Facility Biocontainment and Inactivation A Risk-Management Case Study Part 3

27/03/13
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Facility biocontainment and inactivation: a risk-management case study (Part 3)

Stephen Brooks , Richard Creekmore , Ted Frank , Brian Hasselbalch , Kristin Murray
and Kwame Obeng
Source:
Pharmaceutical Technology. 35.9 (Sept. 2011): p74.
Case study
Document Type:
Full Text: COPYRIGHT 2011 Advanstar Communications, Inc.
http://www.advanstar.com
Full Text:
Title:
Author(s):
This case study on facility biocontainment and inactivation is the third of eight in a series put together by the
Product Quality Research Institute Manufacturing Technical Committee (PQRI-MTC) risk-management working
group. The series is meant to advance the understanding and application of the International Conference on
Harmonization (ICH) Q9 Qualify Risk Management guideline by providing actual examples of risk-management
assessments used by the bio/pharmceutical industry, The introductory article and first case study, on defining
design space, appeared in the July 2011 issue of Pharmaceutical Technology (1).
**********
When a manufacturer produces two or more drug substances in the same manufacturing facility, the facility is
considered to be multiproduct. The facility designs, operations, and controls related to the use for multiple products
should provide for appropriate measures to prevent cross-contamination between products. These controls include
the containment procedures used to prevent the release of hazardous agents within the facility.
There are numerous facility design and operational attributes that may significantly affect the quality of products
being manufactured. These attributes include, but are not limited to, area classifications, open versus closed
processing, utility-system design, cleaning validation/clean-in-place systems, rules regarding equipment sharing, and
critical flows throughout the facility. Facility designs and operations should provide for appropriate segregation of
products to prevent cross-contamination. For facilities with multiple products or processes, the impact of potential
process or product failures on the other operations in the same facility should be evaluated.
The following case study on facility biocontainment and inactivation is the third of eight in a series put together by
the Product Quality Research Institute Manufacturing Technical Committee (PQRI-MTC) risk-management
working group. The series is meant to advance the understanding and application of the International Conference on
Harmonization (ICH) Q9 Quality Risk Management guideline by providing actual examples of risk-management
assessments used by the bio/pharmceutical industry. The introductory article explaining the history and structure of
the series, as well as the first case study on defining design space, appeared in the July 2011 issue of
Pharmaceutical Technology (1). The second study addressed functional equivalence for equipment replacement (2).
In the current case study, two existing manufacturing suites were proposed to be remodeled to accommodate and
contain manufacturing operations involving bacterial fermentation through viable cells of Streptococcus
pneumoniae, a pathogenic Biosafety Level 2 (BL2) organism. These suites were separate
manufacturing areas located adjacent to mammalian cell culture manufacturing-processing areas. Regulatory
guidance requires BL2-Large Scale (LS) waste and residues to be inactivated prior to exiting the manufacturing area
(3). An inactivation autoclave was identified during the initial risk assessment as one of the primary means of
inactivation of BL2 waste and process equipment prior to exiting the fermentation suite. The risk-review step in the
risk-management process identified that there was only one inactivation autoclave in the fermentation suite and that
alternative backup inactivation procedures were desired to maintain continuity of manufacturing operations during
autoclave preventive- and corrective-maintenance activities.
This case study describes the evaluation of various backup inactivation procedures for operational feasibility and
includes a demonstration of an appropriate level of in-activation of the BL2 waste and equipment.
Risk question and risk-assessment method
The risk question developed for the subject case study is: What are the appropriate backup inactivation methods
(i.e., procedures) that are operationally feasible and provide an appropriate level of decontamination capability that
can be utilized in the fermentation suite to inactivate BL2 waste and equipment when the inactivation autoclave is
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unavailable?
Selection of a backup inactivation procedure is a precise exercise requiring an objective evaluation of the
effectiveness of proposed procedures at inactivating the BL2 organism along with demonstration of consistent
execution of these procedures each time they are performed.
Hazards analysis and critical control points (HACCP) is a risk-assessment tool that can be proactively used to
identify and implement process controls that consistently and effectively prevent hazards from occurring. HACCP
involves evaluation of critical procedural limits and determination of how they will be achieved routinely. Because it
is essential that the backup inactivation procedures prevent the release of the BL2 organism outside of the
fermentation suite, HACCP was selected as the risk-assessment tool to use to determine the appropriate preventative
controls.
Risk identification and analysis
For this evaluation, there was only one hazard to consider: the BL2 organism. The HACCP process was
significantly streamlined to control for operator safety and the high level of regulatory requirements for pathogenic
BL2 organisms. The hazard was always considered to be significant in this case study (see Table I).
As shown in Table I, each proposed inactivation mechanism or procedure was deemed crucial because they were
proposed as backups for the primary autoclave inactivation method (which was itself deemed crucial). The
evaluation of the effectiveness of the procedures including how they would be controlled to achieve consistency
among critical parameters is shown in Table II.
Risk control
In this case study, identifying effective backup inactivation methods to compensate for times when the primary
inactivation autoclave is unavailable for use reduces the risk of a breach of containment in the facility. Table II
demonstrates that the backup procedures identified are effective and can be consistently controlled. Table II also
indicates that additional, more detailed procedural controls and more clearly defined functional-area responsibilities
are required to maintain proper containment of the BL2 organism. These additional procedural controls are identified
in the "recommended actions" column of Table II.
Risk documentation and communication
For this case study, the outputs of the risk-assessment process, including recommendations for additional
procedural and functional-area controls, were documented in a risk-assessment report. This report became part of
the operating history of the manufacturing facility and the associated product. The project team of each functional
area affected by the results of the risk assessment reviewed and signed off on the results and recommendations.
The project team assumed responsibility for implementing the recommendations that arose from the quality riskmanagement process.
Risk review
In the case study presented, it may be appropriate to review the backup procedures as additional detailed
procedures are developed. This activity will ensure that the backup procedures are fully effective and controlled in
an effort to contain appropriately the BL2 organism.
Training Tools
This PQRI risk-management case study series includes online training tools, available at
PharmTech.com/PQRIstudies. The PDF trainers include: a HAZOP training guide, a FMEA training guide, a
HACCP training guide, and a Risk Rank Filter training guide.
References
(1.) T. Frank et al., Pharm. Technol. 35 (7), pp. 72-79.
(2.) T. Frank et al., Pharm. Technol. 35 (8), pp. 72-75.
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(3.) NIH, Guidelines for Research Involving Recombinant DNA Molecules, Appendix K (May 2011).
Ted Frank is with Merck & Co; Stephen Brooks, Kristin Murray, * and Steve Reich are with Pfizer; Ed Sanchez is
with Johnson & Johnson; Brian Hasselbalch is with the FDA Center for Drug Evaluation and Research; Kwame
Obeng is with Bristol Myers Squibb; and Richard Creekmore is with AstraZeneca.
* To whom all correspondence should be addressed, at kristin.murray@pfizer.com
Table I: Hazard analysis worksheet
Categories of
items
Actual and potential

hazards introduced,
controlled, or
enhanced at this step
Introduced,
controlled
or enhanced
Are any
potential
safety hazards
significant.
Mixed trash
Biosafety Level 2
(BL2) host organismknown infectious
pathogen
Introduced
Yes
Controlled
Yes
Categories of
items
Introduced,
controlled
or enhanced
Justify
response
What preventative
measures were
applied to prevent the
significant hazard?
Mixed trash
Introduced
BI-2 host
organism
Place trash bag into

another trash bag,
seal for transport, and
sanitize bag exterior.
Place bags in a covered
container for transport
to an external autoclave.
Controled
BL2 host
organism
Inactivation within an
external autoclave.
Categories of
items
Introduced,
controlled
or enhanced
Is this a
critical control
point (CCP)?
CCP rationale
far both
Yes and No)
Mixed trash
Introduced
Yes
This CPP is the

primary means of
containment until
inactivation.
Controlled
Yes
This CPP is the

primary means of
inactivation.
Table II: HACCP plan form for the evaluation of the effectiveness
and control of standard operation procedures (SOPs).
RTD is resistance temperature detector. EH&S environmental
health and safety.
Critical
control
point
Significant
hazards
Place trash
bag into
another trash
Biosafety
Level 2
(BL2) host
Critical
limits
or each
preventive
measure
Bag closure
via tie-knot
Monitoring
What
Closure
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bag, seal for

transport,
and sanitize
bag's
exterior.
Place bags
in a covered
container for
transport to
an external
autoclave.
Inactivation
within
external auto
clave
Critical
control
point
Place trash
bag into
another trash
bag, seal for
transport,
and sanitize
bag's
exterior.
Place bags
in a covered
container for
transport to
an external
autoclave.
Inactivation
within
external auto
clave
Critical
control
point
organism
BL2 host
organism
Critical
limits
or each
preventive
measure
70% vol/vol
Ethanol
concentration
for wipedown
1 min
Ethanol
contact time
for wipedown
Complete
coverage
Ethanol spray
coverage of
bag
12 min
Sterilization
hold timeset at 90
minutes
121[degrees]C
Sterilization
temperature
Monitoring
How
Frequency
Who
Bag closure
via tie-knot
Visual
Once-upon
closure
Trained
technician
70% vol/vol
Certificate
of analysis
Once-upon
release
Quality
Control
1 min
Wall-clock
Once-upon
wipe down
Trained
technician
Complete
coverage
Visualensure
surfaces are
wetted
Once-upon
wipe down
Trained
technician
12 min
Controller
timer
Throughout
cycle
Automated
unit
controller
121[degrees]C
RTD
Throughout
cycle
Automated
unit
controller
Critical
limits
or each
preventive
measure
Verification
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Place trash
bag into
another trash
bag, seal for
transport,
and sanitize
bag's
exterior.
Place bags
in a covered
container for
transport to
an external
autoclave.
Inactivation
within
external auto
clave
Critical
control
point
Place trash
bag into
another trash
bag, seal for
transport,
and sanitize
bag's
exterior.
Place bags
in a covered
container for
transport to
an external
autoclave.
Bag closure
via tie-knot
Bag not
accepted if
not sealed
70% vol/vol
Release of
ethanol for
GMP use
1 min
Placement
of bags into
airlock only
after ethanol
inactivation
performed per
SOP
Complete
coverage
Placement
of bags into
airlock only
after ethanol
inactivation
performed per
SOP
12 min
Cycle tape
reviewed and
retained for at
least 3 years.
Unit is alarmed
if cycle
acceptance
parameters
not achieved.
121[degrees]C
Cycle tape
reviewed and
retained for at
least 3 years.
Unit is alarmed
if cycle
acceptance
parameters
not achieved.
Critical
limits
or each
preventive
measure
Documentation/
Supporting
studies and
records
Bag closure
via tie-knot
None
70% vol/vol
Validation
reports
1 min
Validation
reports
Complete
coverage
Validation
reports
Recommended
actions
SOP for this
activity is
required. Any
bags containing
relabled with
appropriate
external sharps
indicator stickers
to ensure those
bags are routed
for incineration
rather than
autoclave
inactivation.
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Inactivation
within
external auto
clave
12 min
121[degrees]C
Autoclave loads
Flow fot these
are challenged
materials will
monthly with
need to be
Bacillus
proceduralized
stearotherand training of
mophilus.
all impacted
Electronic
functional areas
records of the
will need to be
verifications
determined.
are retained for EMS will need
at least 3
to ensure thet
years.
autoclaved
gowns are not
disposed and
are returned for
laundering.
Frank, Ted^Brooks, Stephen^Murray, Kristin^Reich, Steve^Sanchez, Ed^Hasselbalch, Brian^Obeng,

Kwame^Creekmore, Richard
Source Citation (MLA 7th Edition)
Brooks, Stephen, et al. "Facility biocontainment and inactivation: a risk-management case study (Part 3)."
Pharmaceutical Technology Sept. 2011: 74+. Academic OneFile. Web. 27 Mar. 2013.
Document URL
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id=GALE%7CA284322836&v=2.1&u=capes58&it=r&p=AONE&sw=w
Gale Document Number: GALE|A284322836
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