Reprinted from
PHARMACEUTICAL ENGINEERING®
ISPE Update
The Official Magazine of ISPE
March/April 2006, Vol. 26 No. 2
Risk Management for Highly Hazardous Compound
Manufacturing
by Rochelle Runas, ISPE Technical Writer
C
an highly hazardous compounds, such as steroid hor
mones and cytotoxics, be processed safely in multiproduct facilities? It is a controversial issue that a team
of industry leaders have begun to tackle in hope of shifting
away from the paradigm of separate production facilities.
A team led by Stephanie Wilkins, President,
PharmaConsult US, presented “Risk Management and High
Hazard Compounds” on 25 January to nearly 40 FDA personnel in Rockville, Maryland.
Lesley Burgess and Paul Wreglesworth of AstraZeneca,
Nigel Hamilton of Sanofi-Aventis, Bruce Naumann and Ed
Sargent of Merck, Andy Walsh of Hoffman-LaRoche, and
Stephanie and Julian Wilkins of PharmaConsult US, demonstrated how a risk management approach can help define if
and when certain products and processes need to be accommodated in dedicated or segregated facilities.
“The FDA approached us at the June 2005 ISPE Potent
Compounds Containment Seminar and asked us to provide
them with education on this topic,” said Wilkins. “In general,
the drugs in our industry are getting more and more potent,
and so there is a concern for operator safety and crosscontamination.”
“There is a trend heading toward separate production
facilities, which would be traumatic to the industry, in terms
of cost and time to market. Industry and regulators from
around the world are struggling with this.”
Last February, the European Agency for the Evaluation of
Medicinal Products (EMEA) issued the “Concept Paper Dealing with the Need for Updated GMP Guidance Concerning
Dedicated Manufacturing Facilities in the Manufacture of
Certain Medicinal Products.”
One of the proposals set out in this paper is that, “An
expert agreement should be obtained when and for which
‘certain’ substances separate production buildings should be
mandatory. At the same time, a definition of ‘exceptional
cases’ should be given as to when production in campaigns
may be acceptable in the same building.”
Wilkins said industry leaders in the US and international
organizations such as the European Federation of Pharmaceutical Industries and Associations (EFPIA) are concerned
that the EMEA may be reinforcing the existing paradigm
that high hazard substances immediately call for separate
production facilities, when in fact, some of these substances
can be processed safely in multi-product facilities.
“The ‘exceptional cases’ should be those where physical
and procedural controls cannot show the ability to control
potential cross-contamination to acceptable levels, which
would require separation or dedication of facilities,” Wilkins
©Copyright ISPE 2006
said. “Currently, we are basing decisions on a ‘one size fits all’
approach using product class, definitions, or labels, such as
the emotion-provoking words, potent, cytotoxic, and cytostatic.”
“We are a science-based industry, yet when it comes to
discussing highly hazardous compounds, science goes out the
window and we adopt an approach based on pure emotion!”
said Wreglesworth.
“We need to reprogram ourselves to think in terms of
hazard characterization and risk characterization when we
consider compounds, Wilkins said. “These words take hazard
classes like, carcinogens, mutagens, teratogens, and sensitizers into consideration, but also factor in differences of potency
and actual level of exposure.”
Further complicating the issue are the inconsistencies
found in guidelines across the globe. For example, the
Australian Code of cGMP for Medicinal Products issued in
2002 recommended that cross-contamination be avoided by
“production in segregated areas . . . or by campaign (separation in time) followed by appropriate cleaning.” In the same
year, Health Canada proposed a modification to their guideline that addressed the same issue, but their view was that,
“Campaign production (separation in time followed by cleaning) of the above products is not acceptable.”
And in certain South American countries, cGMP inspections are conducted to a checklist based on the 1992 WHO
guidance, which states, “Areas for preparation of pharmaceutical highly sensitizing products: penicillins, hormones,
cytostatics, or biological preparations have to be independent
and autonomous.”
Currently, guidance on the quality risk management approach can be found in the ICH Q9 document proposed by the
International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use. “But we need to take ICH Q9 a step further and
develop a specific science- and risk-based approach to the
process to determine whether certain products should be
accommodated in dedicated or segregated facilities,” Wilkins
said.
The Risk Management approach presented to the FDA in
January is a systematic process to identify hazards and
understand risks to assist decision-making to implement
appropriate controls. The key components are hazard characterization, risk characterization, exposure assessment,
control of the risks, verification of performance, communication, and review.
The approach utilizes the basic scientific equation, Hazard (the potential for a substance to produce adverse effects)
MARCH/APRIL 2006 PHARMACEUTICAL ENGINEERING
1
ISPE Update
“We’re not looking to create a matrix,” said Wilkins,
“rather, we would like there to be a formal documented approach that examines
issues that affect exposure and realistic solutions.”
x Exposure (contact with the substance) = Risk (the probability that a substance will produce harm under specified conditions of exposure).
The approach should be applied to hazard and risk assessment, but the controls put in place should be determined on
a case by case basis, according to the presentation to the FDA.
“We’re not looking to create a matrix,” said Wilkins, “rather,
we would like there to be a formal documented approach that
examines issues that affect exposure and realistic solutions.”
Wilkins said the team’s goals are to continue dialogue with
the FDA and develop ISPE guidance for the industry in the
areas of Risk Assessment, Risk Management, and Facility
Design for highly hazardous compounds and possibly for all
compounds. The team also plans to provide an expanded
version of its presentation to the FDA at a one-day session at
ISPE’s Annual Meeting in November.
In response to the EMEA’s concept paper, EFPIA experts
sent to the EMEA and the European Commission on 27
January, “EFPIA Proposed Guidance Document on Dedicated Manufacturing Facilities in the Manufacture of Certain Medicinal Products.” The document demonstrates how
the risk-based decision approach can be used to determine
the potential risk of cross-contamination and the type of
controls required. The EFPIA experts also proposed new
wording to the current EU GMP Guide to reduce ambiguity
and allow risk management principals to be applied. The
EMEA is expected to discuss EFPIA’s revised text in early
March.
Wilkins and her team would like to see industry and
regulators worldwide agree on consistency of approach to
hazard and risk assessment, but flexibility of approach in
controlling the risk. “We want everyone to be on the same
playing field and on one that is based on good science,”
Wilkins said.
Mark Your Calendar with these ISPE Events
April 2006
05
06
11
12
13
19
19
20
24 - 26
24 - 27
26
27 - 28
28 - 29
Delaware Valley Chapter Education Series
Week 2 of 6
Puerto Rico Chapter Commissioning &
Qualification Program
Delaware Valley Chapter Student Poster Contest
Delaware Valley Chapter Education Series
Week 3 of 6
New Jersey Chapter Cambrex Tour
Delaware Valley Chapter Education Series
Week 4 of 6
Japan Affiliate Annual Meeting
Midwest Chapter Education and Vendor Day
2006 FDA CGMP China Training Program
ISPE Copenhagen Conferences
Delaware Valley Chapter Education Series
Week 5 of 6
ISPE Brisbane, Australia Training Courses
India Affiliate 2006 Conference
May 2006
01 - 02
03
2
ISPE Melbourne, Australia Training Courses
Delaware Valley Chapter Education Series
Week 6 of 6
PHARMACEUTICAL ENGINEERING MARCH/APRIL 2006
04 - 05
08
08 - 11
10
18
22 - 25
27
ISPE Wellington, New Zealand Training Courses
Delaware Valley Chap 13th Annual Golf Outing
ISPE Atlanta Classroom Training
New Jersey Chapter Golf Outing
Puerto Rico Chapter Method & Product Transfer
Program
ISPE Amsterdam Training
Puerto Rico Chapter Annual Golf Tournament
June 2006
05 - 08
14
15
22
22
25 - 27
27 - 29
27 - 30
ISPE Washington Conferences
Chesapeake Bay Area 2006 Summer Social
New Jersey Chapter Day and Multi-Tract Event
Greater LA Chapter Social Event
Midwest Chapter Golf Outing and Executive
Panel Discussions
2006 ISPE Singapore Conference
INTERPHEX Asia
INTERPHEX Mexico
For more information on these
and other ISPE Events,
visit the Web site at www.ispe.org
©Copyright ISPE 2006
ISPE Update
International Call for Articles
Pharmaceutical Engineering is the Global Information Source for Pharmaceutical Manufacturing Professionals and is the official magazine of ISPE. The
membership of ISPE, therefore your reading audience, includes people participating in multiple fields relating to Pharmaceutical Engineering. This audience
encompasses engineering staff, operators, scientists, and compliance staff from
biologics and pharmaceutical operating companies; vendors supplying equipment
and services to these industries; regulators and government officials; academic
scholars, professors, and students. ISPE provides a network for interaction and
communication between all its members.
Pharmaceutical Engineering is seeking articles with a global perspective. You
are invited to submit an article on one or more topics related to the themes of
upcoming issues. Document your success stories on engineering applications
related to the life sciences industries in your country or around the world.
Articles should be original and unpublished work covering case studies, innovative
solutions or manufacturing innovations. Articles may not contain press releases
and/or product information, as only non-commercial material will be considered.
Articles are peer reviewed, comments are returned to the author for incorporation,
prior to acceptance for publication. Technical writing and interpreter services are
available.
Themes for upcoming Pharmaceutical Engineering issues and deadlines for submitting final articles in late 2006 and early 2007 are listed to the right.
For further information, please visit our Web site at www.ispe.org, and then connect
the following links: Publications, Pharmaceutical Engineering, Submit an Article,
and then Author Guidelines.
2006 - 2007
Pharmaceutical
Engineering
Editorial Calendar
SEPTEMBER/OCTOBER 2006
Theme: Global Trends
Manuscripts due: 3 May 2006
Publishes: 22 Sept 2006
Email or mail both hard and electronic copy of FINAL 3,000 to 5,000 word
manuscripts (no drafts will be accepted), including all figures and tables, biography,
along with the Article Synopsis form and Review Topics to:
NOVEMBER/DECEMBER 2006
Theme: Regulatory
Manuscripts due: 3 July 2006
Publishes: 22 Nov 2006
Gloria Hall
ISPE Editor and Director of Publications
PHARMACEUTICAL ENGINEERING
3109 W. Dr. Martin Luther King, Jr. Blvd., Suite 250
Tampa, Florida 33607 USA
Tel: +1-813-960-2105 Fax: +1-813-264-2816
E-Mail: ghall@ispe.org
JANUARY/FEBRUARY 2007
Theme: Sterile
Manufacturing Operations
Manuscripts Due: 3 Jan 2007
Publishes: 22 May 2007
©Copyright ISPE 2006
MARCH/APRIL 2007
Theme: Automation
Manuscripts due: 2 Mar 2007
Publishes: 20 July 2007
MARCH/APRIL 2006 PHARMACEUTICAL ENGINEERING
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