CLE ANING C OMPLIANCE FO RUM
Is Swabbing a Regulatory
Requirement?
PHILLIP SPEARS/GETTY IMAGES
Jennifer Carlson
Welcome to “Cleaning Compliance Forum.”
This column discusses scientific principles, strategies, and approaches associated with cleaning that are useful to practitioners in compliance and validation.
We intend this column to be a valuable resource for daily work applications. The
key objective for this column: Useful information.
The topic of cleaning is broad and complex. It involves many different industries and many different disciplines within the organization. Cleaning has applications to pharmaceutical and biotechnology products, medical devices, dietary
supplements, cosmetics, and so on—literally every product that is manufactured.
Cleaning involves personnel in formulation development, equipment design and
installation, processing development, analytical method development, manufacturing, testing, and the quality unit. The importance of cleaning is unquestioned.
Cleaning and cleaning validation are often one of the first topics addressed in
regulatory audits. Understanding the basic principles of cleaning is fundamental
to daily manufacturing, problem investigations, corrective action and preventive
action, and other applications. In addition to the diversity of topics in cleaning,
its terminology may be esoteric, intimidating, and often unique to various groups
in the organization.
These considerations make discussion of cleaning compliance a challenging
task. This column addresses the various topics of cleaning with these considerations in mind. We intend to present cleaning topics in a clear and meaningful
way so that our readers in different industries and in different areas within the
organization will be able to understand and apply the principles discussed.
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 Jenna Carlson at [email protected] or to journal coordinating
editor Susan Haigney at [email protected].
KEY POINTS
The following key points are addressed in this article:
•Swab sampling is a direct surface sampling technique for
sampling surfaces
•Personnel who perform swab sampling should be qualified
for performance
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Jennifer Carlson
•Swab efficiency (i.e., % recovery) for the method
and product contact material should be determined
•Extractables from the swab or protein binding to
the swab must not interfere with the method
•Swab sampling has advantages and disadvantages
•Global regulatory guidelines describe various
direct, indirect, or alternative sampling methods
for cleaning validation
•Methods used should be appropriate for their
intended use
•Methods used should be based on process soils
and the ability to detect the soils
•Cleaning validation programs and the method
to detect residues should be based on science
and be scientifically established as appropriate
methods for use.
INTRODUCTION
There seems to be an expectation that everyone
should perform swabbing as part of cleaning validation. Has this become a regulatory requirement?
If so, why is this a regulatory requirement? This
article discusses the advantages and disadvantages of
swabbing, the specific regulatory requirements and
expectations related to swabbing, how to develop
other methods to be used in lieu of swabbing, and
implications for compliance.
WHAT IS SWABBING?
Swab sampling is a direct surface sampling technique
for sampling surfaces. Swab sampling is accomplished by wiping the surface with a swab, typically
saturated with water or another sampling solvent, to
remove residues from a surface. The swab is then
desorbed, and a chemical analysis is performed on
the desorbed material (1).
Because swabbing employs physical forces as well
as chemical forces, qualification of the sampling
techniques should be performed to demonstrate that
the method is appropriate for use. This is necessary
before any conclusions can be made based on the
sample results (2). Swab efficiency (i.e., % recovery)
for the method must be determined to qualify the
method. Also, it is necessary to ensure that extractables of the swab or protein binding to the swab head
do not interfere with the sampling method (3).
Advantages of direct sampling are that areas hardest to clean and that are reasonably accessible can be
evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally,
residues that are “dried out” or are insoluble can be
sampled by physical removal (2).
Disadvantages of direct surface sampling are that
sampling may be impractical when product contact
surfaces are not easily accessible because of equipment design or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small
ports or handling toxic materials, and small intricate
equipment such as micronizers and microfluidizers)
(4). Swab sampling does not cover the entire surface
area of the equipment; sampling sites must, therefore,
be chosen with care (3). A major disadvantage of
swabbing is that it requires physical forces imparted
by trained operators and operator variability can
be significant. The sampling procedure must be as
detailed and specific as possible to help reduce operator variability. Operators must be qualified to meet a
pre-determined percent recovery baseline before they
are allowed to swab as part of a company’s cleaning
validation program. Another significant issue is that
in the past, equipment was designed to be torn down
and cleaned out of place, allowing swab sampling to
be more readily performed. Most equipment today is
designed to be cleaned in place. Tearing down equipment to perform swabbing or direct surface sampling
can be damaging to the equipment.
THE REGULATIONS
European (EU) and International Conference on
Harmonisation (ICH) Q7A guidelines in general state
that sampling should include swabbing, rinsing, or
alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues.
The sampling methods used should be capable of
quantitatively measuring levels of residues remaining
on the equipment surfaces after cleaning (5,6).
The US Food and Drug Administration’s Guide to
Inspections Validation of Cleaning Process states that
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CLE ANING COMPLIANCE FORUM
there are two general types of sampling that have
been found acceptable. The most desirable is the direct
method of sampling the surface of the equipment.
Another method is the use of rinse solutions (2).
Health Canada, Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation
Scheme (PIC/S), and World Health Organization
(WHO) guidelines in general state that there are two
methods of sampling that are considered to be acceptable: direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination
of the two methods is generally the most desirable (7),
particularly in circumstances where accessibility of
equipment parts can mitigate against direct surface
sampling (4, 8).
Regulatory Expectations
Companies should perform both direct and indirect
surface sampling methods to detect potential process
residues that could be carried over into the next batch
or product being produced in the manufacturing
equipment. Each company should specify what sampling methods, direct and indirect, are used as part of
their program and demonstrate that the methods they
use are appropriate for their intended use.
Other Acceptable Methods In Lieu Of Swabbing
The regulations want sampling by both direct and
indirect sampling techniques because both have different advantages and disadvantages. The indirect
or direct sampling techniques chosen by a company
should be qualified to demonstrate that the methods
are acceptable for their intended use. If a possible
source of method variation is operator variability,
then operators must be qualified to conduct sampling
in order to demonstrate consistency.
Swabbing is the most common type of direct
surface sampling. Visual inspection is also a direct
surface sampling method. As technology advances,
new techniques for direct surface sampling, such as
surface Fourier Transform Infrared (FTIR) spectroscopy, are also being evaluated for applicability. The
advantages for direct sampling are also true for visual
inspection, in that areas hardest to clean and that are
reasonably accessible can be evaluated. The one chal12 Journal of GXP Compliance
lenge with visual inspection is that during qualification the visual residue limit (VRL) is established; this
is the amount of residue that is visually detectable
by multiple trained operators, but during execution
visual inspection is a pass/fail test. The direct surface
sampling technique a company uses should be based
on the process soils and the ability of the direct surface sampling techniques to detect the process soils.
IMPLICATIONS FOR COMPLIANCE
Direct and indirect surface sampling should be
performed as part of each company’s cleaning validation program. All sampling methods used, as part
of a cleaning validation program should be qualified
to demonstrate that they are accurate, reliable, have
minimal variability, and are appropriate for their
intended use.
CONCLUSIONS
Cleaning validation programs and the method to
detect residues should be based on science and be
scientifically established as appropriate methods for
use. A “one-size-fits-all” (or one sampling approach
fits all) approach is not appropriate for industry. All
sampling methods used as part of a cleaning validation program must be qualified to demonstrate that
they are appropriate for their intended use.
REFERENCES
1. GMP Regulations, Maas & Peither AG, GMP Publishing,
Schopfheim.
2. FDA, Guide To Inspections of Validation of Cleaning Processes, FDA
Office of Regulatory Affairs. Rockville, MD, 1993.
3. Active Pharmaceutical Ingredients Committee, “Cleaning
Validation in Active Pharmaceutical Ingredient Manufacturing Plants,” Active Pharmaceutical Ingredients Committee,
September 1999.
4. Health Canada, Cleaning Validation Guidelines (GUIDE-0028),
Health Canada, January 1, 2008.
5. EC, “The Rules Governing Medicinal Products in the European
Community,” Volume IV, Good Manufacturing Practices for
Medicinal Products, October 2005.
6. ICH Guidance for Industry, Q7A Good Manufacturing Practice
Guidance for Active Pharmaceutical Ingredients, August 2001.
7. WHO, “Appendix 3, Cleaning Validation,” WHO Expert Com-
Jennifer Carlson
mittee on Specification for Pharmaceutical Preparation, World
Health Organization, Fortieth Report.
8. PIC/S, Recommendations on Cleaning Validation. Document PI 0061, Pharmaceutical Inspection Cooperation Scheme, Geneva,
Switzerland, August 3, 2001.
GENERAL REFERENCES
PDA, “Points to Consider for Cleaning Validation,” PDA Technical
Report No. 29, PDA: Bethesda, MD, August 1998.
Brunkow, R.; Delucia, D.; Haft, S.; Hyde, J.; Lindsay, J.; McEntire,
J.; Murphy, R.; Myers, J.; Nichols, K.; Terranova, B.; Voss, J.;
White, E., Cleaning and Cleaning Validation: A Biotechnology
Perspective, PDA: Bethesda, MD, 1996.
Forsyth, R.J. and Hartman, J.L., “A Risk-Based Approach to Cleaning Validation using Visible Residue Limits,” Pharmaceutical
Engineering, Vol. 28, No. 3, 2008.
DA LeBlanc, “Correlation of Swab and Rinse Sampling Results,”
Chapter 25 in Cleaning Validation: Practical Compliance Solutions for Pharmaceutical Manufacturing, PDA/DHI, Bethesda,
MD, 2006.
DA LeBlanc, “Understanding and Improving Swabbing and Swab
Recovery,” Webinar presented Feb. 26, 2009, Cleaning Validation Technologies, Kodak, TN. GXP
ARTICLE ACRONYM LISTING
EU
European Union
FDA
US Food and Drug Administration
FTIR
Fourier Transform Infrared Spectroscopy
ICH
International Conference on Harmonisation
PIC/SPharmaceutical Inspection Convention and
Pharmaceutical Inspection Co-operation
Scheme
VRL
Visual Residue Limit
WHO
World Health Organization
FUTURE ARTICLES IN THIS COLUMN
Future “Cleaning Compliance Forum” column articles will discuss topics such as worst-case sampling
locations, cleaning effects on the active pharmaceutical ingredient, determining worst-case products,
direct versus indirect sampling methods, establishing visual residue limits, storage of clean equipment,
steam-lining the introduction of new products to
facilities, and calculating acceptance criteria limits.
Suggestions for discussion topics from readers
are most welcome. Please submit suggestions or
comments to column coordinator Jenna Carlson at
[email protected] or journal coordinating editor [email protected].
ABOUT THE AUTHOR
Jenna Carlson is a senior technical manager in Genentech’s Corporate Quality System and Support, Validation department. She
is responsible for developing and overseeing governance activities
for cleaning validation, including the corporate requirements
and procedures. She has more than 11 years experience focusing
on validation and quality assurance. Jenna has held key roles
at leading biotechnology firms including Allergan, Baxter, and
BioMarin, focusing on validation of equipment, cleaning, process,
and methods. She is an author and team member of the PDA task
force developing the new Point to Consider for Biotechnology Cleaning
Validation. Jenna is also a chapter author in Cleaning & Cleaning
Validation for the Pharmaceutical & Medical Device Industries Vol. 1.,
Basics, Expectations, and Principles. She may be reached by e-mail
at [email protected].
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