Identifying the most practical approach to achieve Good Manufacturing Practice (GMP) cleanrooms and cleanroom HVAC in the pharmaceutical industry does not require an “out of the box” or innovative approach. It rests, rather, on the comprehension of and adherence to a set of basic rules that have been penned by several GMP regulatory authorities. Rules are nevertheless open to subjective interpretation and herein lie some potential pitfalls. The International Society for Pharmaceutical Engineering (ISPE) provides invaluable and much needed guidance in this regard.
The most commonly used GMP regulations that govern the design of pharmaceutical cleanrooms and cleanroom HVAC systems include the EU GMP, PIC/S GMP, FDA cGMP, and WHO GMP.
What is clean and how particlebased cleanliness is specified depends on what standards are applied. The world community of cleanroom designers mostly follows the ISO 14644 standard family for this purpose. Cleanroom designers and builders should concentrate on the first five parts of the standard family depicted in Table 1.
ISPE has provided a set of tools that facilitates a clearer understanding of the application of di€fferent GMP regulations, standards and guidelines in everyday work. Without these baselines it would be difficult to find suitable solutions to GMP matters. ISPE creates a bridge between pharmaceutical engineers and regulative authorities by writing baselines, good engineering practices and monthly articles in its ”Pharmaceutical Engineering” magazine.
The ISPE publication series includes ISPE Baselines, ISPE GAMP Guidance documents, ISPE Guides and Good Practice Guides, ISPE Investigational Products Resources, and ISPE Regulatory. This excellent source of reference information combined with engineers’ practical experience allow most clients’ GMP related questions to be solved. Local laws and codes naturally have to be applied in every aspect in order for project goals to be fulfilled. Once a project has started the ISPE general V-model should be followed (see Figure 1)
According to the V-model all GMP projects should start with a properly executed risk assessment based approach which leads to the appropriate Validation Master Plan (VMP) and finally to project-specific User Requirement Specification (URS). All GMP cleanroom projects should follow this generally accepted route:
Every phase has to be approved and completed with documented confirmation before proceeding to the next phase. It all starts from the user requirements and ends with the very same user requirements. All requirements in the URS need to be fulfilled or approved with documented deviations.
User requirements:
When the URS for cleanrooms or cleanroom HVAC is written in the conceptual design phase by the plant operator (often with engineers’ assistance) and approved, one can proceed to the basic design phase (or the functional design). the URS is arguably the most important document in the whole GMP project as it defines all the users’ (GMP) critical demands for the process, clean utilities, cleanrooms, cleanroom HVAC and black utility. URS in the GMP context means a documented definition of the key requirements stated by the user.
The URS must state what GMP regulations should be followed and what cleanliness grades are required. EU GMP and FDA cGMP requirements are the two mostly referred to but also WHO and Japanese regulations can be used if applicable.
Cleanrooms can be constructed in various ways, but the first thing that has to be solved is the layout, which is governed by basic rules. Figure 2 displays the main principle of a shell-like barrier system where the cleanliness grades are always separated by personnel airlocks, material airlocks or pass-through cabinets.
Layout design should only be started once a clear understanding of the user requirements has been gained. The basic rules for airlocks and pressure cascading regimes should, however, be checked first. Here again ISPE has some useful models. See Figure 3 (overleaf ) for a layout with cleanliness grades and pressure cascading.
There are some diff€erences in cleanliness grades between the US and EU which need to be kept in mind when designing cleanrooms for diff€erent regulatory environments. US GMP covers three cleanliness grades: supporting clean areas in two grades and critical areas. EU GMP includes four cleanliness grades: A, B, C and D. This di€fference aff€ects design especially when sterile drugs are produced in aseptic processing.
The crucial role of HVAC:
Once layout work is completed the HVAC designer can begin working. HVAC is only a small part of a cleanroom – but a very important part. Without a well-functioning HVAC system the desired conditions for production might not be achievable. HVAC systems for cleanrooms are relatively expensive and take up much space, but are essential for the critical product parameters.
HVAC systems also represent large operating costs. It firstly needs to be decided what type of ventilation principle would best satisfy the URS requirements: recirculated air or outside air? Recirculated air means a ventilation system where e.g. 80% of air flow is in constant circulation and only 20% is replaced with fresh air from outside. A 100% fresh air system uses non-recirculated air from the outside.
It is preferable to use recirculated air in a cleanroom ventilation system if it is not prohibited for any reason as the use of recirculated air reduces energy consumption and emission levels. Direct and indirect impact systems
It is of critical importance to determine whether the HVAC system has a direct or indirect impact on the product. According to the ISPE guidelines a direct impact system “is expected to have a direct impact on product quality. These systems are designed and commissioned in line with Good Engineering Practice and in addition, are subject to qualification practices that incorporates the enhanced review, control, and testing against specifications or other requirements necessary for cGMP compliance.” ISPE indicates that an indirect impact system “is not expected to have a direct impact on product quality, but typically will support a direct Impact system. These systems are designed and commissioned following Good Engineering Practice only. Indirect impact systems can affect the performance or operation of a direct impact system.”
Once the impact type of the system has been determined, the appropriate commissioning and validation activities can be applied.
Critical parameters:
The so-called critical parameters for products manufactured in a cleanroom environment need to be specified in the URS. According to the ISPE guidelines there are several factors that need to be considered and the onus is on the designer to gather all the relevant information (see the info box for details):
Validation of cleanrooms and cleanroom HVAC:
The first validation activity in cleanroom and cleanroom HVAC projects is the DQ whereas the last is the approval of all the required design documents. When everything is complete a design qualification (DQ) report is drawn up and signed. It is a generally applied approach that construction work cannot be started before design qualification is done.
The next step is construction, which is followed by commissioning (C), installation qualification (IQ), operational qualification (OQ) and finally performance qualification (PQ). Each has to be approved before the next step can start and approval of all steps has to be documented.
ISPE defines commissioning as a “well planned, documented, and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the end-user that results in a safe and functional environment that meets established design requirements and stakeholder expectations”.
Validation on the other hand “ensures that the facility and system qualification (DQ, IQ, OQ and PQ) requirements are communicated and met.”
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