Air cleanliness plays a decisive role, especially in the manufacture of sterile medicinal products. Specifications on air cleanliness can be found in Annex 1 of the EU GMP Guide, in ISO 14644 and in the FDA Guideline on Aseptic Production.
Basic requirements for the GMP compliant design of pharmaceutical workrooms are described in the EU GMP Guide Part 1 in Chapter 3. Additional specific requirements for pharmaceutical cleanrooms can be found in Annex 1 of the EU GMP Guide.
A cleanroom class is not only defined by the air cleanliness grade, but also takes into account a number of other design criteria.
Annex 1 defines the air cleanliness grades A–D for the manufacture of sterile products. In ISO 14644 and the FDA Guideline similar air cleanliness classes are described which differ in detail. This often results in misunderstandings in the interpretation and practical implementation, which can be avoided by consulting technical experts.
There are no binding room classification specifications for rooms used for non-sterile production. However, such a classification can be derived on the basis of the existing air cleanliness grades.
The classification of cleanrooms is confirmed as part of the qualification process. During classification, different operating conditions must be taken into account, which differ with regard to the limit values for particles and germs as well as the associated measurement methods.
Annex 1 (2022) requires manufacturers to create a Contamination Control Strategy (CCS). This overarching document shall define the cleanliness zone concepts with all critical control points. It should include effectiveness assessments of all design, procedural, technical and organisational controls and monitoring measures used to manage the contamination risks.
Compliance with the GMP requirements for clean rooms is achieved through structural design, air handling technology and hygiene measures. These measures are to be defined in advance in the CCS with responsibilities, acceptance criteria, alarm and action limits as well as the procedures and the necessary countermeasures.
Annex 1 provides examples for the assignment of various aseptic and sterile manufacturing process steps to the defined air cleanliness grades.
The term air handing technology is subdivided into the two categories “air handling technology for rooms” and “process air technology”.
In the field of pharmaceuticals manufacturing the basic types of air handling units used are:
Ambient air is interspersed with different substances of various particle sizes and various types. This mixture of substances is to be removed using air filters to a degree that the specified cleanliness standards in a production are upheld.
When developing the design concept of an air handling system for a pharmaceutical manufacturing facility, the external conditions and situation of the site, the requirements placed on the rooms, the climate factors influencing the production process and the requirements associated with the layout must all be known.
During detailed design of the ventilation system the following criteria must be reflected:
The safe, functional and economic operation of an air handling unit in a pharmaceutical environment requires a defined maintenance system and the process/product critical work must be described in the CCS.
The maintenance program includes various activities: inspections serve to identify and assess the current state of the equipment, planned maintenance serves to maintain the desired target conditions and overhauling is necessary to reinstate target conditions.
Production premises and their associated utilities and infrastructure, including air handling units, are of essential significance to the quality of pharmaceutical products. Thus, their qualification is a requirement.
The qualification should be limited to aspects and parameters which have significant impact to product and personal safety according to the risk assessment; for all others, which are required for proper technical functioning of the premises and air handling units, technical acceptance testing according to GEP is sufficient.
The basis for demanding qualification projects is provided by a Qualification Master Plan derived from the User Requirement Specification. One differentiates the process into four consecutive qualification stages. The conclusion of each qualification stage is documented via a qualification report. The scope of the qualification activities depends on the complexity of the construction project and the requirements derived from the product characteristics, for example and the air purity. Comprehensive checklists are meant to help define the qualification effort in sufficient scope and detail.
The equipment, facilities and operating systems shall be evaluated at a sufficient frequency in order to confirm its qualified status. The possibility should be evaluated that minor changes occur over time. Equipment, facilities, plants and systems are to be evaluated at sufficient intervals in order to confirm their qualified status. The possibility that minor changes occur over time should be considered. If there be a need for re-qualification and this is performed at certain temporal intervals, different from those listed in Annex 1, these intervals are to be justified and the success criteria for requalification are to be defined.
Water is one of the most important starting materials for the production of pharmaceuticals and has a decisive influence on product quality. It is therefore subject to defined quality criteria. These quality criteria must be monitored and adhered to in routine operation. The monitoring of the operation of a water treatment, storage and distribution system is supported by certain GMP regulations. These rules and the resulting measures aim to maintain the qualified condition and thus continuously ensure the required water quality.
To ensure the quality-compliant operation of a water system, the regulatory requirements must be translated into company-specific specifications within SOPs. In addition to the SOPs for operating the water system, a service level agreement for maintaining the system is also important.
Malfunctions and failures are unavoidable in practice. Appropriate measures must be defined based on risk analyses to control and handle such situations.
Rouging is a surface phenomenon that occurs frequently in water treatment plants. Moderate rouging has no adverse effect on water quality, but appropriate monitoring measures should be established. Various chemical and electrochemical methods are available to remove rouge deposits.
Another surface phenomenon is the formation of biofilms, which can have a severe impact on the microbiological quality of the water. Here, too, prevention or measures for timely detection and elimination are of utmost importance.
Regular sanitisation of the water generation plant and the storage and distribution system is the only way to prevent biofilm formation. It also serves as a quality assurance measure after maintenance. A distinction is made between thermal sanitisation, in which the system is flushed with hot water, cold sanitisation with ozone and chemical sanitisation with H2O2, for example, as a disinfectant.
In order to ensure the qualified status of the water system over its entire service life, required maintenance of the system components and calibrations of the measurement equipment must be carried out and documented at defined intervals. In addition, the qualification status of the plant must be checked at regular intervals by means of an inspection and, if necessary, restored by means of appropriate requalification measures.
If changes are made to the system, all measures must be planned and released in so-called change requests. All changes must be documented. In the case of critical or quality-relevant changes, a requalification must be carried out for the affected part of the plant.
The final decommissioning of the water system is part of the life cycle and must also be planned and documented.
(Herbert Bendlin, PhD; Fritz Röder)