1. Purpose
The purpose of this Guideline is to describe the requirements for meeting current Good Manufacturing Practice (cGMP) compliance requirements for new and upgraded facilities to be used for the manufacturing of any sterile and non sterile product. The Guideline also aims to provide recommendations on how to achieve compliance with the requirements.
This Guideline defines a consistent approach for establishing facilities for the manufacture of sterile and non-sterile products using the classification set out in, EU Good Manufacturing Practice (GMP) Annex 1, FDA 21 Code of Federal Regulation (CFR) and International Standardization Organization (ISO) 14644-1.
Specific technical details are beyond the scope of this document; however, individuals are referred to the International Society For Pharmaceutical Engineering (ISPE) Pharmaceutical Engineering Guides for New and Renovated Facilities for essential detail. Local legislation, regulatory requirements and engineering standards with respect to facilities will take precedence over this Guideline.
2. Scope and Applicability
This Guideline is applicable to all Operations, Marketing Companies (MCs) and Research and Development (R&D) sites, functions and departments undertaking work, or providing support services, required to meet cGMP or, in absence of a GMP standard, ISO standards. Manufacturing of Active Pharmaceutical Ingredient (API) is excluded from this Guideline.
3. Definitions
3.1 General Manufacturing Areas
Processing and packaging areas where GMP activities are taking place for non- sterile dosage forms. Minimum requirements are discussed with the recognition that additional engineering controls are needed as product potency, degree of separation, degree of exposure, extent of validation, and other considerations enter into particular site product mix and circumstances for example there are requirements for inhalation products being manufactured in Grade D.
3.2 Air Classification
Level (or the process of specifying or determining the level) of airborne particulate cleanliness applicable to a clean room and clean area, expressed in terms of EU Grades, which represents maximum allowable (in particles per cubic metre of air) for considered sizes of particles. The comparison between EU Grades, FDA classification and ISO classes are defined in appendix A.
3.3 Operational
Condition where the installation is functioning in the specified manner, with the specified number of personnel present and working in the manner agreed upon.
3.4 Clean Area
An area with defined environmental control of particulate and microbial contamination constructed and used in such a way as to reduce the introduction, generation and retention of contaminants within the area (Eudralex definition).
4. Responsibilities
It is the responsibility of each site or function to comply with established Guideline when designing new facilities.
It is the responsibility of each site or function to comply with established Guideline when upgrading existing facilities.
It is the responsibility of each site or function to ensure that their designers follow applicable parts of an established Guideline.
5. Guideline
5.1 General Design Aspects
5.1.1 Layout and Space
Any building or buildings used in the manufacture, processing, packing or holding of drug product must be of suitable size, construction and location to facilitate safe and effective cleaning, maintenance, and proper operations to protect the product. The design of the buildings combined with the appropriate operational procedures, must permit segregation of operations and an orderly and logical flow of personnel and materials. The layout must be designed to prevent mix-ups between different components, drug product containers, closures, labeling, in-process materials, or drug products; and must prevent cross contamination. The design of the buildings must minimize exposure of materials and products to the environmental contamination.
5.1.2 External Influence
The buildings must be constructed and maintained with the objective of protecting all manufacturing areas against weather, ground seepage and the entrance and harboring of vermin, birds, pests, pets, contamination from other industries/buildings etc. Additional protection is needed for the clean and controlled areas against particulate contamination, as defined in this Guideline.
5.1.3 Access
For product safety and security reasons, doors to production and storage areas must be secured such that access is only given to authorized personnel. Emergency exits should be sealed for day-to-day operations but providing immediate exit in case of emergency.
5.2 Environmental Conditions
All environmental conditions for clean areas must be classified and maintained in accordance with requirements in EU GMP Annex 1 and FDA 21 CFR, Guidance for Industry “Sterile Drug Products By Aseptic Processing”, September 2004, ISO 14644-1and IPSE Pharmaceutical Engineering Guides for New and Renovated Facilities, Volume 2, Oral Dosage Forms and Volume 3 Sterile Manufacturing Facilities as appropriate. Comparison tables for particles and microbiological organisms see Appendix A – B. Sites manufacturing for global markets should adhere to the strictest requirements described in Appendix A – B in order to meet all market requirements.
5.2.1 Environmental Conditions for Sterile Manufacturing
Sterile manufacturing must take place in clean areas. The areas should be classified in accordance with the requirements in Appendix A – B. All areas must be built and validated to meet these requirements.
The particulate conditions for Grade A should be maintained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. It is accepted that it may not always be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress, for example due to the generation of particles and droplets from the product itself. There should be written justifications for any situation or process steps where this could apply. The particulate conditions for the at rest state should normally be achieved in the unmanned state after a short clean up period of 15 – 20 minutes after completion of operations. This cleanup period should be validated and periodically monitored. In some cases, the processing room and the adjacent clean rooms have the same classification. Maintaining a pressure differential between the processing rooms and the adjacent rooms can provide beneficial separation.
In order to reach Grade A, B and C the number of air changes should be related to the activity of the room. Re-circulation of air within clean areas should not be practiced where the activities are creating dust. Re-circulation should preferably not be used to re- circulate air from areas where different products are handled. In cases where re- circulation is practiced the air should pass a filter system of an appropriate filter efficiency to minimize the potential for cross-contamination. The following activities performed during sterile manufacturing must be conducted in area classified in accordance with the tables below.
5.2.1.1 Terminally Sterilized Products
For those products that are sterilized in their final container/closure system the following apply:
| Grade | Examples of operations for terminally sterilized products |
| A | Filling of products, when unusually at risk *. |
| C | Preparation of solutions, when unusually at risk. Filling of products. |
| D | Preparation of solutions and components for subsequent filling. |
(*) When the product is at risk of contamination from the environment, for example because the filling operation is slow or the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing.
5.2.1.2 Aseptic Preparations
For those products that cannot be sterilized in their final container/closure system the following apply:
| Grade | Examples of operations for aseptic preparations |
| A | Aseptic preparation and filling. |
| C | Preparation of solutions to be filtered, crimping of vials and stoppered vials to be crimped after freeze-drying. |
| D | Handling of components after washing. |
5.2.1.3 Isolator Technology
The use of isolator technology to minimize human interventions in processing areas may result in a significant decrease in the risk of contamination of aseptically manufactured products from the environment.
| Grade | Examples of operations for isolator technology |
| At least D | The background environment for aseptic processing. * |
(*) The air classification required for the background environment depends on the design of the isolator and its application.
5.2.1.4 Blow/fill/seal Technology
The use of blow/fill/seal technology offers a number of aseptic advantages Including minimizing the time between the sterilization of the pack (in situ, on formation) and filling and sealing. Human interventions in processing areas are also minimized and protection is provided against contamination during filling and closing of units.
| Grade | Examples of operations for blow/fill/seal technology |
| A | Blow/fill/seal equipment used for aseptic production. |
| C | The background environment for blow/fill/seal equipment used for aseptic production provided that Clean Area A/B clothing is used. |
| D | Blow/fill/seal equipment used for terminally sterilized production. |
5.2.2 Environmental Conditions for Non-sterile Manufacturing
Non-sterile manufacturing should take place in general manufacturing areas. There are no cGMP requirements to classify these areas with the exemption of manufacturing of inhalation products, which must take place in Grade D. Good engineering practice (GEP) should dictate the basic requirements for these areas. The ISPE Pharmaceutical Engineering Guide for New and Renovated Facilities, Volume 2, Oral Solid Dosage Forms should be consulted. Re-circulation of air within general manufacturing areas should be justified and it should be taken into account process activities that create dust. In cases where re- circulation is practiced the air should pass a filter system of an appropriate filter efficiency to avoid cross-contamination and to prevent recirculation of dust from production. In areas where air contamination occurs during production, consideration should be given to provide localized exhaust systems or other means to minimize potential for cross contamination.
5.3 Production Areas
5.3.1 Layout
The layout of areas must minimize the possibility of product mix-ups. The adequacy of the working and in-process storage space must permit the orderly and logical positioning and separation of equipment and materials so as to minimize the risk of confusion between different medicinal products or their components, to avoid cross-contamination and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
5.3.2 Air Treatment (HVAC)
5.3.2.1 General
Production areas should be effectively ventilated, by air handling units (including filtration control and when necessary temperature and humidity control) appropriate to the products handled, to the operating personnel, to the operations undertaken within them and to external environment. Temperature and humidity controls should be considered in terms of potential adverse effect on the medicinal products during their manufacture and storage, or the accurate functioning of equipment.
Areas were aseptic processing takes place must have temperature and humidity controls. Temperature and humidity controls should, when used, be monitored. Operator comfort should also be taken into account when setting the requirements; particularly when operators wear suits made of synthetic non-breathing materials. Air treatment systems must be designed, validated and monitored to assure required particulate levels.
They must be capable of maintaining the desired positive or negative pressure differences and airflow relative to the surrounding areas of lower grade under all operational conditions. Air treatment systems should be operating continuously even when there is no manufacturing unless in the case of routine maintenance, repair or sustained downtime. The collection of dust in filters in exhaust systems should preferably take place as close to the source as possible. Appendix C summarizes the recommendations for final filters, Air Changes/hour, Pressure differential and temperature.
5.3.3 Alarm Systems
An alarm system must be provided to indicate failure in the supply or exhaust of air. Pressure differentials should be provided as required. These differentials should be monitored, recorded and alarmed as necessary.
5.3.4 Lighting
Adequate lighting must be provided in all areas. Particularly where visual on-line controls are carried out. Light fittings should be designed to facilitate cleaning.
5.3.4.1 Special Requirements in sterile Manufacturing
Lighting for clean areas and clean rooms should be designed to minimize the creation of recess.
5.3.5 Floors, Walls and Ceilings
Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, the floors, walls and ceilings should be smooth, free from cracks and open joints, and should not shed particulate matter. These surfaces should permit easy and effective cleaning, and if necessary, disinfection. All media installations that pass through floors, walls and ceilings must be properly sealed. Ceilings should be constructed to provide protection from less clean areas.
5.3.5.1 Special Requirements in Sterile Manufacturing
Floors, walls and ceilings must be constructed of smooth, hard surface, the materials between walls and ceilings/floors must be coved in Grade A and B.
5.3.6 Windows
Windows must be installed with tight connections to the wall. The number and area of horizontal surfaces in the installation must be kept to a minimum. Windows must be easy to clean, fixed and not capable of being opened. Windows should be in level with walls and ceilings.
5.3.7 Sinks and Drains
Separate process and sanitary drainage must be provided. Drains must be of adequate size and, were connected directly to a sewer, must be provided with an air break or other mechanical device to prevent back-siphonage. They must be easy to clean. The floor must slope locally towards the drain. Overflow outlets should normally not be used. Floor drains with minimal usage should be filled with vegetable oil or contain a trap primer in order to prevent the trap from drying out.
5.3.7.1 Special Requirements in Sterile Manufacturing
Sinks and drains should be prohibited in Grade A and B areas used for aseptic manufacture.
5.3.8 Installations
All permanent pipe work, light fittings, ventilation ducts and other services in classified areas should be designed and installed to avoid uncleanable recesses. Services should run outside the processing areas and should be sealed into walls and partitions through which they pass. The sealed pass through should be designed to withstand vibrations. Fixed equipment should be installed without any recesses where dirt can accumulate.
5.3.9 Airlocks
The use of airlocks should be considered as part of any manufacturing facility design. Airlocks are one means to control containment necessary due to process or product requirements.
Personnel airlocks may be necessary for connection of areas where dust- generating processes are performed or certain active substances are handled. Such airlocks should be provided with cleaning facilities as needed.
The airlocks must have a system in place to prevent the opening of entry and exit doors at the same time. This could be achieved by means of an interlocking system and the doors should be self-closing.
5.3.9.1 Special Requirements for Sterile Manufacturing
Personnel Airlocks
Changing rooms must be designed as airlocks and used to provide physical separation of different stages of changing and to minimize microbial and particulate contamination of protective garments. The changing rooms must be ventilated effectively with filtered air. The final stage of the changing room must, in the at-rest state, be the same grade as the area into which it leads. There should be a step over bench separating the final stage of the changing room from the entry area.
The use of separate changing rooms for entering and leaving the areas is desirable, particularly for changing rooms leading to Grade B areas, and should be designed-in for any new facilities or significant renovations. Hand washing facilities must be provided in the first stage of the changing rooms leading to Grade D or C areas. The use of sinks and running water is undesirable in changing rooms leading to Grade B areas.
Shelves for storage of sterile garments should be provided. A full-length mirror with an enlarged picture of the proper gowning orientation should also be provided for all personnel to check their gowns prior to exit from the changing rooms. Design should be such that it is logical with respect to personnel and the gowning procedure and to minimize human-to-human contact.
Material Airlocks
Airlocks should be provided for the transfer of materials and equipment to and from Grade B areas, where double-ended sterilization equipment is not used for transfer. Double airlocks should be provided when the transfer is from Grade D to Grade B areas. Proper pressure and airflow regimes should be provided to assure air from lesser-classified areas does not move to the higher classification area. Suitable physical separation should be provided within the airlock to promote orderly transfer of materials from the lesser-classified zone to the cleaner zone. Similar principles to those required for personnel airlocks should be adhered to.
5.4 Highly Potent Materials
The requirements to handle highly potent materials such as certain hormones or antibiotics or cytotoxic agents are very specialized. Penicillin drug products must be handled in dedicated facilities. Specialist advice should be sought whenever handling of Penicillin as well as other B-Lactam drug products is being considered in any facility.
5.5 Areas for Sampling and Dispensing
Sampling and dispensing of raw materials and primary packaging materials must take place in areas designed for the purpose and which take into account the nature of the materials being handled from a personnel safety, toxicity, and dust generating (cross-contamination) perspective. Sampling and dispensing areas require, at a minimum, well-engineered controls to minimize any potential for cross contamination. Separate areas with suitable air supply and exhaust and dust control features are necessary. Monitoring of key control parameters for these areas (e.g. differential pressure) is necessary. Adequate space should be provided for equipment for sampling and/or dispensing. Operator comfort should be taken into account when setting the temperature and humidity requirements; particularly when operators are wearing suits made of synthetic non-breathing materials.