GOOD MANUFACTURING PRACTICES REGULATIONS

Building and Facilities

This section requires that the buildings and facilities are adequate, provide specifically defined area for certain operations and are designed to prevent mix-ups. Included are:

Design and construction features Lighting Ventilation, Air Filtration, Air Heating And Cooling Plumbing Sewage and Refuse Washing and Toilet Facilities Sanitation Maintenance

Introduction

Any building or buildings used in the manufacturing, processing, packing or holding of drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance and proper operations.

GMP regulations (a):

There are two main areas of concern regarding the buildings and facilities:

The external environment The internal environment The external environment amenable to the location of well

designed and constructed buildings. It is insufficient that the buildings in which the production operations are to occur are clean, orderly, 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 considered unsuitable.

Design and Construction Features

1-Adequate space for further expansion. 2-Zoning laws to allow anticipated development while

restricting undesirable developments in the vicinity. 3-Availability of water, 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, earth-quakes, foundation instability).

Consideration prior to purchase, construction, or alteration of existing facilities includes the following:

6-Proximity of undesirable activities likely to pollute or act as a source of vermin, insects, odor, or microorganism- such as other industries, disposal sites, or open mining.

7-Availability of a suitable labor force 8-Ability to provide adequate security arrangements. 9-Accessibility to interrelated operations of the

company-R&D, marketing, internally produced intermediates or components.

10-Political situation-government stability, trade policies and taxation, financial incentives.

Cont.

1-Compliance with appropriate laws and regulations and any additional company standards.

2-Site resources and infrastructure such as green spaces, parking, 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- guard posts, cameras.

Having identified a suitable location for the facility, the site development plan is prepared and will include:

5-Buildings—sitting layout, usage, function interrelationships for efficiency, possible expansion, surface finishes.

6-Utilities- design, layout, backup (electricity, nitrogen, chemical operation).

7-Equipment--- design, layout, spares, capacity. 8-Traffic flow (external and internal). 9-Safety 10-External architecture to take into account local

environmental conditions (wind, snow, humidity)and aesthetic appearance blending local atmosphere, comparative image and functionality.

Cont.

11-Ease of maintenance. 12-Selection and use of experienced contractors. 13-Identification of project management responsibility. 14-Validation plans and effective change control

procedure. Provision of design and as-built drawings. 15- Construction materials: A-WALL B- FLOORS C- CEILING D- SERVICES

Cont.

The position of walls should provide an orderly movement of materials and personnel.

Should take into account noise levels to provide acceptable working conditions. (minimize noise)

The walls should minimize the potential for cross-contamination and for component mix-up during storage and interdepartmental shipping.

The walls in manufacturing areas, corridors and packaging areas should be of plaster finish on high-quality concrete blocks or gypsum board to protect from crawling insects and water seepage. The finish should be smooth, usually with enamel or epoxy paint

A- WALL

Prefabricated partitions may be used in packaging areas where flexibility of layout is important.

Prefabricated units have been used in sterile suites where panel joints must be given particular attention.

Walls should be flush without any projections. Outside walls are sealed to prevent moisture, dust and

insects from going through cracks.  

Cont.

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.

Terrazzo provides a hard-wearing finish: both tiles and poured-in-place finishes are available. The latter is .used in the manufacture 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. (Flooring material consisting of chips of marble or granite set in concrete and polished to give a smooth surface )

Ceramic and vinyl tiles usually are not recommended for production areas, and if used, the between-tile sealing should be flush and complete.

B-FLOORS

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.

Epoxy flooring provides a durable and readily cleanable surface. However, the subsurface finish is extremely important.

Cont.

Suspended ceiling may be provided in 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.

C-CEILINGS

i) In the building design, provisions must be made for drains, water, steam, electricity and other services to allow for ease of maintenance.

ii) Access should, ideally, be possible without disruption of activity within the actual rooms provided with the services.

D-SERVICES

Any such building 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, or drug products through building or buildings shall be designed to prevent contamination.

GMP regulations (b):

- The design and layout of the facilities, which must minimize the possibility of mix-ups or contamination.

- Sufficient space must be provided to allow adequate separation of adjacent equipment and operations

- An example: The spatial separation of packaging lines so that packaging components, bulk product and finished product cannot intermix between lines and that dust or spillage from one line cannot result in contamination of adjacent equipment.

The requirements of this section involve:

- A common practice is to introduce a physical barrier between the packaging lines. This need not be a permanent wall, a moveable partition serves the purpose.

- The building design should also take into account the flow of materials and people.

- Neither people, equipment, nor work in process should be moved through areas in which other operations are occurring. This requires that areas used for processing should each have separate access from corridors.

- .

Cont.

- When designing a new facility, it is also of value to consider access of those visitors who intended only to have an overview of the facility or its operations

- Such visitors should be restricted to personnel corridors having visual access to the operating facilities. This minimizes any potential environmental impact from additional people, limits disruption of operational personnel, and eliminates the need for dressing up to visit.

Cont

Operation shall be performed within specifically defined 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 containers, closures, and labeling before disposition.

GMP regulations c:

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.

Cont.

10- Aseptic processing, which includes as appropriate:i. Floors, walls and ceilings of smooth, hard surfaces that are easily

cleanable.ii. Temperature and humidity controls.iii. An air supply filtered through high-efficiency particulate air filters

under positive pressure, regardless of whether flow is laminar or non-laminar.

iv. A system for monitoring environmental conditions.v. A system for cleaning and disinfecting the room and equipment to

produce aseptic conditions.vi. A system for maintaining any equipment used to control the aseptic

conditions.  

Cont

- This section requires that the buildings and facilities are adequate, provide specifically defined areas ( separate discrete areas) for certain operations and are designed to prevent mix-ups.

- A proposal has been made (1991) to revise this section and add “as necessary” to qualify the requirement for separate or defined areas. This was to clearly indicate that separate rooms or partitioned areas are not necessary if other controls exist to prevent mix-ups or contamination. A second proposal in 1995 added the words “ or other control systems”.

Discussion

- Facilities and equipment should be designed and operated to minimize the potential for mix-ups or contamination.

 - Systems control of storage, and flow of materials and

product, can be more effective than physical separation and certainly is more efficient with respect to space utilization and materials handling. For example, Physical movement of materials into and out of quarantine, not only adds cost, but by addition another action, actually increases the potential of error.

Cont.

- Some companies have found segregation using flexible physical areas to be a satisfactory alternative. For example, in warehouse, a quarantine area can be designated around the goods simply by roping off the quarantine goods or by placing floor markings. This arrangement allows easy expansion or contraction of the area to meet changing volumes.

NB: It should be noted, however, that even physical separation will be ineffective in preventing mix-ups and contamination unless accompanied by adequate support procedures.

Cont.

Warehouse includes:

Receiving areas, where materials are unloaded from the delivery transportation, are an access point for air born contamination such as dirt, dust, insects, vermin, birds and even engine fumes from the delivery vehicles themselves. These access points should be protected by flexible curtains to minimize the gap to the outside when vehicles are unloading; air curtains between the receiving bays or areas and warehouse proper may also be used to provide additional protection to the warehouse environment. Insect and rodent traps are usually required.

Cont.

- Sampling, particularly of chemical components, require separate comment. When containers of components are opened for sampling purposes, the contents are exposed for short periods to ambient conditions. Thus the normal warehouse conditions do not expose the materials to unacceptable contamination from other components, particular matter, or microorganisms.

 - Traditionally most warehouses for components and finished products have

been operated under ambient conditions. Generally, this has been adequate since most pharmaceutical products are sufficiently stable under such conditions and stability data are available to support defined shelf-lives.

 

- The prevailing conditions in the warehouse must be monitored and any particularly sensitive products or components should be provided appropriate environments.

 - For relatively stable products, it has been common practice to

omit any specific storage conditions on the labeling : It was then assumed that the USP conditions of room temperature applied.

 - In order to obtain approval for new products, defined storage

conditions must be stated on the labeling of all products.

- Many warehouses have to install air conditioning to control relatively brief exposure to higher temperature in summer months.

 - Articles may be labeled for storage at “controlled room

temperature” or up to 25C or other words based on the same kinetic temperature.

 - The storage period for rejected materials awaiting destruction

should be kept as short as possible.  

Cont.

- These materials take up valuable space and there is always a risk that they may be inadvertently used. Even with the use of a validated storage procedure it may be advisable to maintain physical segregation.

Cont.

i. Inadequate definition/agreement of specification.ii. Different test methodologies used by the supplier and the

customer.iii. Nonvalidated analytical methods.iv. Nonvalidated production procedures at the supplier resulting in

variable quantity.v. Use of untrained analysts.vi. Expected data variability around a specification limit.

Obviously, the cause of any rejection does need to be thoroughly investigated and appropriate corrective action taken and documented.

Rejections of materials could be due to:

- The degree of separation of individual manufacturing and processing operations will be dependent on the nature of these operations

 - Raw materials are usually dispensed in an area specifically

designed to minimize the potential for mix-ups and for cross-contamination. Scales are separated by partitions and are supplied with dust extraction and sometimes laminar air flow. Analysis of air samples confirms that the potential for cross-contamination is negligible.

- Where a manufacturing process requires several different pieces of equipment (e.g., blender, granulator, dryer) these may all be contained in one room or suite of rooms.

 - Processes for different products should use completely

segregated facilities.  

- Packaging and labeling operations are usually kept separate from manufacturing. Even when highly automated process is used, and packaging immediately follows manufacturing, the packaging is usually performed in an adjacent area.

Cont.

- The need to provide physical barriers between packaging lines has already been mentioned.

 - Particular attention needs to be paid to the on-line storage of bulk

product, labeling and filled but unlabelled containers.  

- During packaging operations, individual pieces of line equipment may be broken down. Under these circumstances it may be economically viable to continue the operation and to accumulate part-package product until the effective unit is repaired.

 

Cont.

- Where possible, accumulation tables should be an integral part of a packaging line, Thereby enabling short down-times on equipment to be handled without the need to remove part-packaged product from the line.

 - When the labeling unit breaks down, special care must

be taken to ensure that unlabeled containers do not get onto another line, or even intermixed with a different batch of the same products.

- Protracted breakdown of labeling equipment may result in amounts of unlabeled product in excess of the capacity of accumulation tables. Also some processes are designed to produce filled unlabeled product. This includes sterile products such ampoules and vials which are labeled outside of the sterile suite. In such situation great care must be taken to prevent mix-ups.

 - When labeling is to be performed later, security can be

enhanced by holding the unlabeled product in sealed or locked containers.

Cont.

- The requirement of separate areas for control and laboratory operations does not preclude the use of in-process testing within the manufacturing and packaging areas.

 - The environmental conditions in these areas must be suitable for

the proper operation of the equipment and performing of the testing.

 - The subsection 10 of GMP regulations c emphasizes the special

requirements associated with aseptic processing.  

Cont.

- Recognizing the importance of aseptic processing in the production of injections, The FDA issued a “ Guideline on Sterile Drug Products Produced by Aseptic Processing” 1987. However, with respect to facilities, the guide provides guidance only on air quality, air flow, and pressure differentials. There is no information on surface finishes.

- Floors, walls and ceilings in sterile areas are subject to intensive and frequent cleaning and sanitization; they must be composed of smooth, hard surfaces with minimum of joints. THEY should be resistant to abrasion, not shed particles, be free from holes, crevices and cracks, be sufficiently flexible to accommodate building strains, and be impervious to water, cleaning and sanitization solutions.

 

- Regular examinations should be performed to identify and repair any cracks in the surfaces or around service fittings and windows.

 - Critical rooms such as those for filling of final containers

should preferably have windows to allow supervision without the necessity for access.

 

All service fittings should be flush with surrounding surfaces for ease of cleaning and sanitization

Cont.

 - Temperature and humidity need to be controlled

primarily for the comfort of operations. Conditions in the order of 68 ˚F and 45% relative humidity have been found to be suitable.

 - The most critical factor in aseptic processing is the

microbial and nonviable particulate condition of the air.  

Cont.

- The air is provided by way of high-efficiency particulate air filters (HEPA) and the quality of the air is adjusted to meet the varying needs of the different processing areas. At the points where sterilized containers and closures are exposed and filling and sealing operations occur, air is supplied with less than 100 particles of 0.5 micron or larger and with not more than one colony-forming organism per 100 cubic feet. Airflows of about 90 ft/min are recommended.

 

Cont.

- These sensitive areas should also have a positive pressure differential to adjoining areas of at least of 0.05 inch of water.

 - Within aseptic processing rooms it is usual to additionally

incorporate laminar flow services over and around these most sensitive areas. These laminar flow facilities should direct the filtered air in such a way that particulate matter from equipment or personnel is directed away from the sensitive points.

 

Cont.

- Air quality necessitates appropriate systems and procedures for monitoring. This will include evaluation of pressure differentials between rooms, particulate levels (viable and nonviable) and also temperature and humidity.

 - Cleaning and disinfection of aseptic facilities and equipment

are of importance in the critical areas. Procedures must be validated with respect to both removal of previous product and to demonstrate effective disinfection.

 

Cont.

- Residual amounts of any cleaning or disinfectant agents should be at an acceptably low level.

 - In order to minimize the possibility of microbial

resistance, the disinfectant should be changed periodically. After cleaning and disinfecting, rooms and equipment must be maintained in such a manner.

 

Cont.

Operations relating to the manufacture, processing and packing of penicillin shall be performed in facilities separate from those used for other drug products for human use.

 

GMP regulation d:

- The FDA holds that there is a possibility of a trace amounts of penicillin being released even under well-controlled conditions.

- Separate equipment for use only for products containing penicillin is required. The isolation of penicillin production operations from operations for non-penicillin products is required.

- Separation can be achieved even within a single building by effectively isolating the penicillin operation from other operations

- Separation by the geographical distance or the construction of a separate building is not required, but may be the preferred economic alternative.

   

Discussion

Adequate lighting shall be provided in all areas.- Normally, a range of 30-50 foot – candles ensures worker comfort and

ability to perform efficiently and effectively however 100foot-candles may be needed in some areas, as well as special lighting for some operations, such as inspection of filled vials.

- It is necessary that the light levels 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 to ensure that light levels do no drop below the established minimum.

 

Lighting

GMP regulations:

a) Adequate ventilation shall be providedb) Equipment for adequate control over air pressure, micro-organisms, dust,

humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product.

c) Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas. If air is recirculated to production areas, measures shall be taken to control recirculation of dust from production. In areas where air contamination occurs during production, there shall be adequate exhaust systems or other systems adequate to control contaminants.

d) Air-handling systems for the manufacture, processing and packing of penicillin shall be completely separate from those for other drug products for human use.

Ventilation, Air Filtration,Air Heating and Cooling

1- Placement of air inlet and outlet ports: These should 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 area are removed. This will usually require an alarm system or an automatic cutoff in the event that a filter develops a hole. Dust extraction system should be provided, where appropriate, to further minimize this potential problem

Air handling systems should consider the following factors:

3- The degree of filtration and the air volume 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- Air usually enters room near the ceiling and leaves from the opposite side near the floor.

7- Handling of penicillin products must have separate air handling systems

Cont.

GMP regulations: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 device to prevent back-siphonage

Plumbing

- The water can lose quality in transmission through the public piping system and, of course, through the manufacturer’s system. The manufacturer will test potable water periodically.

- Where it is necessary to provide on-site potable water storage, an automatic chlorination system should be installed, usually at 2-3 ppm.

- Drains, particularly those in production areas, can be a potential source of microbial hazard therefore there must be an air break between drain and sewer to prevent back-siphonage.

- Drains should also be regularly disinfected.    

Discussion

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 appropriate. For example, any product to be disposed of in an 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 pretreatment

Sewage and Refuse

-There are risks associated with the destruction of products-potential for the product to get diverted 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 or other flammable packaging may not need to be returned to bulk

Cont.

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 preferably be incinerated.

Cont.

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.

Cont.

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.

- Toilet rooms are required 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.

- Extra measures to ensure minimum probability of contamination, suggest additional emphasis and activities.

Washing and Toilet Facilities

1 – Eating facilities:

a. Eating and drinking are permitted only in separate eating 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.

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

Cont.

2- For production and materials processing areas:

a. Drinking, eating, smoking, tobacco chewing, and expectoration are prohibited.

b. Tissues and closed disposal containers are readily available.

Cont.

- 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.

Cont.

a. Periodic cleaning of the area during each shift with logging of times and conditions is mandatory.

b. Complete cleaning with cleansing and disinfectant agents daily. Follow-up inspection by supervisory personnel is logged.

c. Specific rest areas for female employees are provided.d. 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.

e. Areas separated from all aseptic spaces by an air lock.

Cont.

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.

Sanitation

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, 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 (7 U.S.C. 135).

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.

- Cleaning and sanitation programs should be adjusted to meet the specific needs of each facility.

- In addition to cleaning of floors, walls and ceilings, there should be attention to dust extraction and air input systems.

- Duct work, especially for dust extraction systems, can come a potential explosion hazard if dust is allowed to accumulate.

- Cleaning procedures should be written in sufficient detail with respect to materials, equipment, process and frequency that they are unambiguous.

- The total elimination of rodents, birds and insects is virtually impossible and the regulations do refer to freedom from infestation.

Discussion

- The use of rodenticides, fungicides, fumigating agents, and other techniques should be combined with good hygienic practices.

- Spilled materials, such as sugar, that might attract creatures should immediately be eliminated.

- Holes in buildings that could provide additional means of access should be blocked.

- Where traps and other lethal techniques are used, there should be frequent examination and removal of corpses, which could in time become a source of further contamination.

- If these traps consistently yield results, attempts should be made to identify and eliminate the source of the problem.

- Frequently rodenticide and other treatments are contracted out . As with any contracted service, the company must assure that the procedures used are viable, achieve the desired results, and that they are followed

 

Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a good state of repair.

Maintenance

- Deterioration of buildings not only presents a poor image of the facility, it can also impact on product quality.

- Cracks and holes in walls, floors, or ceilings can provide access for insects, rodents, birds, dirt or microorganisms. They can also hinder cleaning and sanitation, thereby increasing the potential for cross contamination or microbial multiplication.

- Floor cracks can also become a safety hazard of people or even dislodge materials from trucks.

- The ingress of water from roof leaks can cause significant damage to materials and equipment, give rise to electrical failures and fires and result in damage to the basic structure of the building.

- Additionally, holes in the roof or near the tops of buildings provide ready access to birds, which may then be encouraged to nest within the building.

Discussion

- Damage to insulation or pipes and duct work will detract from the basic purpose of such insulation. It may also result in freezing and eventual leakage of pipes and in the shedding of insulation material into product and equipment.

- Light fittings need regular cleaning to remove any accumulated dust, which can act both as a potential source of contamination and reduce light intensity.

- Where the proper correction of building deficiencies requires shut-down of the area, it may be necessary to resort to temporary repair until adequate time can be made to enact a permanent repair.

- Building inspection and maintenance programs should be defined in writing and a record kept confirming compliance and referencing any repairs performed.

- Services can impact directly on processing and product quality and they must undergo routine maintenance. Essential services will include water, steam, vacuum, compressed air and other gases, electricity, dust extraction, product/material pipelines, drainage and sprinkler system.