THE STANDARD DIN ISO 14644-1:1999: PROGRESS OF THE REVISION

This article describes some very important issues relating to the revision of the fundamental cleanroom standard ISO 14644-1:1999⁽¹⁾. The parallel process of the revision of ISO 14644-2:2000⁽²⁾ is not described since the issues at large are not as fundamental to the cleanroom community.

The process of revision involves input by technical experts within an ISO committee environment, in this case WG (Working Group) 1 of ISO TC (Technical Committee) 209 which met in Milan, Italy in November 2011 and Copenhagen in February 2012. The role of the experts is to bring to the table current scientific and technical knowledge on the subject, and also to table the opinions and requirements developed through national mirror organisations such as BSI (British Standards Institute).

Some of the issues have been reported on previously⁽³⁾⁽⁴⁾ and in a paper by Haertvig et Al in the EJPPS⁽⁵⁾, explaining the basis of the sampling statistics in the ISO DIS 14644- 1:2010⁽⁶⁾ (DIS - Draft International Standard). This present paper builds on the principles developed in that paper, and sets out to explain the areas of concern and some of the technical arguments.

Publication of ISO DIS14644-1:2010 for review and national vote

Close followers of the ISO standardisation process for cleanrooms under ISO TC209 will recall that a DIS (draft international standard), ISO DIS 14644-1, was published at the end of 2010 for the statutory six month DIS review, comment and vote. As has been the case with the complete family of ISO TC209 cleanroom standards, the technical enquiry and vote was undertaken in parallel within the CEN (Committee for European Normalisation) standards community. A convention, called the Vienna Convention, put in place to prevent unnecessary parallel work being carried out in CEN and ISO environments, has been applied to this work.

The DIS enquiry and vote is a very important stage in the standardisation process because it is the first time that the draft documents are opened beyond ISO TC209 for broader public and industry scrutiny. Equivalent English, French, and German language versions are published by national standards bodies, and formal comments are sought. The comments are then submitted back to the ISO central secretariat, together with a national vote. The ISO and CEN rules require that every single comment is considered,  adjudicated upon and reported for the record. In this case, the National voting was in favour of approval of both ISO DIS 14644-1 and ISO DIS 14644-2 subject to comments being addressed.

Extent of comments

Not only is ISO DIS 4644-1:2010 the more important of the two standards, but it was also the one that received the majority of substantive comments. Indeed there were more than 100 substantive technical comments and many more simply editorial. ISO TC209 WG1 met on the 8th and 9th October 2011 to consider the comments and the main issues raised by industry. The nature of the comments, and the likely changes to the DIS were so significant that it was decided that a second DIS enquiry and vote would be required. This will inevitably mean a delay to the revision project but the topic of cleanroom classification was considered to be of such importance that the concerns of industry had to be addressed.

A majority of the comments came from the pharmaceutical and life sciences industries, but there were also some very important comments made by the semiconductor and display screen manufacturing industries. One of the most interesting of these was a serious concern about how the standard should deal with super-large cleanrooms. To help experts understand scale, a Chinese presentation was made that illustrated single cleanroom facilities of up to 40,000 m², with working zones of up to 10,000 m². These are clearly outside the range of expectation envisaged during the evolution of cleanroom standards from the earliest US Federal Standard 209, up to the current ISO 14644-1:1999, and also the ISO DIS 14644-1:2010.

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Sadly, it has to be reported that many of the nations' comments on the draft standard challenged or contradicted some of the important principles developed by their own experts during the two year evolution of the new draft. Whilst this was extremely disappointing, it was felt, that it was more important to work through the issues to ensure the broader acceptance of a revised standard in the future. When challenged, the national experts explained that the DIS had been opened to broader scrutiny than had originally been available within their national mirror committees.

• The main areas of concern identified in the vote and comments were:
• The relevance of the particle concentration values in the classification table.
• The exclusion, at ISO Class 5, of particles ≥5 μm from the classification table.
• The increased number of sample points required for classification of a cleanroom or clean zone compared to the current 1999 version.
• The locating of the sample points within the cleanroom or clean zone (randomisation issues).
• The inclusion of risk based locations specifically selected to certify the cleanliness of critical locations within a cleanroom or clean zone.

The comments and issues in more detail

The role and significance of the classification table.
The first most important change between the existing standard and the DIS is that the classification table (Table 1 in ISO DIS 14644-1:2010) becomes the foundation and basis of classification. The advantage of doing this compared with the use of a formula (as in the 1999 version), illustrated by a table, is that the table can be used more effectively to constrain and guide readers and users into choosing appropriate particle sizes and cleanliness levels. Historians of cleanroom standardisation will remember that this was the basis of US Federal Standard 209E⁽⁷⁾ and its US predecessors.

However, it was reported that many readers of the table believed that, for a given ISO class, the tabulated particle concentrations at different particle sizes actually represented typical particle distributions found in the cleanroom environment. A number of experts, including workers such as Whyte et Al (8) have carried out particle concentration measurement and assessment work that suggests very clearly that this is not the case. During the ISO TC209 WG1 meeting in October 2011, the experts took account of these facts, and even considered proposing a new table that might better represent typical particle distribution at different sizes in cleanrooms. After much deliberation, it was decided that this was a step too far because it would mean a fundamental change to the current understanding of the ISO classes 1 - 9. Following further discussion, it became clear that this only presents a problem more than one particle size is used to classify a level of cleanliness. Within the existing 1999 standard, the last paragraph of clause 3.3 suggests it is legitimate to use more than one particle size, provided there is a reasonable separation in the sizes considered. One possible simple solution to this would be to simply remove this clause. At this juncture it is important to remember that ISO 14644- 1 is a standard that is specifically designed for the purpose of enabling a cleanroom to be defined by its ISO class or classification. This is a formal process, required by ISO 14644 Parts 1 and 2. It is undertaken during the commissioning of a new cleanroom, and then periodically thereafter, to prove continued compliance with the ISO class. In addition to this formal classification, most practitioners, either based on good business practice or, as mandated by a regulatory authority, monitor particulate air cleanliness in real-time. Under these circumstances, selection of more than one particle size might be more appropriate because the object is to look for deviation from a state of demonstrable control, rather than for compliance with a relatively arbitrary value.

The 5 micron particle problem

A major concern for a number of experts was the removal, from Table 1, of the well-known 29/m³ concentration of ≥5 micron particles in ISO class 5 which was in the 1999 version. The clear advice from the experts was that this low concentration of large particles is unreliable to count with current airborne particle counters and is therefore an inappropriate particle size with which to evaluate ISO class 5. There is a clear precedent for this in the discontinued US federal standard 209 E. It is quite difficult to find a reason why the 29 particle limit was included in ISO 14644-1:1999, but it is most likely to have been because there was a significant European input. It is really important to understand that if the new standard is finalised with Table 1not showing a particle concentration for ISO class 5 in the 5 ?m column, then this particle size cannot be used for classification of ISO class 5 in accordance with ISO 14644-1.

This leaves an interesting problem about how to support the regulatory requirements set out in Annex 1 of the EU GMP. In the view of particle counting experts on WG1, the low concentration of 5 μm particles in grades A and B of Annex 1 are just as inappropriate for classification as the low concentration in ISO class 5 in the ISO standard. This is becoming an even more sensitive issue due to the recent replication of the EU GMP Annex 1 requirements in the PIC/S GMP, the WHO GMP and, most recently, the new Chinese GMP regulations. It is because of this that many comments received on ISO DIS 14644-1:2010 requested that the 29 particle limit be replaced. Whilst this matter is not yet concluded, the expert opinion is still that the Table 1 in the cleanroom standard should not include particle concentration sizes that are inappropriate. The experts are currently working on a form of words that would allow pharmaceutical industry regulatory authorities to provide their own guidance outside the boundaries of the standard.

Monitoring is an entirely different matter that has not yet been properly dealt with in ISO 14644-1. WG1 has therefore decided to give very serious consideration to recommending the complete separation of cleanroom classification and real-time monitoring as is already done in EU GMP Annex 1. This guidance also makes clear that the regulatory authorities are most interested in the operational state. The classification of cleanrooms or clean zones in the at rest state is more about defining a benchmark of the effective performance of the environmental control system to give confidence that there is no external contamination contribution within the controlled environment. Real-time monitoring in operation, on the other hand, gives much more important information about the sources of contamination immediately around the process in operation. As the greatest concerns relate to contamination sources from human beings and failed technical systems in the operational state, it would make much more sense to consider 5 ?m particle assessments for real-time monitoring alone. This would be consistent with the scientific approach to the revision of ISO 14644-1 and would remove some of the concerns about increased testing time for classification due to the combination of low concentration limits and a possible increase in the number of sample locations proposed.

Number of Sample locations

The next important subject that WG1 considered was the basis for the new table of sample locations. The experts thought that a look-up table was a more appropriate approach because it allows the cleanroom or clean zone to be divided into fundamental unit areas that have some logic. For very small clean zones, fundamental unit areas of one square metre were considered appropriate, and for larger cleanrooms and clean zones fundamental unit areas of 4 m² were considered to be suitable. The DIS feedback clearly indicated there was confusion between fundamental unit areas and sub-divided regions. The experts are working on improvement to the text to resolve this problem.

It is a basic assumption in the DIS standard, and indeed in the current standard that, within any single fundamental unit area, the cleanliness level is even throughout the area and that therefore a sample taken anywhere in that area is representative of the whole area.

The majority of the DIS feedback demonstrated acceptance that an increase in the number of sample locations would be required to give at least 95% confidence that at least 90 % of all locations do not exceed the class limits. It would also allow the 95% UCL evaluation required for between 2 and 9 locations in ISO 14644-1:1999 to be discarded. This would simplify the classification process, which was one of the demands made by the user community at the outset of this revision process.

Another issue, raised by the Chinese experts, was that of super-large cleanrooms. The main concern was that the proposed new table of sample locations would lead to unnecessarily large numbers of sample locations for very large rooms. The Chinese experts reported that they felt comfortable with a combination of sample locations based on square root of the area of clean zone, plus specific risk based process specific test locations. The problem is best illustrated by considering a single cleanroom area of 10,000 m². In such a situation, the square root rule in ISO 14644:1999 would give only 100 sample locations for a full classification. However, the requirement specified in ISO DIS 14644-1:2010 would give 520 locations because the cleanroom has to be divided into 500 m² parts and the sample table applied to each part. To resolve this, it is likely that the table of sample locations will be used for up to 900 m² and then the square root rule would be applied for larger cleanrooms. The logic of this can be seen on the graph in Figure 1, where 900 m² is the point where the confidence level and the square root rule lines cross.

Fig.1: Sample point number comparison

If the ISO DIS 14644-1:2010 95/90 Confidence Level rule were to be used for cleanrooms greater than 900 m², whilst the confidence level would, theoretically, be acceptable, it is clear that insufficient locations would be tested from a practical point of view, and a pragmatic approach using the square root rule will give a more reasonable number of sample locations.

The other aspect of super large cleanrooms concerns those which have an extremely high ceiling. The experts thought that this could be resolved if the new DIS allowed for several test planes and classification at multiple locations in each test plane.

Random selection of sample locations

During the development of the DIS, the experts had agonised over how to deal with the random selection of previously established fundamental unit areas. The initial concept divided the cleanroom or clean zone into equal fundamental unit areas from which the number of areas in which to sample was specified in the look-up table. Thus a 100 m² clean zone would be divided into 25 fundamental unit areas. The look-up table specifies sampling from 16 of them and the 16 would be selected randomly. There is of course possibility that the 16 could be grouped together and not evenly distributed. An alternative semi-random approach that tried to ensure a more even distribution of sample locations received quite a lot of negative response during the DIS enquiry. Therefore it is more likely that the original approach will be adopted and worked up in more detail over the next few months. A standard number generator, easily found on the Internet, will be used for the random selection.

Terminology used

There is also some confusion about terminology used in the context of sub-dividing a cleanroom or clean zone, with terms such as sub-zone, region, area, sector and so on used. These matters will be resolved by the experts, and will be coordinated with the other standards in the ISO TC209 family. The likely outcome of this, subject to further review and discussion, will be the following:

• Cleanroom
• Clean zone
• Fundamental unit area
• Number of sample points
• Sample point location

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Conclusion: preview of the next draft ISO 14644-1

These are the most likely key points for the second DIS 14644-1 which will be published for comment and national vote sometime in 2012:
1. The classification will NOT include the 5 μm particle concentration of 29 for ISO 5.
2. There will be a note pointing out that the particle concentration limit table does not address either realtime monitoring or any special requirements for counting ≥5 μm particles specified by some regulatory authorities.
3. The sample size calculation will be exactly the same as in the current ISO 14644-1:1999.
4. There will be a look-up table for the number of sampling points for different sizes of area. Fig.2 illustrates how this might look with some sample values.

All points must comply with the class limit for a specific classification class.

Author:
Gordon Farquharson
... B.Sc.(Hons), C.Eng., is a Chartered Consulting Engineer with more than 30 years experience of quality and safety critical processes, facilities and systems used by industries such as Healthcare, Life Science and, Micro-electronics.

Source:
⁽¹⁾ ISO 14644-1:1999 - Cleanrooms and associated controlled environments - Part 1: Classification of air cleanliness. Published by ISO 1999-05-01.
⁽²⁾ ISO 14644-2:2000 - Cleanrooms and associated controlled environments - Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1. Published by ISO 2000-09-15.
⁽³⁾ Farquharson G - Revision of ISO 14644 -`1:1999 and ISO 14644-2:2000, CACR Issue 5, January 2011.
⁽⁴⁾ Neiger J - Reflections on BSI Cleanrooms consultation on draft event, London, March 23 2011, CACR Issue 7, July 2011.
⁽⁵⁾ Hartvig NV, Farquharson GF, Mielke R, Foster M - Sampling plan for cleanroom classification with respect to airborne particles, EJPPS 2011 Volume 16 Number 1.
⁽⁶⁾ ISO DIS 14644-1:2010 - Cleanrooms and associated controlled environments - Part 1: Air cleanliness classification by particle concentration (ACP). Published by ISO for the DIS enquiry and national vote in December 2010.
⁽⁷⁾ US-FED-STD-209E - Federal Standard - Airborne particle cleanliness classes in cleanrooms and clean-zones, published September 11, 1992 and cancelled November 29, 2001 upon publication of ISO 14644-1 Part 1: Classification of air cleanliness; and ISO 14644-2 Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1.