A Cleaning Validation Master

Plan for Oral Solid

Dose Pharmaceutical
Manufacturing Equipment
By Julie A. Thomas
McNeil Consumer Healthcare

ith the benchmark con

Validations of Cleaning Processes
stantly being raised,
July 1993. Each of these will be
}Often,
many companies find
discussed in greater detail in the sec
companies have tions below.
that they are in perpetual valida
tion mode. Often, companies have
executed
executed validations for equipment,
n Objective
cleaning, and processes, but the
n Scope
validations for
documentation no longer stands up
n Introduction
to the latest in validation standards.
n Responsibilities
equipment,
Although these validations are gen
n Philosophy
cleaning,
and
proerally complete and on file, there
n Methodology
are many opportunities to improve
n Schedule
cesses,
but
the
docboth the supporting documenta
Objective
tion and the execution. One way to
umentation
ensure that your companys policies
no longer stands
This section should state the pur
and procedures regarding cleaning
pose of your cleaning master valida
validation are state-of-the-art is to
up to the latest tion plan and define whether you will
assemble a multi-disciplined team
be revalidating current procedures or
from the appropriate manufacturing
validation
prospectively validating new ones.
sites that can review and revise all
Often, the plan will have provisions
components associated with clean
standards.~
for both situations.
ing validation. What follows are
excerpts from a Cleaning Validation
Scope
Master Plan (the Plan) that was painstakingly com
posed and has now become the standard for planning
The scope needs to list exactly which aspects of val
and executing cleaning validations at several manu
idation will be covered in the document and to which
facturing sites.
types of products and/or processes the Plan applies. For
An outline of the Plan contains the following seven
elements, the concepts of which are taken directly example, This document provides steps for planning,
executing, and maintaining equipment cleaning valida
from the FDA publication, Guide to Inspections of
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Julie A. Thomas

tions for oral solid dose products at Your Companys

manufacturing facility in Your City, State.

Introduction

The introduction should let the reader know

what elements will be addressed in the Master
Validation Plan and why a formal plan is necessary.
For instance, This plan is intended to be a roadmap
clarifying the course the Company will take as it
plans and executes the cleaning validations required
by current Good Manufacturing Practices (cGMP).
This program describes and defines the various
categories of cleaning validation, provides the nec
essary protocol elements, and offers guidance for
unexpected results. Furthermore, it includes provi
sions for revalidation and monitoring and serves as
a mechanism to organize and store critical informa
tion that supports the cleaning validation process.

Responsibilities
There are many departments and disciplines
involved in planning for and executing a cleaning
validation. It is necessary to list each contributing
area and the associated tasks for which it is respon
sible. This serves to clarify roles and to ensure that
tasks are not overlooked. Typically, representatives
from Validation, Manufacturing, Quality Control,
Engineering, and Research and Development (R&D)
will be needed. The following are some examples of
departmental responsibilities:
Validation Specialist

Review cleaning procedures

Assist the cleaning validation team in iden
tifying equipment test sites for swab or
rinse samples

Write cleaning validation protocols

Coordinate execution of the cleaning pro
cess with the appropriate departments and
laboratories

Prepare the sampling schedule

Assemble the test data into final report
form for approval
Manufacturing

Provide technical information for the devel
opment of protocols and reports

Review and approve protocols and reports
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Institute of Validation Technology

for accuracy and agreement with operating

practices

Create and/or revise related SOPs and
cleaning checklists

Perform cleaning processes per SOP as
referenced in the validation protocol

Provide documented training for all person
nel responsible for cleaning the equipment
Quality Assurance

Review and approve protocols and reports
for conformance with cGMPs and internal
procedures

Provide analytical technical support

Provide documented training for all person
nel responsible for sample collection and
testing

Collect analytical samples as specified in
the protocol

Perform analytical testing using validated
procedures

Label, package, and send out those samples
that need to be analyzed by an external
laboratory

Review and approve analytical results

Notify departments of test results
Engineering

Inform the affected department in advance
of any anticipated change to the facility or
equipment

Include all utilities and cleaning equipment
in the calibration and maintenance pro
gram

Review and approve equipment drawings
and surface area calculations
Research and Development

Provide swab and surface recovery data for
active ingredients and cleaning agents

Validate analytical test methods for chemi
cal and cleaning agent analyses

Transfer validated methods to the site QC
laboratories and/or contract laboratories

Provide recommended cleaning procedures
for new active ingredients and/or cleaning
agents

Cleaning Validation Philosophy

This section discusses the considerations you

Julie A. Thomas

have made in developing a comprehensive cleaning

validation program, such as how to define equipment
holding time, equipment storage time, and campaign
length. In general, the philosophy section presents the
Companys position on what is being achieved by the
cleaning validation and how it will be demonstrated.
For instance, Cleaning validation is required for all
manufacturing and packaging equipment that comes
into contact with the product or product components
during production. Prior to validation, acceptance
criteria will be developed for active ingredient and
cleaning agent residues. Verification of acceptable
equipment holding time will be included as part of
the validation. Holding time is defined as the time
between the end of the last product manufactured and
the start of the cleaning process. This will demonstrate
that the cleaning procedure effectively removes resi
due after the equipment has remained idle for a speci
fied period of time. Additionally, holding time will be
evaluated to ensure storage conditions are adequate
for a predetermined length of time. Storage time is
defined as the time between cleaning completion and
the next batch processed on the equipment. Campaign
length will be determined jointly by Operations and
R&D and validated with at least three iterations using
the maximum number of batches or maximum length
of time. This approach fully challenges the cleaning
procedure by providing worst-case residues.

Cleaning Validation Methodology

To ensure all of the elements are in place for a
thorough and successful validation, a chronological
methodology should be followed. One such design is
illustrated through the following four phases: devel
opment, planning, execution, and maintenance. (See
Figure 1) In this section of the Plan, it is appropriate
to include the number of sampling/testing iterations
required for each piece of equipment and/or each
analyte. (See Figure 2.)
If you intend to reduce the number of tests
required to validate cleaning after various products
by using a grouping approach, it should be explained
in this section.1

Development Phase
The initial phase of the cleaning validation plan is

preparatory and includes analytical methods valida

tion, recovery studies, surface types, degradants, and
methods transfer. There is a considerable amount of
scientific activity that must be completed before the
validation can begin. These steps are explored in the
following sections.
1. Analytical Methods Validation
Describe how the analytical methods will be
developed and validated for active ingredients, deg
radants (if applicable), and cleaning agent residue.
Validation of the method should assess reproducibil
ity, linearity, specificity, limit of detection (LOD),
and swab and surface recovery. Other elements for
consideration are the instrumentation, swabbing and
dilution solvents, dilution volume, and sample han
dling and storage.2,3
2. Recovery Studies
Recovery studies evaluate quantitative recovery
of chemical residue from both the surface to be
sampled and the swab material to be used for sam
pling. The results confirm the appropriateness of
the sampling method and material used. You should
determine the minimum recovery criteria for each
surface type and state that percentage in this sec
tion. For instance, you may want recovery values of
at least 70% of actual readily soluble residues, but
may choose a much lower recovery value for rela
tively insoluble proteins.4 Most important, you must
provide data to justify the chosen value.
3. Surface Types
Since different surface types have different affini
ties, you may want to choose a few surface materials
to represent the many product contact surfaces used
in manufacturing. For oral solid dose manufactur
ing, you may determine that stainless steel, silicone,
and polypropylene are the most abundant surfaces
and that they also provide varying degrees of poros
ity. A matrix of all surface types and the representa
tive material that will be used in recovery studies is
appropriate. (See Figure 3)
4. Degradants
Many degradant products are more soluble in the
cleaning solvent than are the active ingredients; there
fore, you should determine the degree of degradant
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Julie A. Thomas

Figure 1

Cleaning Validation Flow Diagram

Development Phase
Analytical Method
Validation

Analytical Method
Development

D
 egradant
identification
Transfer

Recovery
Surface types
Planning Phase
Equipment
S
 ample site
selection
Surface area
calculation
Schematic

Analyte Selection
and Acceptance
Criteria

Protocol
Development
 rite
W
Approve
Train

 ctive ingredient
A
Cleaning agent

Cleaning
SOP
 rite
W
Approve
Train

Execution Phase
Protocol Execution
C
 lean
Sample
Test

Pass?

No

Incident
Investigation

Yes

Validation Report
W
 rite
Approve
Maintenance Phase
Monitoring

Change Control
Revalidation

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Institute of Validation Technology

Julie A. Thomas

Figure 2

Cleaning Iteration Summary Requirements

Sample Total Number of Iterations Conditions

Active Residue
3

1 at maximum campaign length or

maximum time period plus holding
time.

2 at maximum campaign length or

time period.

Cleaning Agent Residue

3

3 per cleaning procedure, per piece

of equipment.

testing required based on the toxicity and solubil

ity of potential degradants. Likewise, active ingre
dients should be exposed to the selected cleaning
agent under normal usage conditions to determine
if degradants are formed as a result of the cleaning
process.
5. Analytical Methods Transfer
In this section, you can state how sampling and
analytical methods will be transferred from the
R&D laboratories to the site QC laboratories and
how the analysts conducting validation testing will
be qualified. Reference appropriate SOPs and/or
Development Transfer Report.

Planning Phase
The next phase of preparation is the planning phase.
This is a broad category that focuses on equipment
information, analyte selection, acceptance criteria,
cleaning procedures, and protocol development. At this
point, you are starting to think about what equipment
will be included in the validation, which analytes will
be chosen, and how you will determine acceptance cri
teria. This leads to an in-depth review of the procedures
and, finally, to protocol development.
Figure 3
Recovery Surface:

1. Equipment Information
This section should detail the methodology for
providing specific equipment information. One
option is to prepare a binder containing detailed
surface area calculations, swab sampling sites (with
justification), photos, and schematic diagrams for
each piece of equipment. This binder can be main
tained separately and used as an attachment to the
cleaning validation protocol as needed.
a) Sample Site Selection
Explain how you will select sampling sites to rep
resent the product contact surface area of the equip
ment. One of the best sources of information is the
operator who routinely cleans the equipment. He or
she can certainly point out the areas they find most
difficult to clean. Make the operator part of a larger
team of experts to include representatives from
Validation, QA, and Operations, and let the team
determine the product contact surface areas that are
most difficult to clean and those that are most repre
sentative of the equipment. Sampling these sites will
represent the entire equipment surface area using
the assumption that residue will be evenly distrib
uted over the equipment and that the most difficult
to clean locations will represent the worst case for
residue removal. Include the basis for selecting each

Surface Recovery Matrix

316L Stainless Steel

Polyethylene Silicone

Material Used:

316L Coupon

Plastic Bulk Container

Hose

To Represent:

304 Stainless
Aluminum
Brass

Teflon
Lexan
HDPE

Rubber
EPDM
Neoprene

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Julie A. Thomas

site. For example, sampling sites may be deemed to

be the most difficult to clean, most difficult to dry,
or of different material of construction. Swab sites
Figure 4

Kason Separator

Swab Site

can be indicated with either digital photographs or

suitable diagrams. (See Figure 4)
b) Surface Area Calculation
An accurate surface area must be calculated for
each piece or section of equipment. This can be
done with manufacturers drawings, but should be
confirmed by field measurements. If drawings are
not available, the equipment must be measured to
determine surface area (see Figure 5). Although not
shown here, it is advisable to include the calcula
Figure 5

Surface Area

Swab Number Area Swabbed

1

Screen/ring interface
gasket

Discharge port inside

of top circular area
(top seam)

Total contact S.A. of Kason Separator (in )

2

Total contact S.A. of Filter Socks (in2)

3,171.2
15.6

tions with the schematic diagram in the equipment

information binder mentioned above.
c) Schematic Diagram
To clearly illustrate each piece of equipment, pre
66

Figure 6

Institute of Validation Technology

pare schematic diagrams labeled with the major sec

tions of the equipment. (See Figure 6) The drawings
do not have to be to scale, but should appropriately
represent the equipment. If a schematic is not practical
(i.e., a packaging line), a photograph is acceptable. The
intent is to depict the product contact surfaces that are
included in the calculations. This helps to ensure that
the swab samples are taken from the intended location.
2. Analyte Selection
Analyte selection is required for active, excipi
ent (possibly), and cleaning agent residues. Keep
in mind that you are validating a cleaning proce
dure, not a manufacturing process. In the situation
where the same cleaning procedure is used for many
product formulas, there is an opportunity to select a
representative analyte to cover multiple active ingre
dients and reduce the amount of testing.
a) Actives
If several active ingredients are processed in a single
piece of equipment, a marker active, or guiding sub
stance, can be selected based on the active ingredient
solubility in water, potency, previous production expe
rience, and R&D studies. This reduces the number of
studies required to validate the cleaning procedure.5
b) Excipients

Julie A. Thomas

The removal of excipients can either be con

firmed by visual inspection or through analytical
testing. The approach should be stated here along
with training requirements for individuals perform
ing visual inspection.
c) Cleaning Agents
Testing for cleaning agent residue is essential but
is often an area in which current cleaning validations
are deficient. For most cleaning agents, a marker
compound can be selected for analysis based on the
recommendation of the cleaning agent manufactur
er. Removal of volatile cleaning agents that do not
leave a residue, such as isopropyl alcohol, may not
need to be validated.
3. Acceptance Criteria
The equipment must pass visual and olfac
tory inspection, where appropriate, as defined in
the cleaning validation protocol prior to initiation
of swabbing.6 This is a critical step in the validation
process that, if skipped, can lead to failed results.
a) Active Ingredient
Acceptance criteria for active ingredients should
be based on medical and pharmacological properties
and scientific information. Calculations using the
maximum allowable carryover (MAC) and/or 10ppm
formulas can be used.7
To ensure that all active contact surfaces are consid
ered in the carryover calculation, you may want to iden
tify equipment trains. Acceptance criteria are calculated
using the surface area from the entire equipment train;
however, protocols are executed per each piece of equip
ment. Equipment trains could be designated as follows:
n Granulation granulator system through the
product container
n Compression through printing compression,
film-coating, and printing phases
n Packaging product contact surfaces for each
type of packaging line
b) Cleaning Agent
Acceptance criteria for the cleaning agent marker
should be based on toxicity, limit of detection of
validated assay method, and/or data gathered dur
ing certification studies. Acceptance criteria can be

calculated using a formula such as the No Observed

Effect Limits (NOEL).8
4. Cleaning Procedures
This section should indicate that cleaning procedures
will be developed (or existing procedures reviewed)
prior to the validation. It should also list the required
elements for cleaning procedures, such as temperature,
pressure, water quality, cleaning agent concentration,
spray nozzle location, etc., or it should reference where
these requirements can be found.9 Additionally, you
should describe the process for training the operators
who will be executing the validation studies.10
5. Protocol Development
The next step is to write a cleaning validation pro
tocol for each cleaning procedure that you intend to
validate. The protocol should describe all documenta
tion required to complete the cleaning validation. It
should also present the rationale for using a marker
active to cover validation for multiple products. For
ease of review, include a matrix of the products and
equipment that are covered by each validation, or
reference where this information can be found. For
example, if there are three active ingredients processed
in Fluid Bed Granulator #1, indicate which active will
be used to represent the other two. Likewise, indicate
which pieces of equipment will be used to validate
Figure 7

Equipment Cleaning Matrix

Active A Active B Active C Cleaning

Agent A
Fluid Bed Gran 1
Fluid Bed Gran 2
Starch Kettle 1

the removal of active ingredient and cleaning agent

residues. (See Figure 7)

Execution Phase

When all of the supporting documentation is com

plete, it is time to execute the plan. During the execu
tion phase, you will complete the protocol, investi
gate any nonconformances that may have occurred,
and write a report to summarize your findings.
1. Protocol Execution
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Julie A. Thomas

Typically, three iterations of cleaning, sampling,

and testing using the same procedure are required.
Acceptance criteria for all cleaning iterations must
be met for both the active ingredient and the clean
ing agent. Be sure to reference the procedure where
a detailed description of the chemical swab prepara
tion and sampling methods can be found.
2. Incident Investigation
This section explains how the Company will
handle test failures and nonconformances during
execution of the validation. Once the root cause of
the failure has been identified, options are to addend
the protocol or start over with a new protocol. For
any incident that occurs during validation, docu
ment the investigation along with corrective and
preventive actions. The incident report may contain
elements such as:
n Cleaning validation protocol number
n Incident report number
n Equipment model and location
n Initiator and date
n Incident description
n Root cause analysis
n Corrective actions recommended/taken
n Assessment of effect on product
3. Reports
Describe the report format and content that will
be used to summarize the validation. Reference
appropriate SOPs for detailed report information.
An explanation of all deviations should be included
in the validation report.

Maintenance Phase
The final phase of the Plan should specify how
you will maintain the conditions you have just
validated. This includes periodic monitoring, using
a control of change process, and potentially, revali
dating.
1. Monitoring
This section details how you will ensure that the
conditions used during validation remain in con
trol during routine production. This is especially
important for manual cleaning procedures, where
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Institute of Validation Technology

repeatability is highly dependent on the quality and

consistency of training. Monitoring should include,
at a minimum, a review of changes made to the
cleaning procedure or equipment, visual inspection
of the equipment, and direct observation of employ
ees executing the cleaning procedure. For some
equipment, swab samples for active ingredients may
be necessary in addition to the visual inspection
and observation. Indicate the frequency that you
intend to monitor the cleaning process. Reference
the appropriate SOP for detailed requirements of the
monitoring program.
2. Change Control
Indicate how changes will be managed to ensure
the validated state is maintained. Any change in
the facility, process equipment, cleaning procedure,
cleaning agent, product formulation, or addition
of new products to the equipment train should be
documented and approved via the Change Control
System. The change should be reviewed by the Val
idation Group, Operations, and QA, who will decide
if revalidation is necessary. Reference appropriate
SOPs.11
3. Revalidation
Indicate the criteria that will be used to determine
the need for revalidation. Based on the nature of the
change, a determination will be made as to which,
if any, phases of the validation must be repeated.
Reference where documentation of the revalidation
will be filed.12,13

Cleaning Validation Schedule

Prioritization
As is usually the case, all cleaning validations
cannot commence at one time; therefore, it is nec
essary to set up a priority list. Some situations to
consider are:
n Equipment shared between products contain
ing different active ingredients
n Equipment in contact with raw material with
high potential for contamination
n Unshared primary equipment currently in use
with outdated validations
n Unshared auxiliary equipment used for pro

Julie A. Thomas

duction with limited potential for product

contamination
Tactical Schedule
A proposed schedule, including equipment pri
oritization and target initiation dates, should be pre
sented in this section. This gives an indication that
you have contemplated the order of execution, and
it also provides a tool that can be used to track your
progress.

Summary
There are many aspects of cleaning validation
that must be carefully planned to guarantee a suc
cessful validation program. If you begin with a phi
losophy, this will set the stage for you to develop a
structured approach. By dividing the approach into
sections, such as development, planning, execu
tion, and maintenance, it breaks down the project
into manageable segments. To complete the Plan,
generate a tactical schedule and begin monitoring
progress towards your new and improved cleaning
validation status. o

About the Author

References

1. Jenkins, K.M. and Vanderwielen, A.J. Cleaning Validation: An

Overall Perspective, Pharmaceutical Technology, April 1994,
p. 62.
2. McCormick, P.Y. and Cullen, L.F., Pharmaceutical Process
Validation, 2nd ed., edited by I.R. Berry and R.A. Nash, 1993,
p. 334.
3. Kirsch, R.B., Validation of Analytical Methods Used in
Pharmaceutical Cleaning Assessment and Validation,
Pharmaceutical Technology, Analytical Validation, 1998.
4. Chudzik, G.M., General Guide to Recovery Studies Using
Swab Sampling Methods for Cleaning Validation, Journal of
Validation Technology, Vol. 5, No. 1, pp. 77-81.
5. Hall, W.E., Your Cleaning Program: Is It Ready for the PreApproval Inspection? Journal of Validation Technology, Vol.
4, No. 4, August 1998, p. 302.
6. Alvey, A.P. and Carrie, T.R., Not Seeing is Believing A
Non-Traditional Approach for Cleaning Validation, Journal of
Validation Technology, Vol. 4, No. 3, pp. 189-193.
7. Fourman, G.L. and Mullen, M.V., Determining Cleaning
Validation Acceptance Limits for Pharmaceutical Manufactur
ing Operations, Pharmaceutical Technology, 17 (4), 1993, pp.
54-60.
8. Hall, W.E., Validation of Cleaning Processes for Bulk
Pharmaceutical Chemical Processes, Cleaning Validation An
Exclusive Publication, p. 4.
9. Hall, W.E., Proper Documentation and Written Procedures,
Journal of Validation Technology, Vol. 4, No. 3, pp. 199-201.
10. Tunner, J., Manual Cleaning Procedure Design and Validation,
Cleaning Validation An Exclusive Publication, p. 28.
11. PDA Technical Report No. 29, Points to Consider for Cleaning
Validation, March 1998, p.43.
12. Coleman, R.C., How Clean is Clean? Journal of Validation
Technology, Vol. 2, No. 4, August 1996, p. 278.
13. Jenkins, K.M. and Vanderwielen, A.J., Cleaning Validation: An
Overall Perspective, Pharmaceutical Technology, April 1994,
p. 70.

Julie Thomas is Validation Manager at McNeil

Consumer Healthcare in Round Rock, Texas. She
has 14 years of experience in various aspects of
solid dose pharmaceutical manufacturing. Most
recently, she chaired a company-wide committee to enhance cleaning validation practices and
procedures for all McNeil facilities. She can be
reached by phone at 512-248-4470 or by e-mail at
jthomas1@mccus.jnj.com.

This article presents only one alternative for pre

paring a Master Validation Plan. The views expressed
in this article are strictly those of the author and in
no way represent the view of McNeil Consumer
Healthcare, Johnson & Johnson, or this publication.

Advanstar Communications Inc. All rights reserved.

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