EFFECTIVE GMP

Effective Manual Cleaning

ProceduresDevelopment,
Documentation, Performance,
and Maintenance
Paul L. Pluta and William E. Hall

Effective GMP discusses specific good manufacturing practice (GMP) topics

useful to practitioners in compliance and validation. We intend this column to
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INTRODUCTION
This discussion of Effective GMP addresses key considerations in
the development of manual cleaning procedures, documents reflecting
S. STEWART

these procedures, and their subsequent use in cleaning performance.

Manual cleaning procedures may comprise the entire method of clean-
ing manufacturing equipment, or may be performed in conjunction
with automated cleaning methods. For example, mixing tanks may be
cleaned by an automated clean-in-place (CIP) cleaning procedure while
associated equipment and parts are cleaned manually. Manual cleaning
procedures should be considered as equivalent to manufacturing pro-
cedures regarding overall strategy and approach. After development,
cleaning procedures are documented, validated, and then routinely
used throughout the product lifecycle by trained personnel.

KEY CONSIDERATIONS
The following are key considerations for development, documentation,
and performance of effective manual cleaning procedures:
Manual cleaning procedures must be carefully developed using
scientific and technical principles but should also be practi-
cal and logical. Development work provides the technical basis
for the cleaning procedures. Procedures must be developed with
consideration for validation and ongoing routine use in the manu-
facturing facility throughout the entire product lifecycle.
Technical aspects must be chosen considering the inherent
variability of manual cleaning procedures and must be robust

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EFFECTIVE GMP
enough to ensure the inherent variability
will not result in inadequate cleaning. The
development work should result in a cleaning
procedure that is robust enough to give con-
sistently clean equipment. Procedures may in-
clude excessive washing, rinsing, and mechani-
cal action. This is necessary to compensate for
the inherent variability in cleaning technique
from one operator to another.
Cleaning procedures must specify key ele-
ments of the cleaning procedure. Cleaning
procedures must clearly state the important
activities to be performed by personnel doing
the cleaning. Variation inherent in a manual
cleaning process will be minimized by clearly
stating the key steps in the cleaning procedure.
Cleaning procedures should quantitatively
state the most important process param-
eters. These include cleaning agent concen-
trations, temperatures of cleaning liquids,
scrubbing times, rinsing volumes, and so on.
Any quantitative parameters that have impact
on the efficacy of the cleaning process should
be specified and controlled.
Cleaning procedures must contain enough
detail to ensure consistent performance and
should be clearly stated to prevent misinter-
pretation. Cleaning procedures must clearly
specify critical and key procedural elements.
Procedures that are not sufficiently restrictive
will enable operator variation in the cleaning
process. Operators must not perform steps
that are not specified in the procedure. Manual
variation is controlled by sufficiently detailed
procedures.
Performance of most important process pa-
rameters should require operator signoff and
second verification affirming performance.
The performance of critical or key steps in the
cleaning procedure, just as in manufacturing
procedures, should be affirmed by the opera-
tor. For example, the visual verification of
the cleaned and dried equipment should be
affirmed in writing by both the operator and a
second witnessing individual.
24 Journal of GXP Compliance
Operators should know how to appropri-
ately inspect cleaned equipment and should
be especially aware of the most difficult to
clean locations on equipment. The final step
in the cleaning procedure is the inspection of
the cleaned equipment. Operators should be
trained in the proper way to inspect equipment
with focus on high-risk sections of equipment.
Operators should be aware of factors that may
cause erroneous inspections, such as insuffi-
cient light and equipment wetness. All person-
nel including operators, verifiers, and qual-
ity unit personnel involved with equipment
inspection should have inspection training.
Operators must be adequately trained in per-
formance of manual cleaning procedures and
that training should be documented, periodi-
cally challenged, and frequently monitored.
Training on cleaning procedures requires
actual performance under the supervision of
area experts. Training cannot be by read and
sign. Training should be challenged by testing
and periodic auditing by the quality unit.
Operators must clearly understand cleaning
processes and the potential ramifications of
inadequate cleaning. Operators who perform
cleaning must clearly understand the objective
of cleaning. They must know that inadequate
cleaning may cause harm, illness, or other
medical effects of the consumer as result of
cross-contamination. They must understand
the seriousness of cleaning and perform clean-
ing with this in mind.
Operators must have a comprehensive
knowledge and understanding of the spe-
cific details of cleaning procedure being
performed. Operators who perform cleaning
must clearly understand that cleaning must be
performed as a defined procedure, not some-
thing like washing dishes at home. Operators
must understand that cleaning must be ex-
plicitly performed in the order specified in the
cleaning procedure. There is no flexibility in
performance, and operators must understand
why there is no flexibility.

Manual cleaning must be regularly moni-
tored, and operators should be periodically
observed to maintain the validated state of
the cleaning process. Manual cleaning is a
high-risk process because of its inherent vari-
ability. The ongoing efficacy of manual clean-
ing should be regularly demonstrated. Opera-
tor performance according to procedure should
be periodically reviewed. Periodic review
ensures the operator performance is consistent
with written procedures, which in turn are
consistent with the cleaning validation.
These points are consistent with the concepts
of the US Food and Drug Administrations inspec-
tion guide for cleaning processes (1), the 2008 draft
guidance for process validation (2), and current good
manufacturing practice (CGMP) regulations (3).
CONCLUSIONS
This discussion has addressed key elements of
manual cleaning procedures in support of CGMP
compliance. Manual cleaning is a high-risk activity
because of the inherent variability of personnel
performance. As such, it must be carefully de-
signed and developed, well documented in proce-
dures, and then continually monitored during use.
Carefully written detailed procedures are the most
important aspect of manual cleaning procedures.
Well-trained operators who are knowledgeable
about cleaning and the potential serious effects of
poor cleaning, and who carefully perform the ex-
plicit details of cleaning procedures, are necessary
for successful manual cleaning.
In brief, key elements to assure good manual
cleaning procedures include good technical devel-
opment; clearly written procedures with specified
process parameters that are sufficiently detailed to
Tr o y F u g a t e , C o o r d i n a t o r
minimize variation; performance by well-trained
operators; and period monitoring to maintain
validation. Awareness of these key elements by
manufacturing personnel and quality personnel,
and support of the efforts to accomplish the above
by senior management, will enable a successful
manual cleaning program.
REFERENCES
1. FDA, Guide to Inspections of Validation of Cleaning Processes,
July 1993.
2. FDA, Guidance for Industry, Process Validation: General Prin-
ciples and Practices, Draft Guidance, November 2008.
3. FDA, 21 CFR Part 210, CGMP in Manufacturing, Process-
ing, Packing, or Holding of Drugs and Finished Pharma-
ceuticals, Page 820, Quality Systems Regulations. GXP
ABOUT THE AUTHORS
Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive
industrial development, manufacturing, compliance, and man-
agement experience. He is also adjunct faculty at the University
of Illinois Chicago College of Pharmacy with involvement in
undergraduate and graduate student teaching and mentoring.
Dr. Pluta is Editor-in-Chief of the Journal of Validation Technol-
ogy and the Journal of GXP Compliance. He may be reached by
e-mail at paul.pluta@comcast.net or by phone at 847.607.8153.
William E. Hall, Ph.D., is a technical pharmaceutical con-
sultant with Hall & Associates of North Carolina. Dr. Hall
has more than 50 years pharmaceutical industry experience.
He has consulted with more than 500 clients worldwide on
process validation, cleaning validation, GMP compliance, new
product development, new company startup, APIs, excipients,
devices, vendors, and other topics. He has served as a technical
industry expert to FDA on pending court cases. Dr. Hall spent
several years in academia teaching graduate and undergraduate
courses, and currently serves on the Deans Advisory Council
at both the University of Arkansas School of Pharmacy and
the East Carolina University School of Biotechnology. He may
be reached by e-mail at CleanDoct@aol.com or by phone at
910.264.4334.
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