New ISO Cleanroom Standards: What Will They
Mean For Pharma?
By Heidi Parsons
International experts have made significant changes to ISO’s airborne
cleanliness classification standard—and now is the time for industry to comment.
Since 2000, industries that manufacture products in cleanrooms and other controlled
environments have used ISO Standards 14644-1—Part 1: Classification of air
cleanliness, and 14644-2—Part 2: Specifications for testing and monitoring to prove
continued compliance with ISO 14644-1, as the global standards by which they
validate the cleanliness of their cleanrooms. Last December, the ISO Working Group
(WG) that developed those two landmark documents issued revised versions as Draft
International Standards (DIS). Although the review and approval process for these
documents to reach International Standard status will take more than a year, the DIS
versions may be used now as trade references per agreement between customers and
suppliers. Thus, it is imperative for those involved in cleanroom operations to
understand the procedural changes contained in the Draft International Standards, as
well as the reasons for those changes.
In the new ISO/DIS 14644-1—Part 1: Classification of air cleanliness by particle
concentration, ISO Technical Committee (ISO/TC) 209 WG 1—the global experts
who drafted the revisions—have introduced a simplified classification process that
utilizes a more accurate, statistically based sampling plan. The new plan calls for a
greater number of sample locations and randomized selection of those locations,
allowing for different concentration levels in different parts of the cleanroom. This
approach is designed to ensure with 95% confidence that at least 90% of the
cleanroom area complies with the particle concentration limit.
As in the 1999 Standard, the new DIS edition of ISO 14644-1 provides nine classes of
cleanliness, which specify the maximum allowed particle concentration as a function
of the particle size for each class (see Table 1). Gordon Farquharson, Convenor of
ISO/TC 209 WG 1, points out that WG 1 intentionally avoided making any radical
changes to the principles behind the cleanliness classes. Also, as in ISO 146441:1999, the new ISO/DIS 14644-1 specifies the number of sample locations for
classification and the acceptance criterion for the data (see Table 2). Users will note
critical differences in the content of the latter table versus the guidance for sample
locations in the 1999 Standard.
As for the companion document, the differences between ISO 14644-2:2000 and the
new ISO/DIS 14644-2—Part 2: Specifications for monitoring and periodic testing to
prove continued compliance with ISO 14644-1:XXXX, reflect the new sampling
methodology in ISO/DIS 14644-1.
So, what impact will these Draft International Standards have on the pharmaceutical
and medical device industries? The answer may change as the new documents
undergo the process of becoming International Standards, but from the DIS stage
forward, these documents may be specified in a business contract at any time.
The US Food and Drug Administration (FDA) has yet to weigh in publicly on the new
DIS documents. However, the Division of Manufacturing and Product Quality within
FDA’s Center for Drug Evaluation and Research (CDER) has released a statement
saying, “FDA is supportive of efforts to set standards by organizations such as ISO,
particularly when the documents are internationally harmonized. We had cited the
previous version of 14644-1 in our 2004 Guidance on Sterile Drug Products Produced
by Aseptic Processing. At this time we do not intend to issue a position paper on
ISO/DIS 14644-1, but will review it with interest and expect to see many firms using
this reference to assist in achieving CGMP compliance.”
In addition, as a member of the US Technical Advisory Group (US TAG) to ISO/TC
209, FDA will submit comments to ISO during the six-month comment period that
runs through May 2, 2011. Representing a balanced input of US manufacturers, users,
general interest groups and government experts, the US TAG is developing the
official US position on the new DIS documents.
Anne Marie Dixon, Head of Delegation for the US TAG to ISO/TC 209, explains that
developing the US position entails actively soliciting feedback from regulatory and
non-regulatory stakeholders through the TAG Administrator, the Institute of
Environmental Sciences and Technology (IEST, www.iest.org). “The new DIS
documents represent a significant change to certification and potentially to
validation,” Dixon remarks. “It is vital that anyone impacted by the ISO 14644
standards take a close look at the new drafts and the statistics behind them.”
She adds, “Standards require consensus, both in development and in practice. The
comment period offers users and regulators the unique opportunity to shape these
standards, which are so vital to global manufacturing and commerce.” Comments may
be submitted to the US TAG via the IEST website,
www.iest.org/i4a/forms/form.cfm?id=67.
WG 1 Convenor Farquharson concurs, noting that because the revised sampling plan
is such a departure from the protocol in the 1999 Standard, “I suspect that ISO/DIS
14644-1 will elicit more comments than any other part of the 14644 series.”
Farquharson explains, “Some pharmaceutical manufacturers may not like the random
locations aspect of the new sampling plan. Choosing your sampling locations
randomly each time you measure your cleanroom’s particulate concentration
introduces the possibility that you won’t get the same result this time as you did the
previous time.” He adds that adopting the new approach will also require
manufacturers to test more locations than before, and “they will have to tear up their
current sampling protocols and rewrite them.”
Aware that the new sampling approach would likely generate some controversy,
Farquharson and other members of WG 1 authored a technical paper that was
published in January by IEST as a “Special ISO Edition” of the Journal of the IEST.
Entitled “Sampling Plan for Cleanroom Classification with Respect to Airborne
Particles,” the paper compares the sampling approaches in the 1999 Standard and the
new DIS and explains why statistics dictated the change. The paper is available for
download at the IEST website, and the authors are encouraging widespread
dissemination to promote understanding of the revisions in the new DIS, particularly
during the comment period.
Co-author of the Journal of the IEST paper and the Secretary of ISO/TC 209, Robert
Mielke, suggests that drug and device manufacturers keep the big picture in mind.
“Although the new DIS versions of 14644-1 and 14644-2 and the logic behind them
are important, they only address part of the overall cleanroom qualification and
monitoring equation for the pharmaceutical and medical device industries,” he says.
“Additional tests should be performed; depending on the product that is manufactured
in the cleanroom and where the facility is located, those tests may include
microbiological counts, scan leak tests, air velocity measurements, and others.
Regulatory agencies’ regulations and guidances, such as those issued by the US Food
and Drug Administration (FDA) and the European Medicines Agency (EMA), also
need to be followed.” ISO/DIS 14644-1 and ISO/DIS 14644-2 are available from the
IEST Publications Store at www.iest.org.
Heidi Parsons is the Technical Editor at IEST. As such, she manages Working
Groups, writes articles, and edits ISO 14644 Series documents, IEST Recommended
Practices, and technical papers for the Journal of the IEST.