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1.0 DEFINITIONS

Cleaning Validation is the documented evidence that the cleaning process, operated within established parameters, can perform effectively and reproducibly to produce a drug product meeting its pre-determined specification and quality attributes. Cleaning Validation is performed on 3 consecutive commercial size lots, which may be marketed.

2.0 OBJECTIVE

The objective of the Cleaning Validation is to development of cleaning procedure for pharmaceutical equipments that are not only in line with the cGMP and current regulatory requirements but are also practical, cost effective and based on good science.

3.0 SCOPE

The cleaning validation program covers all the manufacturing facilities, like: Tablet / Capsule, Oral Liquid, External preparation etc.

4.0 INTRODUCTION

The objective of Cleaning Validation of Equipment, utensils and components is to establish sufficient documented evidence to assure that the cleaning procedures can reproducibly remove residue of the product being handled below established acceptance limit. The quantity of residue of the previous product if, within the acceptance limit will not affect quality and Safety of the subsequent product to be manufactured by using same equipment and facility.

5.0 CLEANING AND EXTENT OF CLEANING

In manufacturing process, two different cleaning situations arise and each situation is described as follows;

§� Type A Cleaning

Used only when cleaning between different batches of the same product; i.e. batch to batch cleaning.

§� Type B Cleaning

Used when cleaning between different Product-Batches; i.e. product to product cleaning.

6.0 'DEVELOPMENT OF CLEANING VALIDATION PROGRAM'
Only type B cleaning is subjected to be validated. A systematic cleaning validation program shall be followed by following sub-sections:
Ø Identification of Potential Contaminants

Ø Product Grouping and Worst Case Selection

Ø Manufacturing Equipment Grouping and Worst Case Selection

For any type of cleaning method used, cleaning validation is a basic requirement, samples shall be taken, analyzed and results documented.

Once the cleaning method is validated, it shall be ensured that the method is not changed.

7.0 SELECTION OF SAMPLING METHOD

There are two kind of sampling method shall be followed during validation; e.g. Swab (Direct Surface) Sampling method and Rinse (Wash Water) Sampling Method.

8.0 SELECTION OF ANALYTICAL METHOD

It is important to select an appropriate method for detection of the residue in the cleaning sample. It is generally two types: -

A] Specific Analytical Test Methods which includes: High Performance Liquid Chromatography,

Ultra violate Spectrophotometer (UV) and Microbial Test.

B] Non Specific Analytical Test Methods which includes: Visual Examination, pH, Total Organic

Carbon (TOC) and Conductivity

Non-specific analytical methods shall be utilized to analyze the rinse water sample during cleaning validation / cleaning verification.


9.0 Analytical Method Validation: The analytical method used for evaluation of cleaning efficacy

shall be validated prior execution by some parameters which includes: Limit of detection (LOD),

Limit of Quantification (LOQ), Determination of Recovery Factor and Limit

'10.0'Establishment of Limits and Acceptance Criteria

10.1 Limit Calculation On The Basis Of Therapeutic Dose:

The step-by-step approach shall be followed for the determination of limit. The following formula shall be used;

Step – 1

Purpose: To calculate the limit of active agent in any subsequently manufactured product (LSP).

Information required: (i) Minimum daily dose of the active being cleaned (TD). (ii) Maximum daily dose of the subsequently manufactured drug product (LDD). (iii) Safety factor of the active being cleaned (SF).

Formula:

SF × TD

LSP = ---------------

LDD

Step – 2

Purpose: To determine the residue limit of active contamination level per area of equipment (L2).

Information required: (i) LSP from 1st stage.(ii) The batch size of the subsequent product (BSSP in kg.).(iii) The shared equipment surface area (SESA in cm2).

Formula:

LSP × BSSP × 1000

L2 = -------------------------

SESA

Step – 3

Purpose: To determine the residue limit for the analytical sample (L3).

Information required: (i) The surface area residue limit (L2),(ii) The surface area swabbed (in cm2),

(iii) The amount of solvent the swab is desorbed (in gm.).

Formula:

L2 × Swabbed surface area

L3 = ----------------------------------------

Amt. of desorption solvent

Step – 4

Purpose: To determine the residue limit for the analytical sample considering swab recovery factor (L4).

Information required: (i) Residue limit for the analytical sample (L3).(ii) Swab recovery factor determined by practical experiment.

Formula:

L3

L4 = --------------------------------

Swab Recovery Factor

10.2 Limit Determination On The Basis Of 10 ppm Criterion

As per cGMP, the highest allowable residue of active should not exceed 10 ppm level. On that basis the 10 ppm limit shall be considered conservatively in place of the dosage criterion limit on those case(s) where calculated limit will be greater than 10 ppm.

SO, cleaning of equipment in pharmaceutical industry is the most important part now a day for better health product.

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