Generic Cleaning Validation Protocol
Prepared by Bill Hall, Ph.D., Hall and Associates
(The following document is offered to the readership of the Journal of Validation
Technology as a generic template. As such, this document is intended to serve
as a starting point for the development of a specific protocol for the specific
cleaning situation. Therefore, the document is not intended to be an all-inclusive
document, which covers all potential cleaning parameters. It will still require
customizing to your particular products and equipment.)
I. Objective
(This section should be a brief paragraph indicating what the protocol is
attempting to demonstrate---One example might be "The purpose
of this protocol is to provide documented evidence that the cleaning
procedure for product xyz effectively and consistently reduces
potential residues to levels beyond a pre-determined acceptable level
when manufactured in equipment ABC. To accomplish this, samples
will be obtained following three separate cleanings of soiled equipment."
II. Scope
(This section of the document should address the specific products and
equipment covered by the current protocol. If the protocol is
written for a group of products, then all of the products in the group
should be named. Likewise, if a group of equipment is involved, this
section would be an appropriate place to distinguish whether the protocol
covers the entire equipment train or an individual piece of equipment.)
1
2
III. Introduction
(This section should describe the approach to validation, i.e. whether a
prospective, retrospective, or concurrent approach is being used.
In this regard, it may be useful to refer back to the Cleaning Validation
Master Plan of the company. This would also be an appropriate
place to discuss the grouping of products used in a 'worst case'
approach. For a clinical trial manufacturer or an active pharmaceutical
ingredient (API) facility, a discussion of the approach may involve
cleaning verification as opposed to cleaning validation. This approach
should be discussed in some detail so that the reader will understand and
comprehend the remainder of the document.)
IV. Cleaning Procedure
(At the point of trying to validate a cleaning procedure, the procedure
should be formal and controlled. This formal, controlled document may be
either an approved Standard Operating Procedure (SOP) or may be a part
of the manufacturing batch records or even another formally documented
system. Whatever the form of the documentation, it is important that it be
written and approved by appropriate management including Quality
Assurance/Quality Control. An especially useful means of visualizing the
overall procedure is the use of flow charts. The degree of disassembly of
equipment during cleaning should be specified in the procedure so that
the disassembly does not become an interpretative phenomena. Critical
parameters should be indicated either in this section or in a separate,
specific section for critical parameters. If the cleaning procedure was
developed by another department, e.g. an R & D unit, a pilot plant, or a
development group then a transfer report may be available and should be
cross-referenced in this document.)
3
V. Limits and Acceptance Criteria
(This section of the document is perhaps the most important and most
difficult to prepare. It is important that a scientific rationale be developed
which supports the limit as safe and not presenting any significant danger
to the patient or consumer. It is important that the limits not be an
arbitrary number such as "10 ppm". The limits should be product and
equipment specific. A regulatory inspector might expect to see any or all
of the following types of limits depending on the nature and use of all of
the products manufactured in the same equipment:
Visually clean requirement or limit
Chemical residue limits
Particulate limits
Microbial and endotoxin limits
Cleaning agent limits
Residual solvent limits
Limits for non-specific testing such as residue on
evaporation(ROE), protein, & conductivity
Insoluble material limit
Color limits
Impurity limits
All of these limits should be justified in writing in the protocol. All
calculations pertaining to limits should be retained in the protocol.)
4
VI. Analytical and Microbiological Methods
(Analytical and microbiological methods used for evaluation of cleaning
samples must be validated according to current regulatory expectations.
Many companies choose to document the actual testing methods by
means of formal reports, which are archived in the Quality Control or
Analytical Departments. In this case, it would be necessary to include the
number of the report so that it could be easily retrieved during an
inspection. Of particular interest to regulatory officials will be the issue of
the sensitivity of the method, often expressed at limit of detection (LOD) or
limit of quantitation (LOQ). Another regulatory expectation, which often
falls to the analytical group, is the determination of the recovery factor
associated with typical swab or rinse sampling. Recoveries should also
be included in either the protocol or the methods development validation
report. The inspector will be interested in determining whether the
sensitivity of the test method(s) is adequate for the limit established.)
VII. Sampling Procedure
(An important aspect of the cleaning protocol is determining the methods
that will be used to obtain samples and the locations sampled. It is
important that the areas that are most difficult to clean be sampled since
they represent the 'worst case' locations. Sampling procedures and
locations should be documented in the protocol. Diagrams are often used
to specify the actual locations to be sampled. The method of sampling,
5
swab or solvent rinses, should also be defined in the protocol. It is
important that detailed sampling procedures be prepared and adhered to.
It is also important to specify how the samples will be stored, transported,
and processed.)
VIII. Documentation
(Since documentation is the natural output of validation, it is important to
define systems for collection of the data and presentation in the final
validation report. These data collection forms are often defined in
advance and thus the compilation is easily accomplished during the actual
testing so that it does not require very much time or effort at the end of the
study. Some types of documentation that may be specified in the protocol
are:
original graphs/charts/instrument printouts
training verification records (see also section IX of this document)
equipment/instrument qualification records
calibration and certification records
preventative maintenance (PM) records
analyses and conclusions (see section X of this document)
document review and approval signature sheet)
Additional documentation may be required (i.e. list in not all inclusive)
6
IX. Training
(Training should be completed and documented prior to validation of
cleaning procedures. This includes training of production operators who
carry out the cleaning, training of sampling personnel, and training of
analytical personnel who analyze the samples. Training is often
overlooked and is a potential way that validation can be undermined and
could require revalidation. The verification of training need not be
elaborate but could be handled by a QA audit of training records prior to
implementation of the validation protocol.)
X. Analyses and Conclusions
(The data obtained during the execution of the validation protocol must be
reviewed and evaluated to determine if the acceptance criteria were met.
Any deviations to the cleaning procedure that occurred during the
validation runs should be noted and explained. Any failures of the data to
meet acceptance criteria should be fully noted and investigated. If the
failure is determined to have an assignable cause, then the cause should
be evaluated to determine if it is due to analytical errors or was process
related. It is significant to note that if the failure is found to have an
assignable cause and is not process related, this does not constitute a
failure of the cleaning procedure and, therefore, does not require a repeat.
In the case where all acceptance criteria are met, the analyses and review
section should contain a statement indicating that "all acceptance criteria
were met and the validation was successful.")
7
XI. Approval Sheet
(The final step in completion of the validation protocol is the approval of
the various appropriate disciplines. The departments and levels of
approval are often specified by the Validation Master Plan or the Cleaning
Validation Master Plan or company policy. While there is no regulatory
guideline or regulation, the approvals should include QA/QC in all cases.
A typical approval sheet is shown on the next page. The approval sheet is
normally either the first sheet of the protocol (cover sheet) or the last
sheet. Indeed, the organization of any or all parts of the protocol is at the
discretion of the individual company.)
8
Protocol Approval Sheet
Production:
Signature/Printed Name Title Date
Engineering
Signature/Printed Name Title Date
Validation
Signature/Printed Name Title Date
QA/QC
Signature/Printed Name Title Date
