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A presentation on cleaning

validation

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PRESENTED BY

Rahul SagarM. PharmPharmaceutical-DRA

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contentsIntroductionUS FDA regulatory guidelines for cleaning validationGeneral aspect of cleaning validationTypes of contaminationCleaning validation techniques for micro-organismsCleaning validation documentation chartAcceptance criteria

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Introduction

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IntroductionCleaning validation is documented evidence with

a high degree of assurance that once can consistently clean a system or a piece of equipment to predetermined and acceptable limits. The primary regulatory concern driving the need for cleaning validation is cross contamination of the desired drug substance either by other active pharmaceutical ingredients (API) from previous batch runs or by residues from the cleaning agent used.

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US FDA regulatory guidelines for cleaning

validation

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US FDA has required that the equipment to be clean prior to use (GMP regulation part 133.4). This is one of the basic GMP requirement and it is indicated in more than one section of 21 CFR 211.

Section 211.63 related to the equipment design, size, location, and requirement that equipment used in the manufacture, adequate size, and suitably located to facilitate operations for its intended use.

Section 211.65 states that the construction of equipment's.Section 211.67 further requires that the equipment and the utensils

shall be cleaned.Section 211.180 & 211.182 relates to the record that should be kept

for the maintenance, cleaning, sanitation and inspection of equipment.

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General aspect of cleaning validation

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Objective

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Types of contamination

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Cross contamination with active ingredients

Contamination of one batch of product with significant levels of residual active ingredients from a previous

batch cannot be tolerated.

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Contamination with unintended materials or compounds

While inert ingredients used in drug products are generally recognized as safe or have been shown to be safe for human consumption, the routine use, maintenance and cleaning of

equipment's.

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Microbiological contamination

Maintenance, cleaning and storage condition may provide adventitious micro-organisms with the opportunity to proliferate

within the processing equipment's.

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Cleaning validation techniques for micro-

organisms

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Swab methodSurface rinse methodRODAC plate methodLimulus amoebocyte lysate methodATP bioluminescence method

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Swab methodAfter cleaning the equipment, product contact surface could be swabbed to evaluate surface cleanness. Swabs used should be compatible with the active ingredients and should not interfere with the assay.

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Surface rinse methodSampling and testing of rinse samples for residual active ingredients is a commonly adopted method to evaluate cleanness. This is fairly convenient method in many cases and requires control over the solvent used for rinsing, the contact time and the mixing involved.

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RODAC plate methodReplicate organism direct agar contact plate method (RODAC) all samples will be collected on RODAC plate. Surface, such as wall, floors, and ceiling should be dry and have sanitized within twelve hours of being sampled.

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Limulus amoebocyte lysate method

This techniques was widely used in the biopharmaceutical industry. The LAL test is performed by adding aliquots of sample or test materials to small quantities of a lysate preparation, followed by incubation at 37 °C for 1 hour. the presence of endotoxins causes gel formation of the lysate material.

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ATP bioluminescence method

This type of analysis usually uses ATP-bioluminescence. The bioluminescence techniques is an increasingly important alternative to classical microbiological method.

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Cleaning validation documentation chart

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Acceptance criteria

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Carry over of product residues should meet defined criteria, for example the most stringent of the following 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

Microbiological limit-• Total aerobic microbial count• Total combined yeast and count

Absence of USP indicator organisms i.e.- E.coli, salmonella species

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Standard approaches of cleaning validation

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Question time

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Thanking you…..