JGXP - 2011 - v15n4 - Contamination Control in The Compliance Program PDF
JGXP - 2011 - v15n4 - Contamination Control in The Compliance Program PDF
JGXP - 2011 - v15n4 - Contamination Control in The Compliance Program PDF
Contamination Control in
the Compliance Program
Scott Sutton
IMAGE SOURCE,
IM
O
MEDIC
MEDICALRF.COM/GETTY IMAGES
Microbiology Topics discusses various topics in microbiology of practical use in validation and compliance. We intend this column to be a useful
resource for daily work applications.
Reader comments, questions, and suggestions are needed to help us fulfill
our objective for this column. Please send your comments and suggestions
to column coordinator Scott Sutton at [email protected] or journal
managing editor Susan Haigney at [email protected].
IMPORTANT
PORTA POINTS
Thee follow
following impor
important point
points are discus
discussed:
tThe
to goo
good manufacturing
The contamination
co mina
control plan
n is central
cen
an cturing
practice,
describing
to create
actic , des
ib g the
th procedures
procedu es and
and policies
poli s designed
s
products
under
controlled
p
odu s un
der co
ntro led conditions
ond on
tThe contamination control plan
covers all p
phases of a facilitys
p
y
status
tatus
a s
ttThe contamination
nt
control plan
lan iss a comprehensive document,
describing control of incoming contamination and measures
designed to minimize their impact
tConsistency and application are key to successful execution of the
contamination control plan.
INTRODUCTION
Development of a contamination control plan is critical to the success of
aseptic, terminal sterilization, and non-sterile manufacturing facilities. This
is most obvious in the aseptic arena, where the US Food and Drug Administration has issued clear regulatory guidance on the need for control of
contamination at all stages of the process. What is less obvious is the even
greater need for a plan to address contamination control in non-sterile manufacturing. This need only becomes obvious after a problem has arisen
frequently a problem in contamination control that requires product recall.
The contamination challenge in non-sterile production is different from that
in aseptic production. The objective in aseptic production is to exclude all
microorganisms from the finished product; in the non-sterile environment
it is to control the types and numbers of microorganisms in the finished
58
Scott Sutton
Figure 1:
Example Fishbone diagram for contaminated product.
Training
Raw Materials
SOP not
Correct
Inadequate Hand
Sanitization
Raw Material/Components
Received Contaminated
No Evidence
of Training
SOP Program
Poor Personal Hygiene
(piercings, jewelry,
makeup, illness)
Raw Materials/Components
Contaminated on Sampling
Raw Materials/Components
Contaminated on Storage
Operators Ineffectively
Trained
Inadequate PPE
(foot, coat, face, hair)
Training Program
not in place
Proficiency
Not Reviewed
Regularly
Proficiency not
Demonstrated
Contaminated Product
Sample Hold Compromised
Inappropriate Materials of
Construction (difficult to sanitize,
particulate generation, etc.)
Lack of Air
Quality Control
Air Quality
Compromised
H
HVAC-HEPA
Compromised
Water Generation
System Compromised
Inadequate
Pest Control
Ineffective
Sanitization Agents
+ ,*-1&&)&15,#
Cleaning-Sanitation
Compressed
Agents
Gases
Compromised Product Contact
Surfaces
ot-to-Lot Cleaning
C
g Ineffective
Ine
ve
Lot-to-Lot
//53"r
9//53"r
"0&!2)0
9"0&!2)0
&,2/!"n
9
&,2/!"n
n-Prod
tact
Non-Product
Contact
SSurfaces
Delivery (Hoses)
(H
Water Delivery
Comp
promised
Compromised
W
Q
Water
Quality
Comp
Compromised
P
Piping
Issues
(d
(dead-legs,
reverse
inclines, etc.) Source
e Water
W
Compromised
O er Water
Wa r Issues
Other
9 +!&+$ Wa
91+!&+$Water
9/&--&+$&-"0
Sampling Error
Inadequate Removal
,#&0&)""/&0
Organic Load
Transfer/Sampling
Issues
Sample Transport Compromised
Shift of Environmental
&,2/!"+#/,*
Sensitive to
Resistant Species
Contamin
Contamination of
Cleaning Implements
qu
ration
Inadequate
Separation
off C
Clean and
rty Operations
atio
Dirty
de
Inadequate
Protection
om Uncontrolled
From
Env
Environment
Cleaning
and
Sanitization
Clean
ng a
d Sa
itiza n
Process
Facility
Fac
acili y
products. Regulatory action has extended this consideration even into the realm of personal care products
(e.g., cosmetics, toiletries, and soaps).
Contamination control is central to compliance. The
whole point of current good manufacturing practice
(CGMP) is to produce safe and effective medications
(1). As an indication, the word contamination or its
variants appears no fewer than 24 times in 21 CFR
211. One of the most frequent cause of drug recalls,
lack of sterility assurance, relates directly to the inability of the manufacturer to document adequate protection against contamination by adventitious bioburden.
See the Reference section for a historical review (2) and
a biotech case study on this topic (3).
Diverse markets such as pharmaceuticals, medical
devices, diagnostics, and personal care products have
operated historically under different CGMP. However,
the considerations for contamination control are similar and can be approached from the perspective of root
cause analysis (4). Use of a Cause and Effect diagram
can be an excellent tool in the determination of likely
routes of contamination after the fact during an investigation. It can also be used as a proactive learning tool
for the development of the contamination control plan
(see Figure 1). For those more comfortable with Six
Sigma procedures, this can be revisited as an Ishikawa
Diagram (see Figure 2). The main point here is to
identify, and come to agreement, on the likely causes of
potential problems.
A more traditional proactive approach to risk
management might be through use of failure mode
and effects analysis (FMEA), which can be extremely
useful in determining the most important aspects of
control for your process (5).
Autumn 2011 Volume 15 Number 4
59
MICROBIOLO GY TO PIC S
Figure 2:
Example Ishikawa diagram for contaminated product.
Raw Material/Components
Received Contaminated
Raw Materials/Components
Contaminated on Sampling
Methods
0-8!'#,!6
Not Reviewed
No Evidence Regularly
of Training
Raw Materials/Components
Contaminated on Storage
,"#/32#
(foot, coat, face, hair)
0-%0m
Operators
Ineffectively
Trained
--0#01-,*6%'#,#
(piercings, jewelry,
makeup, illness)
0-8!'#,!6,-2
#+-,1202#"
,-2
,-2
Followed
Correct
#*#4,2
not A4'* *#
'*32'-,1
Tr',',%0-%0+
not in place
0-!#"30#
Inappropriate to Specs
Unvalidated
-,2+',2#"0-"3!299
Sample Hold Compromised
Inappropriate Materials of
Construction (difficult to sanitize,
particulate generation, etc.)
Inadequate
#12-,20-l
Lack of Air
Quality Control
Ineffective
Sanitization Agents
,!-+.2' '*'26-$
Cleaning-Sanitation
Compressed
Agents
Gases
Compromised
0-"3!2-,2!2
Surfaces
Air Quality
Compromised
HV
A Compromised
Water Generation
System Compromised
Water Quality
Compromised
Compro
'.',%113#1
'.
(dead-legs,
reverse
(de
e
inclines, etc.) Source Water
Compromised
ompro se
Transfer/Sampling
Issues
Sample Transport Compromised
Shift of Environmental
'- 30"#,$0-+
Sensitive to
Resistant Species
W2#0
#*'4#06-1#1
#*'4
Compromised
mpro
Sampling Error
Inadequate Removal
-$'1' *#
# 0'1
Organic Load
Inadequate
Separation
equate Sepa
of Clean
Clea and
:
'026<.#02'-,1
<
Contamination
of
Contaminat
Cleaning Implements
Imp
Management
,"#/32#0-2#!2'-,
#0
,
From Uncontrolled
Environment
Machinery
Mach
ery
Mother
h Nature
N t
COMPONENTS
OMPONENTS OF A STRONG
G
CONTAMINATION CONTROL PLAN
The contamination control plan and the protocol
governing the program are essential documents
useful in providing the rationale and methods used
to accomplish three tasks:
tMinimizing the bioburden throughout the
manufacturing processes
tMinimizing the level of batch residual crossover contamination
tMinimizing the level of cleaning material residual contamination.
This article examines the components of the
plan in terms of specific areas of interest in meeting
these three key objectives.
Phases of Manufacturing Operation
The contamination control plan must take into account different stages of facility operational status.
60
At a minimum,
these include the following:
in
tCommissioning and initial start up
tOngoing operations
tShut-down for regular maintenance
tStart-up after scheduled shut down.
These phases will not have the same level of
contamination control. A good plan will discuss the
concerns specific to each of these phases.
Validated Methods
All measures of bioburden in a facility will be
indirect. Bacterial cells cannot be counted on a
surface or in the air. The microorganisms must be
transferred to an agar plate (or some other mechanism) and colony-forming units (CFU) counted. If
the assumption is made that the transfer of microorganisms from the air or from a surface to agar
is consistent, then these numbers can be used to
Scott Sutton
61
MICROBIOLO GY TO PIC S
Scott Sutton
63
MICROBIOLO GY TO PIC S
Environ
al Monitoring
Monito
GMP
GXP Compliance,
2010.
GM
MP Environment,
En
men J GX
ompliance 14(3):22-30,
:22010.
7. Sutton,
SVW and
Su
ut
d AM
A Cundell,
Cun l, Microbial
icrob al Identification
Ide ic
n in
the Pharmaceutical
ical Industry,
ndust y, Pharm
P rm Forum.
F rum. 30(5):18840(5): 8841894,, 2004.
8. Sutton,
SOP
Sutton, S., Thee Importance
Su
Impoortance
nc of a Strong
St
SOP System
Sy tem
m in thee
QC Microbiology Lab, J GXP C
Compliance. 14(2):44-52,
2010.
9. Martinez, J., The Rotation of Disinfectants Principle: True
or False? Pharm Technol. 33(2):58 71, 2009.
10. Sutton, SVW., Disinfectant Rotation-A Microbiologists
View, Controlled Environ., pp. 9-14, July 2005.
11. Donald, T., Vaccines Pulled Due to Potential Contamination, Contamination Control. 4(1):12 13, 2008.
12. Suvarna, K., et al., Case Studies of Microbial Contamination in Biologic Product Manufacturing, Amer Pharm Rev.
14(1):50-56, 2011.
64
ABOUT
AB
A
BO
B
OUTT THE
OU
THE AUTHOR
TH
AUTH
U HO R
Scott
ott Sutton
tto is the
h founder
d and principal consultant
l
off Microbiology Network, Inc (http://bit.ly/n62yFG). He is a recognized
consultant and trainer with emphasis in GMP, investigations,
environmental monitoring, and contamination control as
well as microbiology laboratory audits and operations. He
may be reached at [email protected] or by phone at
1.585.594.8273.