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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 performed.

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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

MethodValidation

Accuracy

Precision

Limit of Detection

Limit of Quantitation

Linearity

Specificity/Selectivity

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 UT

 whereR = 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 criteriaMilligrams 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 J x L 4 x 11827.6

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Equipment usage matrix - A GlimpseTable 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:1. Drying of dirt on surface of equipment2. Microbial proliferation3. 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:1. Any equipment cannot stay ‘clean’ for longer

durations2. The microbial proliferation from a source already

present on surface3. External contamination of microorganism4. 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 ProtocolWhat protocol shall address:o The objective of the validation processo Responsibilities for performing and approving the

validation studyo Description of the equipment to be usedo The interval between the end of production and the

beginning of the cleaning procedureso Cleaning procedures to be used for each product, each

manufacturing system or each piece of equipmento 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 appropriateo Analytical methods including the limit of detection and

the limit of quantitation of those methodso The acceptance criteria, including the rationale for

setting the specific limitso 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 Method ValidationEquipment Details

•Grouping•Matrix •Acceptance criteria

Protocol designing

Execution of cleaning validation

(3 consecutive runs)

Cleaning validation report

Re-validation

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Thank you