Buildings and Facilities

 

1 Design and Construction

It is important to realize that API manufacturing plants are designed and constructed in various different ways depending on the chemistry, the nature of the API, the location of the plant (country, climatic region), GMP philosophy of the individual company etc. Also it is obvious that existing ("old") plants and "state of the art designed" (new) plants are expected to be very different in design and construction. It was for this reason that no detailed instructions on the design and construction of API plants is given in the Q7a document. However both types ("old" and "new" plants) should comply with the principles of this chapter, however they might be approached in a different way.

The design and construction of "new" plants reflect usually the tremendous increase of GMP understanding and principles which has been taken place in the API producing chemical industry during the past years. It is expected that compliance with this chapter for "old" plants (in which API's and intermediates have been produced for many years and which have been frequently inspected by the health authorities in conjunction with various applications and marketing authorisations) can be partially achieved by organisational measures (e.g. SOP`s), but to comply with Q7a it may be necessary to upgrade existing plants to give the required level of protection.

It should also be noted that all literature references made in this guide (especially references to air handling systems/requirements) reflect U.S. standards which may differ from European requirements. Each individual company has to decide on the necessary requirements based on their business, quality and processes.

Production Area

An increase of product protection is expected from early steps to the final API, especially for areas where open handling of the API without further purification is performed (e.g. drying, milling, weighing and packaging etc.).

In principle there are two options to achieve this goal: Open systems (products are handled temporarily in the open environment) or closed systems.

If open systems are applied, a product could be exposed for short period of time (e.g. sampling from a vessel, change of a container during discharging of a centrifuge etc.) or for long period of time (milling, weighing and packaging operations, open filtration, discharging of a tray dryer etc.). This should require different levels of protection. For short term exposure additional procedures may be necessary (e.g. "Only one operation with exposure to the environment at the same time", "Appropriate clothing requirements for the personnel", etc.) to minimise potential contamination. For long term exposure a suitably installed and well maintained air handling systems could ensure the necessary protection.

Some other precautions include:

• Spatial separation
• Protecting equipment during open product handling
  (e.g. covering, glove boxes, isolators etc.)
• Design of piping (should not be located directly above open manholes, discharging devices etc. unless appropriate protecting measures are in place
• Filtering of process gases and solvents

For closed systems in general no additional protection is necessary. The integrity of a closed system is not compromised by sampling operations provided appropriate measures are taken to prevent contamination.

Reactors, fermenters, crystallisers, distillation columns, tank farms, storage containers or other closed equipment may be located outdoors, provided there is no need to protect from weather influences. Also not permanently installed equipment (e.g. bulk containers, etc.) may be stored outside, if adequately protected.

Sometimes (especially in "old" plants) crossing of material or personnel flow can not be avoided. In this instances additional organisational measures (SOPs) should be implemented to ensure prevention from mix-ups and contamination.

Other control systems can be computerised material management systems.

Quarantined and released materials (API's, raw materials, intermediates, could be stored in the same area (but no mix-ups on pallets etc.), provided their status is clearly indicated and/or traceable (labels, computer status) and procedures are in place to avoid unauthorised use. For safety reasons separate storage facilities may be required for classes of materials with hazardous and /or unstable chemical or physical attributes. Separate production areas are required for certain materials.

Analytical measurements (e.g. conductivity, pH, density, N-IR, chromatographic methods) need not necessarily be carried out in separated (laboratory) areas, e.g. in case of online analyses.

2 Utilities

Especially those utilities which are in direct contact with the product e.g. steam distillation or nitrogen blanketing, or in contact to the inner surface of equipment need to be addressed.

When using compressed air with direct product contact it is recommended to use oil free systems.

The frequency of monitoring utilities will depend on the use of the utility and may range from daily (e.g. even online) monitoring to spot checks (e.g. intervals up to once a year) on systems which are carefully maintained. The frequency of testing may be reduced once the company has justified this based on historical data.

Adequate ventilation, air filtration and exhaust systems should be provided if open systems are used.

Regarding air circulation appropriate measures may be e.g.

• selection of suitable filters (and appropriate change of them)
• mixing of returned air with fresh filtered air
• clean up time (e.g. verified by particle measurements) on product change; including cleaning or changing of filters.

Although it is required that permanently installed pipework should be identified, this requirement should be limited to pipework dedicated to a particular medium. Other permanently installed pipework (e.g. connection panels for various solvents and reagents) could be generically identified (e.g. 1R22 to 0R14, a connection between two different reactors).

Pipework for waste (gases, liquids) should be designed and appropriate located to avoid contamination (e.g. vacuum pump, cyclones, scrubbers, common ventilation pipework from reactors/vessels). Back pressure (non-return) valves can be considered as can swannecks. Draining valves should be installed at the lowest points. During design, methods of cleaning of pipework should be considered.

3 Water

Develop a rationale as to what water quality is sufficient and/or which measures may need to be taken to ensure API quality. It is the responsibility of the manufacturer to define the specifications of the water quality by himself to assure the quality of the API. The assessment should take into account the intended use and the final purification step(s) of the API. Suitability depends on the stage in manufacture, intended route of administration or the nature of the API.

Evidence should be available that the water used does not negatively affect the product quality.

Water quality should be monitored by the supplier and the results be reported to the API manufacturer on a routine basis (e.g. quarterly).

Additional in-house testing and monitoring should be considered by the manufacturer according to a predefined and approved plan (including point of use testing, sampling frequency) against predefined specifications that ensure a safe and sound quality of the API (usually meeting guidelines for potable water, unless otherwise justified).

Potable water may be even more suitable for use than treated (softened) water due to measures taken to limit microbial growth.

Validation principles and change control need to be applied for all water systems coming into contact with product(s).

Microbiological testing should consider both suitable online monitoring (e.g. TOC) and point of use testing. Endotoxin testing is carried out offline and the LAL-test is recommended.

4 Containment

Separate containments are limited to penicillins and cephalosporins. Because they may cause anaphylactic shock at very low levels and contamination with these types of materials can only be avoided by use of dedicated facilities.

For certain APIs it may be appropriate to use dedicated or disposable clothing and dedicated equipment including tools for maintenance within the area. Specific clothing requirements should apply to all personnel e.g. maintenance staff, visitors, etc. Facilities for changing clothes or showering should be considered and special hygiene practices should be applied.

5 Sanitation and Maintenance

It has to be pointed out that there is a significant difference between a finished dose manufacturing environment (physical processes) and a chemical plant, where aggressive and corrosive reagents may be used. This significant difference should be considered in defining clean condition. Level of cleanliness required may change from a closed to a open system, also depending on the stage of manufacture. The closer to the end product, the cleaner the production environment should be. Management should assign adequate resources to ensure a good state of cleanliness and maintenance in APIs facilities.

Defined areas for the storage of temporarily used equipment and its status, (cleaned, identified and protected from the environment), should be available.

Cleaning of accidental spills and also routine cleaning programmes should be defined. External contractors are often used for sanitation and facility cleaning activities. They should be trained in GMP and their responsibilities defined in a contract.

In cases rodenticides, insecticides, fungicides, fumigating agents are used to prevent the contamination of equipment, raw materials, packaging/labelling materials, intermediates, and APIs it is not recommended to use these toxic materials in areas where open product handling occurs.