1. Purpose
The purpose of this Guideline is to provide guidance on the design and specification of utilities associated with the manufacture, quality control and storage of API, intermediates and investigational products within an R&D facility.
2. Scope and Applicability
This Guideline applies to the manufacture, testing and storage of investigational medicinal products for human use or for stability studies intended to be filed with the NDA/MAA submissions within R&D.
3. Definitions
3.1 Potable Water (Non-Compendial Water)
Water, that as a minimum, meets national standards for water intended for human consumption that have been documented as at least equivalent to World Health Organization (WHO) guidelines.
The national standards for the USA, Europe and Japan meet or exceed the WHO guidelines. Potable Water is also known as Drinking Water.
3.2 Purified Water
Water produced by a suitable method (e.g., deionization, reverse osmosis, distillation, etc.) from Potable Water to meet specifications as defined by a compendial monograph.
3.3 Water for Injection (WFI)
Water produced by a suitable method (e.g. distillation) from Potable Water, usually with an intermediate purification step(s), to meet specifications as defined by a compendial monograph.
3.4 Building Management System (BMS)
System management hardware and software systems that allow computerized automation or microprocessor controlled operation, data collection and management of HVAC systems.
3.5 Classified Areas
Pharmaceutical facility areas that require validated and controlled environmental air systems.
3.6 Clean (Pure) Steam
High quality steam produced from purified water (or better) with a distribution system constructed of non-rusting materials and used in applications that may directly contact product contact surfaces.
3.7 Heating, Ventilation and Air Conditioning Systems (HVAC)
Systems made up of mechanical, air filtration and electrical devices to create and maintain specific levels of temperature, humidity, pressure differentials and airborne cleanliness for designated environments.
3.8 High Efficiency Particle Air Filter (HEPA)
Filters designed to provide air that is 99.97% particle free for particles 0.3µm and larger, reduce microbial air contamination and provide a uniform velocity of air along parallel flow lines.
3.9 House Steam
Steam produced from potable, softened or deionized water with a distribution system made of iron or steel and treated with additives to minimize corrosion and only used in applications with non-product contact.
3.10 Utility System
Basic site or building services (power, water, etc.) required to operate a pharmaceutical facility.
4. Responsibilities
4.1 Line Management
The Line Management of R&D in conjunction with Engineering & Facilities at each site is responsible for:
* Ensuring that the utility systems of the respective facility are adequately designed, installed, qualified and maintained to meet cGMP and business requirements.
4.2 R&D Quality Management
R&D QA is responsible for:
* Ensure that appropriate systems are in place to operate a pharmaceutical facility.
* Approving plans, protocols and final reports relating to the installation, qualification and use of the utilities associated with the development, manufacture, quality control and storage of API, intermediates and investigational products.
5. Guideline
5.1 HVAC
5.1.1 General GMP Requirements
The HVAC system must be designed appropriate to the products (APIs, intermediates, investigational products) handled and operations performed.
Manufacturing area HVAC systems must prevent the infiltration of contaminants from external sources including recycled exhaust air, and cross contamination between HVAC systems must be avoided. Additionally, these systems require qualification/validation and change control procedures.
For warehousing and product storage areas temperature monitoring and where appropriate temperature control is required.
Building Management or Monitoring Systems used in the control and monitoring of critical HVAC data in classified areas must be validated.
5.1.2 Air Quality
The quality of air needed in classified areas is based on the products handled and operations performed.
Air quality and air classifications for non-sterile operations must be designed to follow appropriate regulatory requirements and industry practices. For APIs the level of product exposure and the point in the manufacturing process should be considered when defining the air quality required.
Additional restrictions must be defined when handling, processing and storing highly potent materials such as antibiotics, hormones, radioactive materials or cytotoxic compounds. In addition, products that could cause potential allergic reactions such as penicillin and cephalosporins must be effectively controlled via the use of dedicated and separate facilities. HVAC systems serving microbiological laboratories must be separate from HVAC systems serving production areas.
5.1.3 Air Quantity/Air Flow Patterns/Room Pressurization
The requirements for the HVAC system to deliver the appropriate quantity of air for defined purposes for a room or work area must follow available international standards.
5.1.4 Temperature and Humidity
Requirements for temperature and humidity must take into account the needs of the product, process and employees.
5.2 Water
5.2.1 Water Systems
Water used in pharmaceutical operations must be suitable for its intended use and if processed to achieve defined quality, the treatment process must be validated and monitored with appropriate action and alert limits.
5.2.2 Potable Water
Typical use of potable water is manufacture of non-sterile APIs, washing of API manufacturing equipment and initial washing of formulated product manufacturing equipment.
5.2.3 Purified Water
Used typically as ingredient water in manufacturing non-sterile dosage forms and is the preferred water used in the final purification step for the manufacture of APIs. Further typical use is for final rinsing of manufacturing equipment for non-sterile dosage forms and for certain laboratory uses.
5.2.4 WFI
Used typically as ingredient water in sterile product manufacturing and for final rinse of equipment used in sterile product manufacture.
5.3 Steam
There are primarily two types of steam systems used in the pharmaceutical industry, house (plant) steam and clean steam. Each system must meet the minimum qualitative and quantitative specifications defined in the user requirements at each point of use at the pressure specified.
House steam systems may use potable, softened or deionised water and may be constructed of iron, steel or stainless steel. Additives such as hydrazines or amines are permitted to reduce rusting and condensate may be reused. House steam must not be used in applications for which contact with product or product contact surfaces is possible.
Feed water for clean steam systems must be purified water. The materials of construction must be stainless steel or other non-rusting material and no additives of any type may be used. Condensate may or may not be reused.
Clean steam quality must be tested at use points against USP/EP, monograph “Water for Injection”.
For the sterilization of porous loads steam quality testing must be performed for steam systems supplying moist heat sterilizers.
5.4 Electricity
Electrical systems in use throughout R&D vary greatly from site to site and system to system, but there are some minimum parameters that should be reviewed. The system must meet specification requirements for frequency, phase and voltage stability during periods of use. There must be schematics and documentation of all system components and use points.
For critical systems back up supplies or un-interruptible power supplies should be considered.
5.5 Compressed Air Systems
The installation and operation of compressed air systems within the cGMP areas of each facility must be defined and monitored. Requirements for air contacting product include validation of the system, and as a minimum absence of moisture, limit for hydrocarbons/oil and instructions for filtration according to international standards and compendial monographs.
5.6 Other Gas Systems
All gas systems, for product contact, including nitrogen, oxygen or other gases must meet minimum purity and quality specifications as defined by the process requirements. Gas supplies must be tested or certified to meet all quality and purity requirements as appropriate according to international standards and compendial monographs.