Objectives of process monitoring
In the context of monitoring pharmaceutical production processes, i.e. the collection and recording of production-relevant data, the collection, recording and storage of data regarding air cleanliness and other parameters related to the air in production rooms is frequently required.
Distinction must be made between
Data important for product quality and safety must be collected, processed, recorded and stored in the pharma monitoring system of the HVAC system, which is an integrated element of the general pharma monitoring system of the production process. On the other hand: collection, processing, recording and storage of technical data relevant for the correct and stable operation of the HVAC system is the responsibility of that system's automatic control system which frequently is integrated into the general building management system of a facility.
Data management stipulations
Data proving the correct and stable operation of the HVAC system are an essential element of quality assurance in the context of manufacturing sterile and other sophisticated pharmaceutical products. As a consequence, such data become an integral part of the batch documentation. Which data require collection and recording, and to what extent, must be decided case-specifically for each production task. Computerized systems are employed for continuous or at least frequent collection, processing and storage of data. Such computerized systems are required to meet the regulatory requirements stipulated in Annex 11 to the EU GMP Guide and in the respective FDA determinations.
Computerized systems of this kind require validation (see GMP MANUAL Chapter 9 Computer System Validation). The most appropriate base for doing so is the exhaustive GAMP 5 Guideline edited by ISPE, the International Society for Pharmaceutical Engineering. The regulatory authorities of Europe and the USA have contributed substantially to the preparation of this guideline.
Core elements of computerized data protection schemes are:
Access to data must be assured for a long period of time: at least well beyond the expiry date of the product. In many nations also legislative requirements for data storage must be observed.
Automatic control systems of HVAC systems and the superior building management systems are, as a rule, not capable of being validated - due to their extensive ramifications throughout the entire building complex of a site. Therefore, it is imperative that data management for process monitoring purposes be completely independent from the building control system: it must be impossible for the building control system to interfere into process monitoring. Persons authorized for interference into the building control system will, as a rule, not have access to the pharma monitoring system.
Buildings and their HVAC systems employed, for example, for the manufacture of sterile products, will require monitoring of both physical and microbiological parameters. At today's state-of-the-art only physical measurement parameters permit data collection, recording, evaluation and long-time storage by means of automatic computerized systems. Only computerized systems are capable of generating and recording automatic alarms.
Where the continuous collection of measurement data makes little sense or where this is impossible due to fundamental reasons - as, for example, data collection with present-day microbiological procedures - measurements may be performed and recorded manually. A physical parameter for which manual measurement is indicated is surveillance of the pressure difference between the upstream and the downstream side of HEPA filters. Here quarterly, half-yearly and even annual data recording is sufficient.
Measurement instruments utilized in the context of pharmaceutical process monitoring for data collection of physical and microbiological parameters must be recalibrated in periodical intervals, independently whether they are incorporated into computerized monitoring systems or serving for periodical manual measurements. The interval between recalibrations is normally one year.
Air cleanliness and other room air data
In the following only parameters shall be discussed which are of general relevance in the context of pharma monitoring of HVAC systems.
Figure 3.J-1 Data types for pharma monitoring
Besides the data type 2 physical parameters identified in Figure 3.J-1 all microbiological measurement parameters are subject to periodical measurement and assessment. Such microbiological parameters are particularly important in the context of process control of sterile processing operations, however there are cases even in non-sterile production where such data should be collected and stored.
Regarding microbiological monitoring of sterile manufacturing operations, differences exist between European and US requirements: In its Guidance for Industry on Sterile Drug Products Produced by Aseptic Processing, FDA requires only the active sampling of airborne microorganisms, complemented by measurement of microbial sedimentation as an optional test. Annex 1 to the EU GMP Guide, on the other hand, includes the sedimentation test into the specified monitoring parameters, and also requires surface cleanliness tests of critical processing areas as well as the testing of sterile gloves if they serve for interference into Grade A areas. The numerical limits in the FDA Guidance for Industry are not identical with those in the European GMP Guide. The frequency of microbiological sampling should be determined according to the level of risk and can vary from more than once per batch or shift to once every three months or every half year. The topic of microbiological monitoring is discussed in detail in GMP MANUAL Chapter 11.E Environmental monitoring.
Dr. Hans H. Schicht, Consultant, Switzerland
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