Professional Documents
Culture Documents
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
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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
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Limit of Quantitation
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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.
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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.
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Stability
• Stability of swab solvent /
rinse solvent
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Recovery
• Recovery by swab / rinse
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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
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Equipment usage matrix A Glimpse
Table of Acceptance criteria by Dose criteria
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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
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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
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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
•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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