Effective Manual Cleaning Procedures-Development, Documentation, Performance, and Maintenance

1) The document discusses key considerations for developing, documenting, and performing effective manual cleaning procedures, including: clearly specifying critical steps, quantifying important parameters, ensuring consistent performance through detailed procedures, and operator training, monitoring, and verification. 2) Operators must be well-trained on cleaning procedures and understand their importance for preventing contamination. Training should be documented and periodically evaluated. 3) Effective manual cleaning requires procedures that minimize inherent variability, performance by well-trained operators, and regular monitoring to maintain validation over time. Support from management is important for success.

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Effective Manual Cleaning Procedures-Development, Documentation, Performance, and Maintenance

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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
be a useful resource for daily work applications. The primary objective for this
column: Useful information.
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 Troy Fugate at [email protected] or journal
coordinating editor Susan Haigney at [email protected].

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

Autumn 2009 Volume 13 Number 4 23

EFFECTIVE GMP

enough to ensure the inherent variability Operators should know how to appropri-
will not result in inadequate cleaning. The ately inspect cleaned equipment and should
development work should result in a cleaning be especially aware of the most difficult to
procedure that is robust enough to give con- clean locations on equipment. The final step
sistently clean equipment. Procedures may in- in the cleaning procedure is the inspection of
clude excessive washing, rinsing, and mechani- the cleaned equipment. Operators should be
cal action. This is necessary to compensate for trained in the proper way to inspect equipment
the inherent variability in cleaning technique with focus on high-risk sections of equipment.
from one operator to another. Operators should be aware of factors that may
Cleaning procedures must specify key ele- cause erroneous inspections, such as insuffi-
ments of the cleaning procedure. Cleaning cient light and equipment wetness. All person-
procedures must clearly state the important nel including operators, verifiers, and qual-
activities to be performed by personnel doing ity unit personnel involved with equipment
the cleaning. Variation inherent in a manual inspection should have inspection training.
cleaning process will be minimized by clearly Operators must be adequately trained in per-
stating the key steps in the cleaning procedure. formance of manual cleaning procedures and
Cleaning procedures should quantitatively that training should be documented, periodi-
state the most important process param- cally challenged, and frequently monitored.
eters. These include cleaning agent concen- Training on cleaning procedures requires
trations, temperatures of cleaning liquids, actual performance under the supervision of
scrubbing times, rinsing volumes, and so on. area experts. Training cannot be by read and
Any quantitative parameters that have impact sign. Training should be challenged by testing
on the efficacy of the cleaning process should and periodic auditing by the quality unit.
be specified and controlled. Operators must clearly understand cleaning
Cleaning procedures must contain enough processes and the potential ramifications of
detail to ensure consistent performance and inadequate cleaning. Operators who perform
should be clearly stated to prevent misinter- cleaning must clearly understand the objective
pretation. Cleaning procedures must clearly of cleaning. They must know that inadequate
specify critical and key procedural elements. cleaning may cause harm, illness, or other
Procedures that are not sufficiently restrictive medical effects of the consumer as result of
will enable operator variation in the cleaning cross-contamination. They must understand
process. Operators must not perform steps the seriousness of cleaning and perform clean-
that are not specified in the procedure. Manual ing with this in mind.
variation is controlled by sufficiently detailed Operators must have a comprehensive
procedures. knowledge and understanding of the spe-
Performance of most important process pa- cific details of cleaning procedure being
rameters should require operator signoff and performed. Operators who perform cleaning
second verification affirming performance. must clearly understand that cleaning must be
The performance of critical or key steps in the performed as a defined procedure, not some-
cleaning procedure, just as in manufacturing thing like washing dishes at home. Operators
procedures, should be affirmed by the opera- must understand that cleaning must be ex-
tor. For example, the visual verification of plicitly performed in the order specified in the
the cleaned and dried equipment should be cleaning procedure. There is no flexibility in
affirmed in writing by both the operator and a performance, and operators must understand
second witnessing individual. why there is no flexibility.

24 Journal of GXP Compliance

Tr o y F u g a t e , C o o r d i n a t o r

Manual cleaning must be regularly moni- minimize variation; performance by well-trained

tored, and operators should be periodically operators; and period monitoring to maintain
observed to maintain the validated state of validation. Awareness of these key elements by
the cleaning process. Manual cleaning is a manufacturing personnel and quality personnel,
high-risk process because of its inherent vari- and support of the efforts to accomplish the above
ability. The ongoing efficacy of manual clean- by senior management, will enable a successful
ing should be regularly demonstrated. Opera- manual cleaning program.
tor performance according to procedure should
be periodically reviewed. Periodic review REFERENCES
ensures the operator performance is consistent 1. FDA, Guide to Inspections of Validation of Cleaning Processes,
with written procedures, which in turn are July 1993.
consistent with the cleaning validation. 2. FDA, Guidance for Industry, Process Validation: General Prin-
ciples and Practices, Draft Guidance, November 2008.
These points are consistent with the concepts 3. FDA, 21 CFR Part 210, CGMP in Manufacturing, Process-
of the US Food and Drug Administrations inspec- ing, Packing, or Holding of Drugs and Finished Pharma-
tion guide for cleaning processes (1), the 2008 draft ceuticals, Page 820, Quality Systems Regulations. GXP
guidance for process validation (2), and current good
manufacturing practice (CGMP) regulations (3). ABOUT THE AUTHORS
Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive
CONCLUSIONS industrial development, manufacturing, compliance, and man-
agement experience. He is also adjunct faculty at the University
This discussion has addressed key elements of of Illinois Chicago College of Pharmacy with involvement in
manual cleaning procedures in support of CGMP undergraduate and graduate student teaching and mentoring.
compliance. Manual cleaning is a high-risk activity Dr. Pluta is Editor-in-Chief of the Journal of Validation Technol-
because of the inherent variability of personnel ogy and the Journal of GXP Compliance. He may be reached by
performance. As such, it must be carefully de- e-mail at [email protected] or by phone at 847.607.8153.
signed and developed, well documented in proce-
William E. Hall, Ph.D., is a technical pharmaceutical con-
dures, and then continually monitored during use. sultant with Hall & Associates of North Carolina. Dr. Hall
Carefully written detailed procedures are the most has more than 50 years pharmaceutical industry experience.
important aspect of manual cleaning procedures. He has consulted with more than 500 clients worldwide on
Well-trained operators who are knowledgeable process validation, cleaning validation, GMP compliance, new
product development, new company startup, APIs, excipients,
about cleaning and the potential serious effects of
devices, vendors, and other topics. He has served as a technical
poor cleaning, and who carefully perform the ex- industry expert to FDA on pending court cases. Dr. Hall spent
plicit details of cleaning procedures, are necessary several years in academia teaching graduate and undergraduate
for successful manual cleaning. courses, and currently serves on the Deans Advisory Council
In brief, key elements to assure good manual at both the University of Arkansas School of Pharmacy and
the East Carolina University School of Biotechnology. He may
cleaning procedures include good technical devel-
be reached by e-mail at [email protected] or by phone at
opment; clearly written procedures with specified 910.264.4334.
process parameters that are sufficiently detailed to