Hospital pharmacy sterile drug preparation laboratories are subject to increasingly stringent regulations and requirements. With the publication of the new Pharmacopoeia XI guidelines and the increasing requirements of standards for the preparation of dietary mixtures, cytostatics or antibiotics, the guidelines for the design and organisation of rooms in which these medicinal products are prepared are changing. Increasing emphasis is being placed on the standard and quality of the materials used in construction and the functioning of the ventilation system, in order to ensure the desired class of cleanliness in accordance with GMP.
According to the requirements of the Pharmaceutical Law, GMP requirements and the Pharmacopoeia, sterile medicinal products must be prepared in a Class A cleanroom in a Class B environment. Class A is customarily a laminar flow cabinet, placed in a Class B room, which is the preparation and holding space for the product being prepared. According to Good Manufacturing Practice guidelines, a Class A cleanroom in a Class B environment is a set of rooms with the highest requirements for particulate air purity and microbiological purity. The detailed requirements for these parameters are described in Annex 5, Annex 1 of the Regulation. The design process for this type of room requires consideration and knowledge on the part of the architect, tradespeople and installers, as it is very easy to create an oversized room with the wrong parameters for positive pressure and number of air changes, with the consequence of being unable to maintain the cleanliness class in the future or very high room maintenance costs.
In this publication, we would like to ask ourselves - if the preparation of a sterile drug laboratory, purity class B, is such a complex task - where does the role of the pharmacist begin? Is collaboration between the user and the designer, and later the contractor, necessary?
To answer this question, we need to start with the process of designing the laboratory rooms. A structure called the room division concept is created during the initial meetings, consultations with the architect. The concept shows the location of the sterile drug preparation room, personnel and material airlocks, doors, serving windows and equipment. At the final stage, the ventilation system (HVAC) elements can be plotted, visualising the cleanroom zones. It should be borne in mind that all elements of such a concept should ultimately comply with current building code and industry requirements. It should also be kept in mind that only a dialogue between the designer and the user will produce the desired result.
Is collaboration between the user and the designer, and later the contractor, necessary
At this stage, it is extremely important for the designer to be aware of the type of processes and their flow in terms of planning the flow of personnel, materials and substrates correctly. When we say flow, we mean the way in which people, equipment and waste are transported so that all the requirements of the standards regarding the non-crossing of clean and dirty routes are met. At this stage, the pharmacist's knowledge of the drug product preparation processes, the requirements for waste storage and disposal, and how many people are involved in the production process at the same time will be helpful. Even if one does not have this knowledge, can benefit from the expertise and experience of an external consultant.
The creation of the room division concept initiates the design process and the creation of the architectural documentation. According to GMP requirements, in parallel to this process, the user should prepare a document called User Requirement Specification (URS). This is reflected not only in pharmaceutical law documents but also in general guidelines such as ISO 9001:2000 - Definition of product-related requirements.
- legislative guidelines
- process description
- critical environmental parameters
- requirements for wall, floor and ceiling constructions
- requirements for HVAC
- requirements for the cleanroom qualification process
- personnel and material loads
- other process-specific guidelines
- requirements for BMS/RMS
The URS is created both when carrying out construction/reconstruction under the 'design-build' formula and under decoupling formulas. In the implementation of the design-build formula, the URS is the basis for the creation of the Functional and Utility Programme (FUP), which is used to determine the planned costs of design works and construction works, description of the subject matter of the contract, preparation of the offer, especially with regard to calculation of the offer price and performance of design works.
The role of the pharmacist is particularly important here, as it is up to him/her to determine how detailed the URS will be, how much information necessary to meet the requirements of pharmaceutical law will be included in it. The more the user is involved in the process, by searching and collecting information about materials and requirements for the cleanroom, the more useful content, from a design point of view, the URS will contain.
Once the concept of sectioning the rooms and the User Requirements Specification have been successfully completed, it is time to design the materials to be used for the laboratory and the building elements.
Basic guidelines that support the user in the organisation of a cleanroom include ISO 14644 and the CSM (Cleanroom Suitable Materials) agreement. Equally important are industry standards, which in the case of hospital pharmacy include: Standards for Parenteral and Enteral Nutrition or Quality Standards in Oncology Pharmacy of the Polish Pharmaceutical Society. The ISO standard and the CSM provide guidance on the type of materials to be used for walls, floors or ceilings in controlled areas.
According to the information contained therein, all materials dedicated to cleanrooms must not release particles from their surface and should be resistant to mechanical damage, cleaning agents and disinfectants. The universality of these guidelines means that they can be applied to virtually any industry that is required to operate a production process in a cleanroom. At the same time, these regulations impose strict requirements on the contractor, which means that latex paint on the walls or porcelain stoneware on the floor will not be allowed. It will also not be possible to place plasterboard on the ceiling, as is often the case. In place of the walls, there will be pharmaceutical panels made of galvanised, powder-coated steel. Sockets, fittings and all connections will be routed in the panel. Connections at the joints of the modular construction, siliconised with a special sealant designed for cleanrooms.
When selecting ceilings, the acceptance criteria will be similar to those for walls. Due to the direct contact of the black zone, with the ventilation duct system and electrical installations, with the cleanroom zone, cleanroom ceilings are subject to special attention. The use of traditional technologies with plasterboard is not a good solution in this case. In addition to dustiness and the limited durability of the material (e.g. during failure, flooding, etc.), these solutions have another key disadvantage, their connections do not guarantee the tightness of the entire system. This means that contaminants can move from the black zone to the clean class, thus generating product contamination. For this reason, metal ceiling solutions will be used in the cleanroom, in the form of tiles with a 600x600 mm grid, hung on a metal frame and siliconised. Such solutions will also guarantee much greater resistance of the material to pressure differences between rooms and clean zones.
An equally important element in a cleanroom is the floor. Made of high-quality resin or in the form of PVC flooring, it complements the modular construction. The floor must be characterised by exceptional resistance to mechanical damage and durability in use. The choice of flooring for a cleanroom also depends on the type of load that the surface has to bear when transporting heavy loads or when accumulating the finished product on pallets/cuvettes.
The user should prepare a document called User Requirement Specification (URS)
A separate issue is the requirements for HVAC systems for cleanrooms. To achieve a high ISO cleanliness class, 6-8 air changes per hour are not enough. Protecting the product from particles and the threat of biological agents requires a protective barrier. This barrier is made up of pressure and air, which, when injected into the room quickly enough and in sufficient quantity, washes personnel, products and equipment of contaminants. When designing the clean zone, the requirements of ISO 14644 should be taken into account, including the fact that a min. 10-15 Pa difference in pressure. In practice, this means that in cleanliness class B, the smallest number of overpressure bars will be 45 Pa, assuming that only personnel locks lead into the room.
In addition, the air handling unit should be hygienically designed in accordance with the VDI 6022 and VDI 3803: 2010 guidelines and meet GMP criteria in the following respect:
- all construction materials must be resistant to common disinfectants and cleaning agents
- internal covers must be made of materials with chemical and mechanical properties resistant to scratching during cleaning
- all components of the air handling unit must be easily accessible for cleaning,
- the drainage system must allow for efficient drainage after intensive cleaning and protect the device from secondary contamination,
- the components exposed to degradation due to humidity should be made of stainless steel, e.g. heat exchanger frames, condensate drainage trays,
- lighting should be installed inside the unit
- inspection windows should be used to allow checking cleanliness inside the unit without stopping its operation
- smooth surfaces should be used on the inside of the unit and materials should be used to eliminate protruding sharp fasteners such as sheet metal screws
- full air tightness of housing and door is required
The final stage of design is to delineate the requirements for the RMS.
The name RMS is an acronym for: Room Monitoring System. As a separate installation, it is used in areas of industry or laboratories that require continuous monitoring of the production and storage environment. The most important tasks of an RMS are to warn of exceeded environmental conditions and to archive data on prevailing conditions for quality control and product safety monitoring purposes.
The RMS system should provide continuous monitoring of parameters in the cleanrooms of the hospital pharmacy. LCD displays indicating the value of the temperature, positive pressure and humidity parameters should be mounted on the walls, at the entrance to each cleanroom so that staff can monitor the environmental conditions before starting work. The user must not enter a room where the environmental parameters are different from those set, as this may indicate a problem in the operation of the HVAC system.
The RMS should also support refrigeration equipment, i.e. fridges and fridge-freezers and freezers throughout the hospital pharmacy. The RMS should be a subordinate unit to the BMS but at the same time be able to operate independently of the BMS.
The key benefits of the correct design of the RMS system present themselves in the correct functioning of the laboratory premises, including:
- continuous monitoring of critical air parameters such as pressure cascade, temperature and relative humidity
- continuous monitoring of temperature in cooling equipment,
- monitoring the power supply status of critical equipment (heaters)
- visualisation of the status of individual parameters in selected rooms
- notification (alarming) of exceeding admissible limits for critical parameters
- recording and archiving of values of monitored parameters and system operation
- alarming, reporting
At each step in the design of the laboratory, the pharmacist should provide oversight. Participating in the conception of the room division, constructing the URS and actively participating in the process of delineating the industry requirements provides a solid basis for building a laboratory that meets the highest requirements of pharmaceutical law and operates smoothly for many years.
