to the chemicals with which it is likely to
      come into contact.

i.    Terrazzo provides a hard-wearing finish; both tiles and poured-in-place finishes are available. The latter is preferable for manufacturing
      areas, and if tiles are used, care must be taken to ensure effective sealing between the tiles, which otherwise could become a harboring 
      area of dirt and microorganisms.
ii.    Ceramic and vinyl tiles usually are not recommended for production areas. However, if used, the between-tile sealing should be flush and
       complete.
iii.    Welded vinyl sheeting provides an even easy to clean surface. This is not practical for heavy traffic areas, but can be of value in
       production areas, especially for injectables. Here the lack of joints improves the ease of cleaning and sanitation.

c.    Ceilings, Suspended ceilings may be provided inn office areas, laboratories, toilets, and cafeterias. They usually consist of lay-in
       acoustical panels of nonbrittle, nonfriable, nonasbestos, and non-combustible material.
       
            Manufacturing areas require a smooth finish, often of seamless plaster or gypsum board. All ceiling fixtures such as light fittings, air outlets and returns, PA system and sprinkler heads should be designed to assure ease of cleaning and to minimize the potential for accumulation of dust.

d.    Services. In the building design, provisions must be made for drains, water, stream, electricity, and other services to allow for ease of maintenance. Access should, ideally, be possible without disruption of activity within the actual rooms provided with the services.

(b)    Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mix-ups between different
        components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The
        flow of components, drug product containers, closures, labeling, in-process materials and drug products through the building or
        buildings shall be designed to prevent contamination.

(c)    Operations shall be performed within specifically denied areas of adequate size. There shall be separate or defined areas or other such
        control systems for the firm's operations as are necessary to prevent contamination or mix-ups during the course of the following 
        procedures:

(1)    Receipt, identification, storage, and withholding from use 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;
(2)    Holding rejected components, drug product container, closures, and labeling before disposition;
(3)    Storage of released components, drug product containers, closures, and labeling;
(4)    Storage of in-process materials;
(5)    Manufacturing and processing operations;
(6)    Packaging and labeling operations;
(7)    Quarantine storage before release of drug products;
(8)    Storage of drug products after release;
(9)    Control and laboratory operations.

LIGHTING:

Adequate lighting shall be provided in all areas.
In order to meet lighting requirement, it is necessary for the manufacturer to define the term "adequate". This may be done by defining the amount of light (lux or foot-candles) reaching the working surface for each area involved in the production of pharmaceuticals. Public standards exist for some types for work. Normally, a range of 30-50 foot-candles ensures worker comfort and ability to perform efficiently and effectively; however, 100 foot-candles may be needed in some areas, as well as special lighting for some operations, such as inspection of filled vials. Once the light levels have been defined, it is necessary that they may be measured periodically and the results recorded. The specifications should call either for replacement of light sources when some level above the established minimum has been reached or alternatively, routine replacements of light sources on some schedule that has been shown adequate to ensure that light levels do not drop below the established minimum.

VENTILATION, AIR FILTRATION, AIR HEATING AND COOLING:

(a)    Adequate ventilation shall be provided.
(b)    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.
(c)    Air-handling systems for the manufacture, processing and packing of penicillin shall be completely separate from those for other drug products for human use.

Air-handling systems should consider the following factors:

1.    Placement of air inlet and outlet ports. These should be sited to minimize the entry of airborne particulates or odors from the surrounding areas. Outlets should not be sited near inlets.
2.    Where recirculation of air is acceptable, adequate precautions must be taken to ensure that particulates from a processing areas are removed. This will usually require an alarm system or an automatic cutoff in the event that a filter develops ahole. Dust extraction systems should be provided where appropriate, to further minimize this potential problem.
3.    The degree of filtration and the air volumes should be matched to the operations involved.
4.    Temperature and humidity conditions should provide personnel comfort-which will enhance employee performance.
5.    Where differential pressures are required between adjacent areas, suitable monitoring equipment must be provided. For example, solids manufacturing areas are usually maintained at a negative pressure in relation to adjacent rooms and corridors in order to minimize the possibility of dust migration to these other areas.
6.    The siting of final air filters close to each room being services eliminates concerns regarding the possibility of small leaks in the air duct system. Air usually enters rooms near the ceiling and leaves from the opposite side near the floor.

PLUMBING:

(a)    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 shall meet the standards prescribed in the Environmental Protection Agency's Primary Drinking Water Regulations set forth in 40 CFR Part 141. Water not meeting such standards shall not be permitted in the potable water system.

(b)    Drains shall be of adequate size and, where connected directly to a sewer, shall be provided with an air break or other mechanical deice to prevent back-siphonage.

SEWAGE AND REFUSE:
Sewage, trash, and other refuse in and from the building and immediate premises shall be disposed of in a safe and sanitary manner.

A pharmaceutical plant may consider disposal in several different ways:

1.    Product disposal. Any product requiring disposal should initially be separated from its packaging if approved landfill site should not be left in impermeable glass, plastic, or other containers which would significantly delay destruction. Tipping of product to bulk or crushing would be viable pretreatments. There are risks associated with the destruction of products-potential for the product to get diverted, legitimately or otherwise, during the disposal sequence and contamination of groundwater. Disposal procedures should involve agents with a proven record of dealing with such sensitive materials or the use of company personnel to accompany the material from plant to disposal. Ideally, incineration procedures have preference over landfill. Where incineration is used, product in plastic of other flammable packaging may not need to be returned to bulk.

2.    Printed packaging disposal. The disposal of printed packaging components including labels, inserts, and cartons poses no health risk. However, ineffective disposal, such as into public landfill, can give rise to public concern that product may be associated with the packaging. Such materials should preferable be incinerated.

3.    General trash and sewage. Normal local services will usually be adequate for trash and sewage. However, internal procedures should be sufficiently rigorous and monitored, to ensure that product and packaging waste does not get intermixed. Containers used within the plant to accumulate waste materials should be clearly marked to denote their designated use.

WASHING AND TOILET FACILITIES
Adequate washing facilities shall 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.

In addition to GMP regulations, Occupational Safety & Health Administration (OSHA) regulations impact on washing and toilet facilities. These require toilet rooms to be separate for each sex except where individual locked toilet rooms are available and also define the minimum number of water closets based on the number of users. The legal requirements of Good Manufacturing Practices specify minimum facilities for personnel. Management concern with employee morale, and extra measures to ensure minimum probability of contamination, suggest additional emphasis and activities.

1.    Eating facilities:
a.    Eating and drinking are permitted only in separate eatiung facilities well segregated from all production areas . Smoking is permitted
       only where an adequate disposal device is provided and apart from production areas.
b.    Prominent signs indicating these rules are posted at entrances to production areas.
c.    Enforcement procedures against violators are taken by management.
d.    Permanent facilities for breaks and people bringing lunches are required. Cafeterias serving hot meals are ideal to reduce the amount of
       food, a potential contamination source, being brought into the plant.

2.    For production and materials processing areas:
a.    Drinking, eating, smoking, tobacco chewing, and expectorations are prohibited.
b.    Tissues and closed disposal containers are readily available.

3.    Lavatories and lockers:
a.    Adequate in number for the number of personnel employed.
b.    Conveniently located to all areas.
c.    Hot shower facilities are provided
d.    Disinfectant soaps are utilized.
e.    Adequate ash and waste receptacles are provided.
f.    Periodic cleaning of the area during each shift with logging of times and conditions is mandatory.
g.    Complete cleaning with cleaning and disinfectant agents daily. Follow-up inspection by supervisory personnel is logged.
h.    Specific rest areas for female employees are provided.
i.    Eating and drinking are not permitted. Foods and beverages for meals and breaks may be stored only in lockers and then removed to a 
      separate eating area.
 j.    Areas separated from all aseptic spaces by an air lock.

SANITATION
(a)    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.
(b)    There shall be written procedures assigning 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.
(c)    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, lableling materials, or drug products and shall be followed. Rodenticides, insecticides and fungicide shall not be used unless registered and used in accordance with the Federal Insecticide Fungicide, and Rodenticide Act
(d)    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.