In any industry, manufacturing operations must be carried out under clean and hygienic conditions. However, in the pharmaceutical industry, the condition of the premises assumes critical importance because of the nature of the products being manufactured. Both the external and internal environments must be geared to be conducive to maintain the quality and safety of drug products. Special care must also be taken to prevent contamination of the products and therefore, the location, design, construction, and layout of premises is a vital part of the Good Manufacturing Practices (GMP) regulations. ‘Premises’ refers to the buildings and facilities where pharmaceutical processing is done. These places must comply with cGMP requirements.
Premises must be located in a site that is of a size suitable to house all the different departments. The nature of manufacturing and testing to be performed, the magnitude of the operation in terms of daily production levels, the number of products that will be processed, and the storage space required for raw material, in-process and finished goods are some of the important factors to be considered when choosing a location. Other factors such as availability of power, water, labor workforce, and closeness to transport hubs may also impact this decision. From the GMP point of view, the most important factor is the climatic condition and hygiene levels in the surroundings. Pharmaceutical premises must ideally be located away from polluting industries as otherwise, it will burden the air handling and water handling systems.
According to Schedule M of the Drugs and Cosmetics Rules, factory buildings must be situated in a place that avoids contamination risk from the external environment (for example from open drains, public lavatory, open sewage lines, or industry that produces gaseous fumes or strong odors or generates smoke, dust or other chemical emissions).
Design and Construction:
The building used must be designed, constructed, and maintained in a manner that permits drug production under hygienic conditions. It must be suitable for the operations being performed. The layout of the premises must be such that it reduces the risk of errors, and also avoids the buildup of dirt and cross-contamination that may affect drug product quality. Construction and layout of the building must allow for a sequential and logical flow of the production process and movement of personnel and materials. It must also permit regular cleaning, repair, and maintenance work without harming product quality.
The walls, ceilings, and floors of the building must be smooth and crack-free, easy to clean and disinfect. Surfaces must not shed particles; they must be kept smooth and without any open joints where dust can accumulate.
The building must be supplied with adequate light, water, power supply, and ventilation and must be fitted with systems to maintain the temperature and humidity of different areas at desired levels. There must be arrangements to protect against the entry of pests, insects, rodents, etc.
The fittings, ducts, pipes, and ventilation points must be designed in such a way that they do not produce difficult-to-clean recesses. Such points must be located to be easily accessible for maintenance work without having to enter the manufacturing areas.
Sensitive drug manufacturing areas must be air-conditioned to achieve the optimum temperature and humidity conditions. All areas must receive filtered air – the filtration and air change rate must be designed to achieve the desired clean area classification. Some of the important factors that influence this rate include the quality of the input air, size of the room, the heat load of the room, room pressure to be maintained, dust generated during processing in that room, number of personnel working in the room, etc. An air change rate of 6 to 20 air changes per hour is the norm.
Lighting facilities too must match requirements – for example, visual inspection areas must be brightly lit; light-sensitive drug manufacturing requires amber lighting provisions, etc.
Water systems shall be installed to provide water of quality commensurate with the requirements of the drug product. Potable water may be used for washing and cleaning but better quality water as purified water or distilled water must be used during the manufacturing and testing operations. Water storage tanks must be designed to maintain the quality of the water and prevent microbial growth.
All areas inside the building must be cleaned regularly and cleaning records must be maintained. Drains must be sized correctly and be designed to prevent back-flow of contents. They must be closed as far as possible; if open channels are unavoidable, they must be kept shallow to allow easy cleaning and disinfection.
Wastes from the manufacturing area must be disposed of in keeping with regulations of the Environment Pollution Control Board. Waste materials that have to be disposed of must be stored safely. Any wastes that are inflammable, hazardous, or toxic must be stored in a segregated area while awaiting disposal. Bio-medical waste must be disposed of as per regulations of Bio-Medical Waste (Management and Handling) Rules, 1996. Rejected drugs must be stored separately and destroyed in keeping with regulations.
Restrooms, toilets, and refreshment areas must be located far from manufacturing areas. They must not be in direct communication with areas where materials are manufactured, tested, or stored. Animal testing laboratories too must be isolated from these areas, with separate entrances and dedicated air-handling systems.
Sanitation of Sterile Areas:
Sterile areas must be cleaned and sanitized often in keeping with an approved cleaning protocol. More than one type of disinfectant must be used to ensure effective bactericidal action. Regular monitoring of cleanrooms must be performed to detect the presence of contaminating microorganisms. Cleaning procedures must be validated to verify that disinfectant residues are detected and removed during cleaning. Detergents and disinfectants used in sterile areas must be sterile before use. For spaces that are inaccessible inside the sterile room, fumigation may be used to reduce microbial contamination. Occasional cleaning with a sporicidal agent must be part of the cleaning routine since spores are resistant to the common disinfectants.
The temperature and relative humidity of the premises must be controlled to ensure the area complies with material and product requirements, as well as regulatory requirements. Attention must also be given to operator comfort wherever possible. Airlocks must be built to separate low-humidity areas from higher humidity areas; this prevents the migration of moisture that would otherwise overload the Heating Ventilation and Air Conditioning (HVAC) system.
The systems used for humidity control must be designed to avoid introducing any contaminants.
Dust and vapors must be extracted at the source and not allowed to travel elsewhere. The dust extraction system must have adequate transfer velocity to make sure that the dust is truly carried away and does not merely settle into the ducting of the system.
The general direction of airflow in a room must be designed to remove vapors and dust generated in the area. It must also consider the location of the operator to make sure he/she does not contribute to contamination. It is often preferred to introduce air into the room using ceiling diffusers, and extract the room air through vents at low heights on the wall to provide a flushing effect as the air moves out of the room. In the case of processes that generate a vapor that is lighter than air, the extraction grilles will need to be positioned at a higher level.
World Health Organization (WHO) defines contamination as, “The undesired introduction of impurities of a chemical or microbial nature, or of foreign matter, into or on to a starting material or intermediate, during production, sampling, packaging or repackaging, storage or transport.”
The most common sources of contamination are dust, skin, hair, microorganisms, grease, chemicals, and particulate matter. Such contamination can be controlled by controlling the environmental conditions as well as personnel factors.
Environment control is exerted by having a well-designed HVAC system that efficiently removes the contaminants that may get introduced. Regular cleaning and controlled entry and exit of materials and personnel into the clean areas can also help avoid contamination.
Personnel hygiene is a must and they must be trained to follow the prescribed dress code, procedures for entry and exit into clean rooms, and gowning procedures.
Cleanroom refers to a controlled environment where the level of contamination is kept very low to meet requirements specified in terms of the number of particulates per cubic meter. To achieve this controlled environment, air enters the cleanroom through High-Efficiency Particulate Air (HEPA) filters that remove particles greater than or equal to 0.3 microns in size.
US Food and Drug Administration Guideline for Air Classification
Cleanroom Classification as per Schedule M
WHO Air Classification System for Manufacture of Sterile Products
WHO defines cross-contamination as, “Contamination of a starting material, intermediate product or a finished product with another starting material or material during production.”
Manufacturing areas must be designed to prevent both contaminations of drug products and cross-contamination between products. Contamination may be avoided by controlling the quality of air in a room and by ensuring hygiene and clothing change of workers entering into the manufacturing area. Cross-contamination is a little more difficult to control.
The risk of cross-contamination is greater when dry material processing takes place because dust is generated and spreads rapidly. The most common sources of cross-contamination include dust, vapors, gases, particles, sprays, residues on equipment surfaces, operator’s clothing, or skin.
The most dangerous contaminants include sensitizing materials, hormones, living organisms, cytotoxic materials, and highly active compounds.
Measures to Prevent/ Reduce Cross-contamination
1. Manufacturing the product in dedicated areas which are self-contained.
2. Manufacturing on a campaign basis – complete the production process and then ensure a thorough cleaning before starting a new product batch on the same line.
3. Using premises that are appropriately protected through airlocks, air-extraction systems, and pressure differentials.
4. Preventing re-entry or re-circulation of untreated air.
5. Using protective clothing.
6. Regular testing for the presence of residues.
Preventing Dust Migration in Non-dedicated Facilities
Sometimes, it may be necessary to manufacture different products in different areas of the same premises. In such situations, care must be taken to ensure dust from one area doesn’t move into another area where a different product is being processed.
Containment of air is achieved by two methods – displacement or pressure differential.
This concept relies on maintaining a high airflow in combination with a low-pressure differential. It is often used in areas where dust generation is high. Air is supplied into the corridor, from where it flows through the doorway and into the room, and gets extracted out from the back of the room. The room door must be kept closed and air entry is through a door grille. The air should move with a velocity that’s high enough to ensure no turbulence in the doorway may cause dust to escape.
Pressure Differential Concept:
This relies on the use of low airflow in combination with a high-pressure differential. This concept works best in areas that are no-dust or low-dust. The pressure differential between clean and less-clean areas must be great enough to ensure air containment and prevent reverse-flow of air; however, it must not be high enough to cause turbulence in the area. Generally, pressure differentials of 5Pa to 20 Pa are acceptable; the most commonly maintained value is 15 Pa. Too low-pressure differentials must be avoided because they lead to a reversal of airflow, and contamination. If unavoidable, it is advised to simultaneously use airlocks too.
These areas must be fitted with devices to control and monitoring devices that must be qualified before use. Regular calibration of these devices is also necessary. There must also be an alarm system linked to the pressure controller to alert personnel to any critical change in the pressure differentials.
The barrier which separates two controlled areas is called an airlock. It generally has two or more doors to regulate the movement of air. Airlocks can be of three types – cascade type, bubble type, and sink type.
(a) Cascade airlocks: These airlocks have lower pressure on one side, and higher pressure on the other side. For example, in tablet manufacturing areas, the corridor is at higher pressure, and the cubicle where drug processing occurs is at lower pressure. Thus, air moves from the corridor to the cubicle and prevents the dust-containing drug from entering the corridor.
(b) Bubble airlocks: These airlocks have higher pressure inside than on both outer sides. For example, in parenteral manufacturing areas, the high-pressure inside drives air away from the room into the corridor. Thus, entry of contaminants that may damage the drug inside the sterile cleanroom is prevented.
(c) Sink airlocks: Here, the pressure on both sides of the airlock is very high so that no contaminant can escape from the cubicle. This type of system is used in facilities used to manufacture harmful substances like toxins or poisons.
In all these airlocks, doors must open into the side having higher pressure so that it will close automatically and faster. The airlock must be designed with an interlocking system so that both doors cannot open at the same time. The opening of either door must be linked to the sounding of an alarm.
Air changes must be carried out at higher rates within the airlock – generally, 20 air changes per hour are the minimum prescribed rate. Airlocks must be empty; no material should be stored in them.
Additional Considerations Regarding Premises
Storage areas must have sufficient space for the materials to be stored in a systematic and organized manner according to their categories such as starting materials, intermediates, bulk products, finished products, packaging materials, released products, quarantined products, rejected products, recalled products, and returned products.
These areas must be clean, well-lit, dry, and be maintained at specified temperatures. In case of special storage conditions (for example, cold conditions), the conditions must be monitored and controlled.
Receiving bays must allow cleaning of incoming material if necessary. The received material must be kept in quarantine until sampling, testing, and approval. Entry to this area must be restricted. Materials that have been rejected or returned or recalled must be physically separated from other materials. Separate storage areas must exist for holding materials that are dangerous or highly active (for example – narcotics, highly inflammable solvents, radioactive materials, poisons, etc.).
Sampling areas for starting materials must be sufficiently separated to avoid contamination or cross-contamination.
Products that are highly active (such as hormones, antibiotics, cytotoxic drugs) or highly sensitizing (penicillin, for example) must be manufactured in dedicated and self-contained facilities. Other products must not be manufactured here.
In facilities where multiple product batches are being simultaneously manufactured, there must be measures in place to prevent cross-contamination. Besides, there must be sufficient in-process storage space to prevent the occurrence of mix-ups.
Quality Control (QC) Laboratory Areas
QC laboratories must be located in an area separate from production. In the laboratories, separate areas must exist for biological, microbiological, and radioisotope testing and these areas must have dedicated air handling units. Sufficient space must be provided for storing samples, solvents, reference standards, and laboratory records with no chances of mix-ups between different samples drawn for testing. Air supply to QC laboratories must be separate from the unit supplying air to production areas.
Instruments that are sensitive to temperature and humidity must be housed in separate rooms. Care must be taken to prevent vibrations and electrical interference from reaching them.
Pharmaceutical companies pay a lot of attention to setting up quality management systems and validation studies to ensure regulatory compliance. Along with this, they must pay attention to the maintenance of their facilities and premises so that there is no risk of product contamination which may lead to damaging situations such as a product recall. Having self-inspection programs, regular maintenance activity, and good housekeeping practices will ensure that companies remain in compliance with regulatory requirements.
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