Hans H Schicht
Dr Hans Schicht Ltd Contamination Control Consulting
Attention to good manufacturing practice (GMP) principles applies not only to industrial large-scale production of medicinal products but also to the typical manufacturing tasks of hospital pharmacies, such as recipe-specific preparations and small-scale production of hospital-specific specialties. Although many processing operations do not require air cleanliness-controlled environments, there are some important exceptions: manufacturing operations with a high risk of microbiological product contamination or with a combined risk both for the product and the worker (eg, during the preparation of cytostatic infusions). Air- cleanliness requirements for sterile processing are specified in Annex 1 of the GMP guideline for medicinal products(1) (see Table 1) and in the corresponding Pharmaceutical Inspection Cooperation Scheme (PIC/S) guidelines.(2)
The GMP compendia stipulate objectives to be met in generic terms. For converting these requirements into up-to-date technical solutions and proving their effectiveness, they refer to other compendia (international standards where possible).
Since 1990, such standards are being developed for cleanroom technology as a joint effort of the International Organization for Standardization (ISO) and the European Committee for Standardization (CEN). As a consequence, the standard drafts thus elaborated are submitted to a parallel ISO and CEN approval procedure. If accepted, they are published in the standards collection of both entities. Subsequently, all CEN nations are required to incorporate them – within 6 months – into their national collections of standards. Thus, publication in 28 national standards collections is guaranteed from the beginning, which of course furthers worldwide adoption and acceptance. In parallel, CEN members are required to withdraw any national standards on the same subject matter.
The EN ISO cleanroom standards, which address all application areas of cleanroom technology, are composed of two families (see Table 2):
- The EN ISO 14644 series covering general contamination control topics.(3)
- The EN ISO 14698 series on biocontamination control issues.(4)
The column “Status” in Table 2 identifies the actual state of approval of each work item, the approval procedure being subdivided into three stages:
- Informal circulation as committee draft (CD), with the objective of inviting technical comments from the nations actively involved in cleanroom standardisation.
- First formal circulation as draft international standard (DIS) for the parallel ISO and CEN enquiry, inviting technical and editorial comments and requesting a generic statement on the merits of the draft by means of a preliminary vote.
- Second formal circulation as final draft international standard (FDIS) for the parallel ISO and CEN voting, leading – if successful – to approval and subsequent publication in the ISO and CEN collections of standards.
In addition to the work items listed in Table 2, the elaboration of an international standard devoted to the important issue of surface cleanliness has recently been initiated.
From DIS status onwards, these standards:
- Can be purchased through the national standardisation bodies and their sales outlets.
- Can be used as reference documents and as base documents for projects and customer/supplier agreements.
- Are considered to represent the state-of-the-art in any legal dispute.
As soon as they have reached DIS status, international standards should be given priority over national standards and over guidelines and recommended practices elaborated by professional societies.
With 10 international cleanroom standards now in the DIS stage and beyond, most contamination control topics of interest to hospital pharmacies are now addressed.
Air-cleanliness classification in EN ISO 14644-1
For more than 30 years, US Federal Standard 209 was the leading standard worldwide for classifying cleanrooms. The latest edition, 209E, published in 1992, was officially withdrawn in 2002 and replaced by the corresponding ISO standard.
The air-cleanliness classification scheme according to EN ISO 14644-1 is based upon a formula (see Table 3). The range of particle diameters for air-cleanliness classification extends from 0.1mm to 5mm. Thus, it is focused upon the detection capabilities of the discrete-particle counter, the reference test method for demonstrating compliance with ISO 14644-1. Tests need to be conducted with calibrated instruments, and class limits must be met with the rigours of the 95% upper confidence limit.
Comparing the EN ISO air-cleanliness classes with the GMP room grades as given in Table 1, good harmonisation is apparent for particles >-0.5mm. Unfortunately, there is no harmonisation for particles >-5mm and above.(5)
Overview of remaining parts of the EN ISO 14644 series
The following information focuses on the standards of direct relevance to hospital pharmacies.(6)
EN ISO 14644-2 establishes the minimum requirements for reclassification and requalification work, as well as the minimum time intervals between subsequent reclassifications. During periodic requalification, tests should at least comprise:
- Confirmation of the air cleanliness class.
- Pressure differentials between rooms.
- Verification of airflow rate (with turbulent airflow) or air velocity (with unidirectional airflow).
In the case of hospital pharmacies, leak testing of the installed terminal high-efficiency particulate air (HEPA) filters protecting the grade A areas is also strongly recommended. Extraordinary requalifications should be performed after significant changes to the installation and after major maintenance operations (eg, replacement of the terminal HEPA filters).
EN ISO 14644-3 provides guidance for the acceptance and qualification tests of physical parameters and for the corresponding measuring activities related to process monitoring. A total of 14 measuring tasks are addressed. In addition, the minimum performance requirements for the test instruments are detailed.
EN ISO 14644-4 offers comprehensive and systematic guidance for design, construction and startup of cleanrooms, including guidance for qualification checks and tests, and contains, for example, a systematic compilation of all the determinations to be agreed between purchaser–user and designer–supplier during development and realisation of a cleanroom system. It is condensed into a comprehensive checklist covering 12 subject areas with a grand total of 151 items. If the design is cross-checked with this guideline, it is almost impossible for something of importance to be overlooked.
EN ISO 14644-5 addresses the operational aspects of cleanrooms with a focus on the principal hazards: cleanroom clothing, personnel, stationary equipment, and materials, as well as portable and mobile equipment and cleanroom cleaning.
EN ISO 14644-7 establishes requirements for separative enclosures, such as clean air hoods, glove boxes, isolators and minienvironments. Guidance is limited to issues not covered in EN ISO 14644-3 and 14644-4: for example, isolator-specific measurement tasks such as integrity testing of containments and glove-sleeve systems (which are important subjects for hospital pharmacies where isolators are used increasingly for the preparation of cytostatic infusions).
Additionally, application-specific guidance is found in the PIC/S recommendation PI 014-2.(7)
Review of biocontamination control standards
The EN ISO 14698 series of standards addresses biocontamination control issues of utmost relevance to hospital pharmacies.
EN ISO 14698-1 is devoted to the general principles and measurement of biocontamination. It provides guidance on the measurement of airborne biocontamination and on microbiological sampling of surfaces, textiles and liquids. It also covers the validation of air sampling and laundering processes, as well as personnel training.
EN ISO 14698-2, which focuses on the evaluation and interpretation of biocontamination data, distinguishes between the requirements for the initial monitoring phase, when procedures are set up, tested, evaluated and validated, and those for handling biocontamination data resulting from routine process monitoring.
EN ISO standards: performance and quality benchmarks
The EN ISO cleanroom standards establish universally recognised performance and quality yardsticks for ensuring GMP compliance of the critical production areas of hospital pharmacies.
- Auterhoff G, editor. EC guide to good manufacturing practice for medicinal products and active pharmaceutical ingredients. Aulendorf (Germany): Cantor Verlag; 2002.
- PIC/S PE 009-2. Guide to good manufacturing practice for medicinal products. Geneva: Pharmaceutical Inspection Convention (PIC), Pharmaceutical Inspection Co-operation Scheme PIC/S; July 2004.
- EN ISO 14644. Cleanrooms and associated controlled environments. Geneva: International Organization for Standardization (ISO); Brussels: European Committee for Standardization (CEN).
- EN ISO 14698. Cleanrooms and associated controlled environments – biocontamination control. Geneva: International Organization for Standardization (ISO); Brussels: European Committee for Standardization (CEN).
- Schicht HH. The revised Annex 1 to the EC GMP guideline: upon an often skipped cause of wasting time & resources in the pharmaceutical industry. GMP Rev 2003;2(3):7-11.
- Schicht HH. The ISO contamination control standards – a tool for implementing regulatory requirements. Eur J Pharm Parenter Sci 2003;8(2):37-42.
- PIC/S PI 014-2. Recommendation on isolators used for aseptic processing and sterility testing. Geneva: Pharmaceutical Inspection Convention (PIC), Pharmaceutical Inspection Co-operation Scheme PIC/S; July 2004.
International Organization for Standardization
European Committee for Standardization (CEN)
European Commission – Pharmaceuticals – Regulatory frameworks
Pharmaceutical Inspection Cooperation Scheme (PIC/S)