Many ISO standards are under a rolling revision process and moves are afoot to revise the biocontamination control standard ISO 14698. Tim Sandle reviews the process and looks at how the standard might develop.
Recent progress was made on the revision process being undertaken on the international cleanroom standard ISO 14698. This standard covers biocontamination control and is currently divided into two parts:
- Part 1: General principles and methods1
- Part 2: Evaluation and interpretation of biocontamination data2
Although the title is ‘biocontamination’, the focus of the standard is essentially environmental monitoring. The purpose of environmental monitoring is the collection of data relating to the numbers or incidents of micro-organisms present on surfaces, in the air and from people within a cleanroom. In addition, non-viable particle counting, a physical test, is undertaken in conjunction with viable monitoring because of the relationship between high numbers of non-viable particles and viable counts.3 ISO 14698 addresses viable contamination.
The ISO 14698 standard is not as widely adopted as its sister, ISO 14644, which covers most of the physical aspects of cleanroom used and operations, including particle counting. The reasons for the limited adoption of the ISO 14698 relate in part to the fact that it is not mentioned in any GMP guidance (ISO 14644, for instance, is referred to in both EU GMP and the FDA guidance on aseptic filling).
Another reason relates to its vagueness. For example, the standard does not inform the user in any great detail of how to go about undertaking environmental monitoring due to a predominance of other guidance on environmental monitoring, such as that provided by the United States Pharmacopeia (USP) chapter <1116> and PDA Technical Report Number 13.
The lower profile of ISO 14698 could be set to change. Led by a European delegation, a vote was taken in January 2013 at the nominated ISO committee that decides whether standards should be reviewed or not. The decision – with only one vote against by the US – was taken to proceed with a wholesale revision.
Although full details of the changes have yet to emerge, the review process has begun. A number of possible changes to the content and the format for the standard have been discussed in committees as well as by professional societies.
The revision process
The decision to proceed with what is expected to be a comprehensive review of ISO 14698 was made by ISO/TC 209 (Working Group 2) in January 2013, but the decision was not made without some difficulties. There were various points under discussion, such as the purpose of the standard and whether it had a role in the wake of other environmental monitoring standards; its application (to healthcare, pharmaceuticals, the food industry and medical devices) and contents. The most vocal opposition came from the US representatives who were concerned about the potential costs arising for US businesses in the event of the standard being adopted, and the risk that the standard would take a different path from the recently updated USP cleanrooms chapter <1116>.
The most vocal opposition came from the US representatives who were concerned about the potential costs
It is worth noting that a vote to proceed with a revision does not, in itself, mean that the revised standard that emerges from the working group will be accepted when the final draft is voted on. The International Organisation for Standardisation (ISO) body is made up of 161 nations. Any new or revised standard must be voted upon and for an ISO to be accepted it needs to reach agreement from more than 75% of the member countries. Once agreed, the majority of member countries will adopt the ISO standard as their national standard.
This update could become important as ISO 14698 becomes referenced in GMP (possibly EU GMP) – something that those involved in the update are keen to see happen.
At this stage, the revisions that will be proposed to the ISO 14698 standard remain speculative. However, based on discussions with the European contingent, some of the possible changes are outlined below, along with some explanation about the significance of the change. They are to:
a) Include detail of how to classify airborne biocontamination in cleanrooms, including methods of measurement and the validation of sampling methods.
b) Include detail concerning approaches to classify and monitor cleanroom surfaces.
For the above two areas, a discussion around the setting of a routine sampling plan may be included. Furthermore, given the advances in recent years in relation to rapid microbiological methods, a section will probably be added that discusses emerging technology.
c) Have a section on the setting of microbial monitoring limits.
The revised standard may or may not adopt an incident rate approach, similar to USP <1116>, rather than assessing cleanliness in relation to a pre-defined action level. In relation to limits, text may be added relating to the expression, interpretation and reporting of results together with some recommendations for data trending. Text should also be added for action to be taken in the advent of results falling outside of established alert and action limits.
d) Include risk management and assessment techniques.
A risk assessment procedure would be useful to help users to determine locations for environmental monitoring. Importantly, regulatory authorities are increasingly asking drug manufacturers about this subject. The likely methodology for this is Hazard Analysis Critical Control Points (HACCP), a risk assessment tool for examining the main points of contamination concurrence in a process that was developed within the food industry but which has increasingly become commonplace in pharmaceuticals.
This would be in the context that a higher number of Staphylococci may be more acceptable than lower numbers of E. coli (this would depend upon the type of product, the patient population and route of administration).
f) Include consideration of some of the weaknesses of environmental monitoring sampling methods, such as active (volumetric) air-samplers, which could be outlined.
Guidance relating to the qualification, validation and verification of environment, methods and equipment is lacking in the industry and any guidance provided would prove a useful addition.
g) Introduce a possible classification scheme for maximum permitted viable counts in a similar way to ISO 14644’s tables for particle counts.
This last part has proved to be the most controversial. At present particle counting is applied to newly built, modified or commissioned cleanrooms; whereas viable counting is generally applied to cleanrooms when in use. The proposal with the standard would be to add viable count monitoring to cleanrooms at start-up with an expectation to classify these in a similar way to particle classification. This could mean that an average (mean) count is used to assess the cleanliness level within the cleanroom.
The proposal with the standard would be to add viable count monitoring to cleanrooms at start-up with an expectation to classify these in a similar way to particle classification
This proposed change could be achieved through the introduction of classification tables, with the view that cleanrooms will be classified in a similar way to the requirements of ISO 14644-1 (which considers the particulate classification of cleanrooms). For this part, the standard would specify levels of microbial cleanliness, expressed by species of interest and by incidence rates.
In terms of the format, it appears that the current two parts of the standard would be reduced to one (larger) document. Furthermore, the new standard will probably form part of the ISO 14644 family; although there is also a possibility of a new family of standards being generated.
In relation to context, the current standard refers to ‘cleanrooms’. My understanding of the planned revision is that reference to ‘cleanrooms’ would be removed because cleanroom refers to something that is assessed by the concentration of airborne particulates.
The removal would also allow the standard to be used by other sectors that do not use traditional cleanrooms, such as the food industry. Instead the term ‘controlled environments’ may be used.
Reflections
The revision process for ISO 14698 will be an interesting one and potentially could be important if it were to be referenced in a regulatory document such as EU GMP. There is certainly a need for a biocontamination standard given the paucity of guidance material available.
If an average count were to be used to assess a clean area for classification this would contrast with the current USP approach , thereby creating a clash between standards
However, it is debatable whether the aim of the revised standard – to have a viable classification approach for cleanrooms – is appropriate. Cleanrooms are clean if verified by their physical parameters and remain so provided people do not enter them. The current thinking of orientating monitoring locations and frequencies towards risk seems a more sensible approach.
Looking at it from another aspect, if an average count were to be used to assess a clean area for classification this would contrast with the current USP approach that looks at incident rates, thereby creating a clash between standards.
However the standard develops, it will be important that none of the changes made to the standard contradicts EU GMP, FDA guidance or the USP <1116> chapter, otherwise the cleanroom community will be presented with additional costs and technical difficulties.
Tim Sandle represents Pharmig on the BSI LBI/030 committee, which is the UK section for the review of the ISO 14644 and ISO 14698 standards. He also hosts a cleanroom and microbiology discussion site at www.pharmamicroresources.com.
References
1. ISO 14698-1: Cleanrooms and associated controlled environments – Biocontamination control – Part 1: General principles and methods. International Organization for Standardization ISO, Geneva (September 2003)
2. ISO 14698-2: Cleanrooms and associated controlled environments – Biocontamination control – Part 2: Evaluation and interpretation of biocontamination. International Organization for Standardization ISO, Geneva (September 2003)
3. Sandle, T. (2011): ‘Environmental Monitoring’ in Saghee, M.R., Sandle, T. and Tidswell, E.C. (Eds.) (2011): Microbiology and Sterility Assurance in Pharmaceuticals and Medical Devices, New Delhi: Business Horizons, pp293–326
