A PRACTICAL APPROACH FOR CLEANING VALIDATION

Excerpts from guidelines - Objective

To avoid contamination of the following pharmaceutical product in the subsequently manufactured products.

Excerpts from guidelines - Objective

To design and carry cleaning in a way that contamination is reduced to an acceptable level.

Excerpts from guidelines - Objective

To have a documented evidence that an approved cleaning procedure will provide clean equipment.

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.

Acceptance criteria - Principles

The limits should be practical, achievable and verifiable. Grouping:
roduct specific !leaning "alidation for all products, Grouping into product families and choosing a #worst case# product, Grouping into groups of ris$ %e.g. very soluble products, similar potency, highly to&ic products, difficult to detect'.

Acceptance criteria
Carry-over of product residues should meet defined criteria, for example the most stringent of the following two criteria: Chemical
(o more than ).*+ of the normal therapeutic dose of any product will appear in the ma&imum daily dose of the following product, (o more than *) ppm of any product will appear in another product,

Visual
(o quantity of residue should be visible on the equipment after cleaning procedures are performed. 7

Acceptance criteria
Microbiological dosage form limit for oral solid

Total aerobic microbial count cfu"g Total combined #east and mold count

- NMT

!!!

- NMT

!! cfu"g

$bsence of %&' indicator organisms i(e( - )(coli - &( aureus - &almonella species

Grouping (Bracketing)
)*uipment usage &olubility Therapeutic activity

Method Validation
Accuracy Precision Limit of Detection Method Validation Limit of Quantitation 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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+imit of ,etection
The lowest amount of analyte in a sample which can be detected but not quantitated as an e&act value.
(The Limit of Detection is mostly a parameter of limit tests)

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+imit of -uantitation
The lowest amount of analyte in a sample which can be quantitatively determined with defined precision and accuracy under the stated e&perimental 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
&tability 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
.ecovery by swab " rinse
The recovery of active by swab,rinse method should be established %Generally accepted minimum recovery is -)+', 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 = RxSxU 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 =
IxKxM JxL where I = K = M = J = L = 0.001 x minimum daily dose of product A number of dosage units per batch of final mixture of product B. 4 in.2/swab. maximum number of dosage units of product B taken/day. 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 11 !7."

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Equipment usage matrix - A Glimpse

Table of Acceptance criteria by Dose criteria

Minimum acceptance by #$se c%ite%ia = 0.001 x & x M = 0.001 x 10 x !5000 x 4 = 0.0!1 mg/swab 'x( 4 x 11 !7."

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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 !"uipment #old Time ($!#T
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 e"uipment for manufacture of the next product (%!#T
Effects of EHT: !. "ny equipment cannot stay #clean$ for longer durations 4. T%e microbial proliferation from a source already present on surface 5. E&ternal contamination of microorganism 6. E&ternal contamination of ot%er c%emical 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 ob.ective of the validation process o /esponsibilities for performing and approving the validation study o 0escription of the equipment to be used o The interval between the end of production and the beginning of the cleaning procedures o !leaning 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 1ny routine monitoring requirement

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Equipment cleaning Validation Protocol

What protocol shall address: o 2ampling procedures, including the rationale for why a certain sampling method is used, o !learly defined sampling locations o 0ata on recovery studies where appropriate o 1nalytical 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 3ther products, processes, and equipment for which the planned validation is valid according to a 4brac$eting5 concept o 6hen /e7validation will be required.

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Equipment cleaning Validation Protocol

What parameters shall be studied during cleaning process 1t what point does a piece of equipment become clean8 6hat does visually clean mean8 0oes the equipment need to be scrubbed by hand8 6hat is the most appropriate solvent or detergent8 6hat is the temperature of solvent used8 6hat quantity of solvent is used for cleaning8 1re different cleaning processes required for different products in contact with a piece of equipment8 9ow many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment8

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Summary
)%$*uct *etai+s ./uipment #etai+s Met,$* -a+i*ati$n

0%$uping Mat%ix 1cceptance c%ite%ia

Re&validation

)%$t$c$+ *esigning

7+eaning 3a+i*ati$n %ep$%t

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.xecuti$n $2 c+eaning 3a+i*ati$n 45 c$nsecuti3e %uns6

Thank you
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