Cleaning Validation

CLEANING VALIDATION

DECEMBER 2008

1. PRINCIPLE

1.1
Pharmaceutical products and active pharmaceutical ingredients
(APIs) can be contaminated by other pharmaceutical products or
APIs, by cleaning agents, by micro-organisms or by other
material (e.g. air-borne particles, dust, lubricants, raw materials,
intermediates, auxiliaries). In many cases, the same equipment
may be used for processing different products. To avoid
contamination of the following pharmaceutical product, adequate
cleaning procedures are essential.

1.2
Cleaning procedures must strictly follow carefully established
and validated methods of execution. This applies equally to the
manufacture of pharmaceutical products and active
pharmaceutical ingredients (APIs). In any case, manufacturing
processes have to be designed and carried out in a way that
contamination is reduced to an acceptable level.

1.3
Cleaning Validation is documented evidence that an approved
cleaning procedure will provide equipment that is suitable for
processing of pharmaceutical products or active pharmaceutical
ingredients (APIs).

1.4
The objective of the Cleaning Validation is the confirmation of a
reliable cleaning procedure so that the analytical monitoring may
be omitted or reduced to a minimum in the routine phase.

2.
PURPOSE AND SCOPE

2.1 These guidance notes describe the validation of cleaning
procedures for the removal of contaminants associated with the
previous products, residues of cleaning agents as well as the
control of potential microbial contaminants.

2.2 These guidance notes apply to the manufacture of
pharmaceutical products (final dosage forms) and of active
pharmaceutical ingredients (APIs).

3. GENERAL

3.1
Normally only cleaning procedures for product contact surfaces
of the equipment need to be validated. Consideration should be
given to non-contact parts into which product may migrate. For
example, seals, flanges, mixing shaft, fans of ovens, heating
elements etc.

3.2
Cleaning procedures for product changeover in the case of
marketed products should be fully validated.


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CLEANING VALIDATION

DECEMBER 2008

3.3 Generally in case of batch-to-batch production it is not
necessary to clean after each batch. However, cleaning intervals
and methods should be determined.

3.4
Several questions should be addressed when evaluating the
cleaning process. For example:

-
At what point does a piece of equipment or system become
clean?

-
What does ‘visually clean’ mean?

-
Does the equipment need to be scrubbed by hand?

-
What is accomplished by hand scrubbing rather than just a
solvent wash?

-
How variable are manual cleaning processes from batch to
batch and product to product?

-
What is the most appropriate solvent or detergent?

-
Are different cleaning processes required for different
products in contact with a piece of equipment?

-
How many times need a cleaning process be applied to
ensure adequate cleaning of each piece of equipment?

3.5
Cleaning procedures for products and processes, which are very
similar, do not need to be individually validated. It is considered
acceptable to select a representative range of similar products
and processes concerned and to justify a validation program,
which addresses the critical issues relating to the selected
products and processes. A single validation study under
consideration of the “worst case” can then be carried out which
takes account of the relevant criteria. This practice is termed
"Bracketing".

3.6
At least three consecutive applications of the cleaning procedure
should be performed and shown to be successful in order to
prove that the method is validated.

3.7 Raw materials sourced from different suppliers may have
different physical properties and impurity profiles. Such
differences should be considered when designing cleaning
procedures, as the materials may behave differently.

3.8
Control of change to validated cleaning procedures is required.
Re-validation should be considered under the following
circumstances:
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CLEANING VALIDATION

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3.8.1 Re-validation in cases of changes to equipment, products
or processes; and

3.8.2 Periodic
re-validation at defined intervals.

3.9 Manual methods should be reassessed at more frequent
intervals than clean-in-place (CIP) systems.

3.10 It is usually not considered acceptable to "test until clean". This
concept involves cleaning, sampling and testing, with repetition
of this sequence until an acceptable residue limit is attained.
For the system or equipment with a validated cleaning process,
this practice of "test until clean" should not be required. The
practice of "test until clean" is not considered to replace the
need to validate cleaning procedures.

3.11 Products that simulate the physicochemical properties of the
substance to be removed may be used instead of the
substances themselves, where such substances are either toxic
or hazardous.

4. DOCUMENTATION

4.1
A Cleaning Validation Protocol is required laying down the
procedure on how the cleaning process will be validated. It
should include the following:

-
The objective of the validation process;

-
Responsibilities for performing and approving the validation
study;

-
Description of the equipment to be used;

-
The interval between the end of production and the
beginning of the cleaning procedures;

-
Cleaning procedures to be used for each product, each
manufacturing system or each piece of equipment;

-
The number of cleaning cycles to be performed
consecutively;

-
Any routine monitoring equipment;

-
Sampling procedures, including the rationale for why a
certain sampling method is used;

-
Clearly defined sampling locations;

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-
Data on recovery studies where appropriate;

-
Analytical methods including the limit of detection and the
limit of quantitation of those methods;

-
The acceptance criteria, including the rationale for setting the
specific limits;

-
Other products, processes, and equipment for which the
planned validation is valid according to the “bracketing”
concept; and

-
When Re-validation will be required.

4.2
The Cleaning Validation Protocol should be formally approved
by the Plant Management, to ensure that aspects relating to the
work defined in the protocol, for example personnel resources,
are known and accepted by the management. Quality
Assurance should be involved in the approval of protocols and
reports.

4.3
A Final Validation Report should be prepared. The conclusions
of this report should state if the cleaning process has been
validated successfully. Limitations that apply to the use of the
validated method should be defined (for example, the analytical
limit at which cleanliness can be determined). The report should
be approved by the Plant Management.

4.4
The cleaning process should be documented in an SOP.

4.5
Records should be kept of cleaning performed in such a way
that the following information is readily available:

-
The area or piece of equipment cleaned;

-
The person who carried out the cleaning;

-
When the cleaning was carried out;

-
The SOP defining the cleaning process; and

-
The product, which was previously processed on the
equipment being cleaned.

4.6
The cleaning record should be signed by the operator who
performed the cleaning and by the person responsible for
Production and should be reviewed by Quality Assurance.



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CLEANING VALIDATION

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5. PERSONNEL

5.1
Operators who perform cleaning routinely should be trained in
the application of validated cleaning procedures. Training
records should be available for all training carried out.

5.2 It is difficult to validate a manual, i.e. an inherently
variable/cleaning procedure. Therefore, operators carrying out
manual cleaning procedures should be supervised at regular
intervals.

6. EQUIPMENT

6.1
The design of the equipment should be carefully examined.
Critical areas (those hardest to clean) should be identified,
particularly in large systems that employ semi-automatic or fully
automatic clean-in-place (CIP) systems.

6.2
Dedicated equipment should be used for products, which are
difficult to remove (e.g. tarry or gummy residues in the bulk
manufacturing), for equipment which is difficult to clean (e.g.
bags for fluid bed dryers), or for products with a high safety risk
(e.g. biologicals or products of high potency which may be
difficult to detect below an acceptable limit).

7. MICROBIOLOGICAL
ASPECTS

7.1
The existence of conditions favorable to reproduction of micro-
organisms (e.g. moisture, temperature, crevices and rough
surfaces) and the time of storage should be considered. The aim
should be to prevent excessive microbial contamination.

7.2
The period and when appropriate, conditions of storage of
equipment before cleaning and the time between cleaning and
equipment reuse, should form part of the validation of cleaning
procedures. This is to provide confidence that routine cleaning
and storage of equipment does not allow microbial proliferation.

7.3
In general, equipment should be stored dry, and under no
circumstances should stagnant water be allowed to remain in
equipment subsequent to cleaning operations.









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8. SAMPLING

8.1
Samples should be drawn according to the Cleaning Validation
Protocol.

8.2
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, particularly in
circumstances where accessibility of equipment parts can
mitigate against direct surface sampling.

A. Direct Surface Sampling

(i) The suitability of the material to be used for sampling and
of the sampling medium should be determined. The
ability to recover samples accurately may be affected by
the choice of sampling material. It is important to ensure
that the sampling medium and solvent are satisfactory
and can be readily used.

B. Rinse Samples

(i) Rinse samples allow sampling of a large surface area. In
addition, inaccessible areas of equipment that cannot be
routinely disassembled can be evaluated. However,
consideration should be given to the solubility of the
contaminant.

(ii) A direct measurement of the product residue or
contaminant in the relevant solvent should be made when
rinse samples are used to validate the cleaning process.

9. DETERGENTS

9.1 The efficiency of cleaning procedures for the removal of
detergent residues should be evaluated. Acceptable limits
should be defined for levels of detergent after cleaning. Ideally,
there should be no residues detected. The possibility of
detergent breakdown should be considered when validating
cleaning procedures.

9.2 The composition of detergents should be known to the
manufacturer. If such information is not available, alternative
detergents should be selected whose composition can be
defined. As a guide, food regulations may be consulted. The
manufacturer should ensure that he is notified by the detergent
supplier of any critical changes in the formulation of the
detergent.

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CLEANING VALIDATION

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10. ANALYTICAL
METHODS

10.1 The analytical methods should be validated before the Cleaning
Validation Study is carried out.

10.2 The analytical methods used to detect residuals or contaminants
should be specific for the substance to be assayed and provide
a sensitivity that reflects the level of cleanliness determined to
be acceptable by the company.

10.3 The analytical methods should be challenged in combination
with the sampling methods used, to show that the contaminants
can be recovered from the equipment surface and to show the
level of recovery as well as the consistency of recovery. This is
necessary before any conclusions can be made based on the
sample results. A negative result may also be the result of poor
sampling techniques.

11.
ESTABLISHMENT OF LIMITS

11.1 The pharmaceutical company's rationale for selecting limits for
product residues should be logically based on a consideration of
the materials involved and their therapeutic dose. The limits
should be practical, achievable and verifiable.

11.2 The approach for setting limits can be:

-
product specific Cleaning Validation for all products,
-
grouping into product families and choosing a ‘worst-case’
product,
-
grouping into groups of risk (e.g. very soluble products,
similar potency, highly toxic products, difficult to detect).

11.3 Carry-over of product residues should meet defined criteria. For
example, the most stringent of the following three criteria:

(a) No more than 0.1%of the normal therapeutic dose of any
product will appear in the maximum daily dose of the
following product,

(b) No more than 10ppm of any product will appear in another
product,

(c) No quantity of residue should be visible on the equipment
after cleaning procedures are performed. Spiking studies
should determine the concentration at which most active
ingredients are visible,



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(d)
For certain allergenic ingredients, penicillins,
cephalosporins or potent steroids and cytotoxics, the limit
should be below the limit of detection by best available
analytical methods. In practice this may mean that
dedicated plants are used for these products.

11.4 One cannot ensure that the contaminate will be uniformly
distributed throughout the system. It is also an invalid conclusion
to make the assumption that a residual contaminant would be
worn off the equipment surface uniformly or that the
contamination might only occur at the beginning of the batch.

11.5 In establishing residual limits, it may not be adequate to focus
only on the principal reactant since chemical variations (active
decomposition materials) may be more difficult to remove.

12. REFERENCE

12.1 PIC/S document, PI 006-3: Recommendations on Validation
Master Plan, Installation and Operational Qualification, Non-
Sterile Process Validation, Cleaning Validation.