A PRACTICAL APPROACH FOR

 
CLEANING VALIDATION

 
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Excerpts from guidelines ­ Objective
• To avoid contamination of
the following
pharmaceutical product in
the subsequently
manufactured products.

 
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Excerpts from guidelines ­ Objective
• To design and carry cleaning
in a way that contamination
is reduced to an acceptable
level.

 
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Excerpts from guidelines ­ Objective
• To have a documented
evidence that an approved
cleaning procedure will
provide ‘clean’ equipment.

 
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Excerpts from guidelines ­ Objective
• To confirm a reliable
cleaning procedure so that
the analytical monitoring
may be omitted or reduced
to a minimum in the routine
phase.

 
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Acceptance criteria ­ Principles
• The limits should be practical,
achievable and verifiable.
• Grouping:
• 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).

 
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Acceptance criteria
Carry-over of product residues should
meet defined criteria, for example the
most stringent of the following two
criteria:
Chemical
• No more than 0.1% of the normal therapeutic dose
of any product will appear in the maximum daily
dose of the following product,
• No more than 10 ppm of any product will appear in
another product,
Visual
• No quantity of residue should be visible on the
equipment after cleaning procedures are
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performed.  
Acceptance criteria
Microbiological limit for oral solid
dosage form

Total aerobic microbial count - NMT 1000

cfu/g

Total combined Yeast and mold count - NMT 100 cfu/g

Absence of USP indicator organisms i.e. - E.coli

- S. aureus
- Salmonella species

 
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Grouping (Bracketing) 
• Equipment usage
• Solubility
• Therapeutic activity

 
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Method Validation

Accuracy
Precision
Limit of Detection
Method Limit of Quantitation
Validation
Specificity/Selectivity
Linearity
Ruggedness/Robustness

 
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Accuracy
• Accuracy is the measure of exactness of
an analytical method, or the closeness of
agreement between the measured value
and the value that is accepted as a
conventional true value or an accepted
reference value

 
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Precision
• The Precision of a method is the degree
of agreement among individual test
results, when the procedure is applied
repeatedly to multiple samplings of a
homogeneous sample

 
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Limit of Detection

The lowest amount of analyte in

a sample which can be detected
but not quantitated as an exact
value.

(The Limit of Detection is mostly a parameter of limit

tests)

 
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Limit of Quantitation

The lowest amount of analyte

in a sample which can be
quantitatively determined
with defined precision and
accuracy under the stated
experimental conditions.

 
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Specificity/Selectivity
The Specificity of a method defines the ability
of the method to measure the analyte of interest
to the exclusion of other relevant components.

Selectivity describes the ability of an analytical

method to differentiate various substances in a
sample.

 
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Linearity
• The linearity of a method is its ability to
elicit results that are directly, or by a well
defined mathematical transformation,
proportional to the concentration of
analyte in the sample

 
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Ruggedness / Robustness
• Ruggedness is the of reproducibility of the test
results obtained for identical samples under
normal (but variable) test conditions.

• The Robustness of a procedure is a measure of

its capacity to remain unaffected by small but
deliberate variations in the method parameters
and provides an indication of its reliability in
normal usage.

 
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Stability
• Stability of swab solvent /
rinse solvent

The stability of swab solvent or rinse

solvent should be established (during its
hold period) to prove that once swab/rinse
is collected the active is stable till end of
the analysis

 
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Recovery
• Recovery by swab / rinse

The recovery of active by swab/rinse

method should be established (Generally
accepted minimum recovery is 50%), and
corrective factor should be considered for
every result.

 
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 Cleaning validation approach for 
Solid Dosage form 
(Swab method)

 
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Formulae
• 10 ppm Criteria

Milligrams of active ingredient in product A permitted/4 in.2 swab area =
 
R x S x U
T
 where
R = 10 mg active ingredient in product A/kg of product B.
S = Batch size in kilograms of product B.
U = 4 in.2/swab. (Swab surface area)
T = equipment surface area in common between products A and B 
expressed as square inches.

 
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Formulae
• Dose criteria
Milligrams of active ingredient in product A permitted/4 in.2 swab area = 

I x K x M
J x L
where
I = 0.001 x  minimum daily dose of product A
K = number of dosage units per batch of final mixture of product B.
M = 4 in.2/swab. 
J = maximum number of dosage units of product B taken/day.
L = equipment surface area in common between products A and B 
expressed as square inches.

 
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Data Collection
 Batch sizes (in Kg) of all products 
 Batch sizes (in number of dosage units) of all products
 Minimum daily dose of all products
 Maximum daily dose of all products
 Common surface area between all the products
 Equipment list used for all the products
 Equipment details with design 
 Calculation of contact surface area of all equipment
 Matrix for common equipment between two products

 
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Equipment usage matrix ­ A Glimpse

 
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Equipment usage matrix ­ A Glimpse
Octagonal blender

 
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Equipment usage matrix ­ A Glimpse

 
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Equipment usage matrix ­ A Glimpse

 
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Equipment usage matrix ­ A Glimpse

 
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Equipment usage matrix ­ A Glimpse
Common surface area

 
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Equipment usage matrix ­ A Glimpse
Table of product to product common surface area

 
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Equipment usage matrix ­ A Glimpse
Table of Acceptance criteria by 10 ppm criteria

Minimum acceptance by 10 ppm = R x S x U = 10 x 5.75 x 4 = 0.019 mg/swab

T 11827.6

 
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 Equipment usage matrix ­ A Glimpse
Table of Acceptance criteria by Dose criteria

Minimum acceptance by Dose criteria = 0.001 x K x M = 0.001 x 10 x 25000 x 4 = 0.021 mg/swab

JxL 4 x 11827.6

 
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Equipment usage matrix ­ A Glimpse
Table of product to product common surface area

 
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Dirty Equipment Hold Time (DEHT)
The time from the end of manufacturing until the
beginning of the cleaning process is called dirty
Equipment Hold Time (DEHT)

Effects of DEHT:
4. Drying of dirt on surface of equipment
5. Microbial proliferation
6. Difficult removal of contaminant

Generally accepted DEHT is 12 or 24 hours, where critical it shall

be validated.

 
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Clean Equipment Hold Time (CEHT)
The time from the end of the cleaning process until
the beginning of the use of the cleaned equipment for
manufacture of the next product (CEHT)
Effects of CEHT:
3. Any equipment cannot stay ‘clean’ for longer durations
4. The microbial proliferation from a source already present
on surface
5. External contamination of microorganism
6. External contamination of other chemical entities

Generally accepted CEHT is 24 to 72 hours, where ever critical it

shall be validated.

 
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Equipment cleaning Validation Protocol
• Basis of protocol design
– Equipment specific
– Product specific

 
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Equipment cleaning Validation Protocol
What protocol shall address:
o The objective of the validation process
o Responsibilities for performing and approving the
validation study
o Description of the equipment to be used
o The interval between the end of production and the
beginning of the cleaning procedures
o Cleaning procedures to be used for each product, each
manufacturing system or each piece of equipment
o The number of cleaning cycles to be performed
consecutively,
o Any routine monitoring requirement

 
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Equipment cleaning Validation Protocol
What protocol shall address:
o Sampling procedures, including the rationale for why a
certain sampling method is used,
o Clearly defined sampling locations
o Data on recovery studies where appropriate
o Analytical methods including the limit of detection and
the limit of quantitation of those methods
o The acceptance criteria, including the rationale for
setting the specific limits
o Other products, processes, and equipment for which the
planned validation is valid according to a “bracketing”
concept
o When Re-validation will be required.

 
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Equipment cleaning Validation Protocol
What parameters shall be studied during cleaning process
• At what point does a piece of equipment become clean?
• What does visually clean mean?
• Does the equipment need to be scrubbed by hand?
• What is the most appropriate solvent or detergent?
• What is the temperature of solvent used?
• What quantity of solvent is used for cleaning?
• 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?

 
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Summary

Product details Equipment Details Method Validation

•Grouping
•Matrix Protocol designing
•Acceptance criteria

Re-validation

Execution of cleaning
Cleaning validation validation
report (3 consecutive runs)
 
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 Thank you

 
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