Correlates Physical and Bio Principles of Steam Sterilization

For the first time, both the physical and microbiological sciences for steam sterilization
cycles are addressed in one reference document for manufacturers and regulators looking
to develop or asses a sterilization program—PDA’s Technical Report No. 1 (Revised
2007), Validation of Moist Heat Sterilization Processes: Cycle Design, Development,
Qualification and Ongoing Control. This document revises PDA’s flagship Technical
Monograph No. 1, Validation of Steam Sterilization Cycles (1978), the first expert
pharmaceutical industry reference manual produced by a task force of volunteer PDA
members.
There are two general scientific elements to the validation of moist heat sterilization
processes, one on the physical characteristics of the steam, temperature and pressure
relationships and the other on the biological characteristics of bioburden and
bioindicators. While both the physical and biological sciences are essential tools in the
development of a moist heat sterilization cycle, the biological aspect has traditionally
been the primary focus of many U.S. companies.
Companies operating in/for the European marketplace, on the other hand, have placed
more emphasis on the physical and steam quality aspects when validating a steam
sterilization cycle. The two sciences complement each other and are included in a
synergistic fashion in this technical report.
The 2007 edition includes newly added Chapter 3, “Sterilization Science,” which
describes essential scientific tools used for the design, development and qualification of
sterilization cycles. This chapter provides a user-friendly overview of sterilization
models, process indicators and thermal science and steam quality. Loaded with this
information, the document outlines an approach that is scientifically sound and up-to-date
and able to help firms meet the regulatory requirements in all major pharmaceutical
markets.
At a June 26-27 workshop in Chicago to publicly introduce the new technical report, task
force contributors (see page 24 for a complete list of contributors to TR-1) discussed how
the merging of the two sciences broadens the document’s usefulness to regions beyond
North America and commented on the challenges this effort entailed.
“One of the challenges in the entire process of this development was to actually make this
document applicable to all regulatory areas of the world as much as possible,” stated
Rich Levy, PhD, Senior VP of Scientific and Regulatory Affairs, PDA. “And this took a
degree of negotiation and a significant comment period. We wanted to make sure the
scientific principles were generally accepted in those geographies more broadly and that
they still were scientifically sound based on a review process.”

PDA President Bob Myers added, “In this particular case, there was a little bit different
focus in Europe versus the United States on moist heat sterilization, and I think we were
able to accommodate both points of view. You will see in the list of contributors, well
known scientists from industry (United States and European Union), Medicines and
Healthcare products Regulatory Agency (MHRA – United Kingdom) and the U.S. FDA.
There were strong views on the importance of the various approaches when we began the
process, but by early 2007 they were blended into a consensus document. This should be
a technical report that can be used just about anywhere in the world.”
The document works to harmonize the two scientific viewpoints, according to Michael
Sadowski, Manager, Sterility Assurance, Baxter Healthcare. “One of the things this
document advocates is establishing agreement between both physical and biological sides
of things as far as qualification,” he said. “And that is really important because the two
really need to go hand in hand. You cannot look at one and not the other. In the case of
physical, you can think that you have the right temperature on your heat penetration units
inside of a porous/hard goods load, but because the thermocouple cannot understand what
the steam quality is in that area, you may have a dry heat situation and have drastically
different biological results. From a biological standpoint, the same type of thing is true.
You want to be able to show that physically you can predict what is going to happen
biologically.” The two approaches, he said, “really complement each other.”
The document recommends establishing a relationship between the physical and
biological results.
The document recommends establishing a relationship between the physical and
biological results. “There is going to be some variability,” explained Sadowski, “but you
want to be able to understand why you have differences, if there are significant
differences, because there might be a process problem that you are not aware of.”
The inclusion of the thermal science/steam quality section was critical to building the
international consensus for the document. As the document explains, understanding the
basics of thermal science (thermodynamics) is essential to the design and control of moist
heat sterilization.
The section specifies important properties of the various heating media used that are
critical to ensuring the industrial reproduction of the specific temperature pressure
relationship in a saturated steam cycle established during cycle design. Carrying over
these relationships in routine production is vital to ensuring effectiveness of the cycle.
The thermodynamics section includes charts depicting the heat capacity of steam, water
and steam-air mixtures. These demonstrate that steam and water possess similar heating
capacities (on a volume basis); however, steam does not require forced circulation to
transfer heat, whereas superheated water does.
The heat delivery rate of steam-air mixtures depends on the ratio of air to steam and the
forced circulation of the medium throughout the sterilizer. Steam-air mixtures have a

much lower heat capacity per volume than water or steam but still can be effective when
properly applied.
The document describes three types of steam that can be used for moist heat sterilization
cycles: plant, process and pure. Regarding the latter type, section 3.3.3 covers steam
quality testing. Referencing the European Committee for Standardisation’s EN 285,
“Sterilization – Steam Sterilizers – Large Sterilizers” (1996), the section states:
For sterilization of porous/hard goods, steam quality characteristics should be evaluated
as part of the qualification of the steam supplied to the sterilizer; and should be repeated
at regular intervals and documented in internal company policy or in accordance with
applicable regulatory requirements.
At the Chicago workshop, Keith Shuttleworth, Senior Consultant, Keith Shuttleworth &
Associates, discussed the thermal dynamics portion of the document. He underscored the
need to monitor the quality of the steam when it is used as a sterilant because its physical
properties “can have a profound impact on its performance and the performance of the
sterilizer.” Extended equilibration times, unexplained biological indicator failures, wet
loads and excessive temperatures are some of the measurable effects of poor steam
quality, he explained. As a heating agent, on the other hand, the physical properties of
steam will have little impact on its performance. The scientific principles in Chapter 3 set
the groundwork for the content in the remaining chapters of the technical report, which
cover process development and process qualification. Earlier drafts of the document
delved into installation qualification (IQ) and operational qualification (OQ), but
PDA’s Board of Directors decided a year-and-a-half ago to scale back the coverage to
keep it more in line with the original 1978 monograph.
In Chicago, Levy noted the addition of a chevron diagram (see figure 1), which provides
a visual guide to the process of establishing and qualifying a steam sterilization cycle:
“We tried to go in a life cycle format for the way in which you would go about the
validation of a moist heat sterilization process. So we used a chevron diagram, and we set
this up in what we thought would be a logical progression of the steps you would take to
establish a moist heat sterilization program. We stayed with the original concept of
Technical Monograph No. 1, meaning that sterilization was the underpinning, the
foundation, and everything we did would have that foundation of sterilization science.
The overarching goal was to explore validation. And we divided it roughly into two
areas, process development and process qualification. IQ and OQ would be left to another
technical report. We then broke this down further into steps we felt people would need to
take if they followed best practices to come up with a moist heat sterilization program.”
The document outlines best practices but does not establish standards for sterilization
validation. It does not always address region-specific regulatory expectations, but
provides up-to-date, scientific recommendations for use by industry and regulators.
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Figure 1: Application of the Science of Sterilization
“That is another key thing to bring up about this document,” said Sadowski in Chicago.
Throughout a peer-review process that the document was subjected to in 2006 (see “TR-1
Model Adopted for All PDA Tech Reports” in the Science & Technology Snapshot, page
10), he noted that “a lot of folks were asking for us to be very prescriptive on everything
from the Z-value of biological indicators, to equilibration time, to you name it. And one
of the things we wanted to do again was to present the foundation of science to
everybody, so that they had the background to be able to make the appropriate decisions
in regards to their sterilization program.”
Levy added, “We pride ourselves in having our technical reports be nonprescriptive.
They don’t tell you, ‘you must do these things.’ Rather, they really give you insight into
best practices, and we wanted to continue that with this document.” While the 2007
revision of TR-1 is intended to be a single-source guide, it includes a comprehensive
reference section. Works cited are appropriate and up-to-date scientific publications,
international regulatory documents, journal articles, technical papers and books.
In addition, work on Technical Report No. 1 has spurred the revision of several related,
existing PDA technical reports and the identification of necessary complementary
technical reports. These include:
• Technical Report No. 3 (Revised), Validation of Dry Heat Processes Used for
Sterilization and Depyrogenation
• Technical Report No. 30 (Revised), Parametric Release
• New Technical Report, Biological Indicators for Sporicidal Gassing Processes:
Production, Control and Use
• New Technical Report, Steam in Place

• New Technical Report, Sterilizer Systems: Design, Commissioning, Operation,
Validation and Maintenance
Several of these projects grew from “a number of the elements dropped off and out of the
current Technical Report No. 1 to bring it more in line with the original monograph,”
stated Levy. “Many people spent quite a bit of time developing the revised TR-1, and we
are making sure that we don’t lose that good work.” The new technical report projects
“are all elements that were in varying degrees discussed in some of the earlier drafts.”
One dropped topic not to be included in a PDA technical report, Levy noted, is container
closure integrity. “We felt that was well-documented and didn’t require a technical
report. However, that may change in the future.”
Furthermore, PDA is publishing the 12th edition of Microbiology and Engineering
Sterilization Processes, by Irving Pflug, PhD, University of Minnesota. Pflug’s
influential book is referenced a number of times in both the original moist heat
sterilization technical monograph and the new technical report. Pflug was recognized as
one of the PDA’s six outstanding scientists in 2006.
“Irving Pflug brought the science of sterilization to PDA and to the industry from the
food industry in about 1977,” Myers told workshop attendees in Chicago. “PDA engaged
him to educate and train our membership through a series of classes on moist heat
sterilization. He has compiled his body of work developed over the years and has recently
agreed that we can sell his book to provide users the detailed science of sterilization. It is
referenced a number of times in the technical report and justifies much of the science
applied today.”
Publication of Technical Report No. 1 (Revised 2007) will bring to a new generation of
pharmaceutical professionals a greater understanding of the underlying sterilization
sciences and how to balance them when designing, developing, qualifying and
controlling steam sterilization cycles.
TR-1 Task Force Members and Contributors
A PDA volunteer task force of 40 scientists from North America and Europe worked on
Technical Report No. 1 (Revised 2007), producing a technical guide on moist heat
sterilization that should be applicable in all regulatory environments.
James P. Agalloco, Agalloco & Associates
James E. Akers, Ph.D., Akers Kennedy & Associates
Wilf Allinson, GlaxoSmithKline
Thomas J. Berger, Ph.D., Hospira
Frank Bing, Abbott Laboratories (retired)
Göran Bringert, GE Kaye Instruments
Gary Butler, Steris Corporation
Jean-Luc Clavelin, Eli Lilly & Co.
Peter Cooney, Ph.D., FDA (retired)
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PDA Letter, July/August 2007, Volume XLIII, Issue #7
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Phil DeSantis, Schering-Plough
Peter Dürr, F. Hoffmann-La Roche AG
Kristen D. Evans, FDA
John G. Grazal, AstraZeneca
Nigel Halls, Ph.D., IAGT. Ltd.
Paul Hargreaves, MHRA
Andrew D. Hopkins, MHRA
Martin A. Joyce, Ph.D., GeneraMedix Inc.
David Karle, Steris Corporation
Bernard Kronenberg, Bakrona Basel AG
John W. Levchuk, Ph.D., FDA (retired)
Richard V. Levy, Ph.D., PDA
Steen Loevtrup, Novo Nordisk A/S
Timothy F. Lord, Eli Lilly & Co.
Genevieve Lovitt-Wood, G.I. Lovitt & Associates
Russell E. Madsen, The Williamsburg Group, LLC
Vittorio Mascherpa, Ph.D., Fedegari Autoclavi Spa (retired)
David W. Maynard, Maynard & Associates
Robert B. Myers, PDA
James E. Owens, Baxter Healthcare (retired)
Irving Pflug, Ph.D., University of Minnesota (retired)
Dario Pistolesi, Ph.D., Fedegari Autoclavi Spa (retired)
Anthony Pochiro, AG Edwards and Sons
Jarmo Saari, Leiras OY
Michael Sadowski, Baxter Healthcare
John T. Shirtz, Baxter Healthcare
Keith Shuttleworth, Keith Shuttleworth & Associates Ltd.
Finlay Skinner, Skinner Pharm-Assist
Ian Symonds, GlaxoSmithKline
Kevin D. Trupp, Hospira
Dieter Witthauer, Ph.D., Novartis
Richard T. Wood, Ph.D. (retired)
William Young, Baxter Healthcare (retired)