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CLEANING VALIDATION

Represent By:- MR. SATPUTE VISHNU DATTATRAY.

M.PHARM 1st YEAR (2015-2016) DEPARMENT OF QUALITY ASSURANCE

R.C.Patel Instiute of Pharmaceutical Education & Research, Shirpur

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CONTENTS:-Introduction.US FDA regulatory guidelines for cleaning

validation.Objective.Microbial consideration.Sampling method.Acceptance criteria.Conclusion.References.

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INTRODUCTION Cleaning 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.

Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment in the pharmaceutical industries.

The basic mechanism involved in removing the residues and contaminants from the equipment are mechanical action, dissolution, detergency and chemical reaction.

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US FDA regulatory guidelines for cleaning validation.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 and location.

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Section 211.65 states that the construction of equipment's.

Section 211.67 state that equipment cleaning and maintenance.

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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OBJECTIVE

The objective of the cleaning validation is to verify the effectiveness of the cleaning procedure for removal of product residue, degradation products, preservative, excipient. and/or potential microbial contamination, or by other material (e.g. air borne particles, dust, lubricants, raw materials, intermediates).

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Microbial considerations

a) The existence of conditions favorable to reproduction of microorganisms (e.g. moisture, temperature, crevices and rough surfaces) andthe time of storage should be considered. The aim should be to prevent excessive microbial contamination.

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b) The period and when appropriate conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.

c) In general, equipment should be stored dry, and under no circumstances should stagnant waterBe allowed to remain in equipment subsequent to cleaning operations.

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Sampling Techniques.The selection of either of these techniques

must be consistent with sound scientific judgment and must support the objective of the study, which is to demonstrate that the amount of residual material in the equipment has been reduced to acceptable level.

There are three known sampling method.Swabbing method:- This method of sampling is the most commonly used and involved taking an inert material (e.g.:-cotton wool) on the end of the probe(referred as swab) and rubbing it methodically across the surface.

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The swab are added with dilution solvent and these solvent were analysed by suitable analytical instruments for the presence of residue of previous products

Multiple swabs can be taken to improve surface recovery.

The surface scrutinized is usually an area of 10 cm by 10 cm and located in the more problematic region of the apparatus.

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Example of “Difficult to clean” locations of an RMG:

Wiping should be unidirectional at a time. Parallel strokes should be employed to cover entire swab area.

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Advantages:-Dissolve and physically remove sample.Economical and widely available.Applicable to active, microbial, and cleaning

agent residues.

Limitations:-Result may be technique dependentEvaluation of large, complex, and hard to

reach areas difficult (e.g. pipes work, valves, large vessels).

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Rinse sampling

Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant.

A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.

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Advantages:-Applicable for actives, cleaning agents and

excipients.Allow sampling of a large surface area.Easy to sample.Limitations:-Limited information about actual surface

cleanliness in some cases.Inability to detect location of residues.May be difficult to accurately define and

controlled the areas sample, therefore Usually use for rising an entire piece of equipment, such as vessel.

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Placebo sampling method.

placebo sampling can be used to detect residues on equipment through the processing of a placebo batch subsequent to the cleaning process.

It is appropriate for active residue, cleaning agent, particulate and microbial testing.

Placebo are used primarily to demonstrate the lack of carryover to the next product.

The placebo should mimic product attributes. The equipment characteristics also impact the choice of the placebo batch size.

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Advantages:-placebo contact the same surfaces as the

product.Applicable for hard-to-reach surface.Required no additional sampling steps.

Limitations:-Difficult to determine recovery (contaminants

may not be evenly distributed in the placebo.)Takes longer and adds expense since equipment

must be cleaned after the placebo run.

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Acceptance criteriaChemical determination:-

a) NMT 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the subsequent product,

b) NMT 10 ppm of any product will appear in another/next product.

c) For certain allergic ingredient, penicillin cephalosporin of steroid and cytotoxic, the limit should be below the limit of detection.

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Microbial contamination:- Total aerobic counts a) Bacterial count :- NMT 20 CFU b) Molds :- NMT 02 CFU

Physical determination:- No quantity of residue should be visible on the equipment after cleaning procedures are performed

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Clean environment and clean operations is the heart of pharmaceutical activities.

Four basic requirements of cGMP are safety, identity, strength and purity which can be achieved by cleaning process and its proper validation.

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REFERENCES :-

Kumar Satinder, Shashikant, & Prashar Bharat: “A Review on Concept of Cleaning Validation in Pharmaceutical Industry.” International Research Journal of Pharmacy, 2012; Vol. 3(7): 17-19.

www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=211

www. hsa.gov.sg . Babita Lodhi, Poonam Padamwar, & Arif Patel: “Cleaning Validation for the

Pharmaceuticals, Biopharmaceuticals, Cosmetic and Neutraceutical Industries.” Journal of Innovations in Pharmaceuticals and Biological Sciences, 2014; Vol 1(1): 27-38.

Kumar V.S., Sanjeev T., & Sharma P.K.,: “Overview of Cleaning Validation in Pharmaceutical Manufacturing unit.” International Journal of Advanced Research in Pharmaceutical & Bio Sciences, 2012; Vol.2(2): 154-164.

P.V. Waghmare, A.S.Chinchole, B.N.Poul, & O.G.Bhusnure: “A Brief Review on Cleaning Validation and its Significance in Pharmaceutical Industry.” an International Journal of Pharmaceutical Sciences, 2013; Vol 4(4): 165-192

Dipak k. Sarker, A Quality Systems and Control For Pharmaceuticals, p. no.- 39-41 10/13/2015

Thank you