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Pharma Times - Vol 42 - No. 07 - July 2010 21 * E-mail:[email protected] Introduction Cleaning validation is a documented process that proves the effectiveness and consistency in cleaning a pharmaceutical production equipment 1 . Validations of equipment cleaning procedures are mainly used in pharmaceutical industries to prevent cross contamination and adulteration of drug products hence is critically important 2 . The prime purpose of validating a cleaning process is to ensure compliance with federal and other standard regulations. The most important benefit of conducting such a validation work is the identification and correction of potential problems previously unsuspected, which could compromise the safety, efficacy or quality of subsequent batches of drug product produced within the equipment. This paper provides a review of the current trends in cleaning validation and its related importance. Objective The objectives of equipment cleaning and cleaning validation in an Active Pharmaceutical Ingredient (API) area are same as those in pharmaceutical production area. In both these areas efforts are necessary to prevent contamination of a future batch with the previous batch material. The cleaning of 'difficult to reach' surface is one of the most important consideration in equipment cleaning validation. Equipment cleaning validation in an API facility is extremely important as cross contamination in one of the pharmaceutical dosage forms, will multiply the problem. Therefore, it is Cleaning Validation and its importance in Pharmaceutical Industry S. Lakshmana Prabu 1 *, T.N.K. Suriyaprakash 2 1 Dept. of Pharm. Technology, Anna University-Tiruchirappalli, Tiruchirappalli - 620 024. 2 Dept. of Pharmaceutics, Periyar College of Pharmaceutical Sciences for Girls, Tiruchirappalli-620 021. important to do a step-by-step evaluation of API process to determine the most practical and efficient way to monitor the effectiveness of the cleaning process. It is necessary to validate cleaning procedures for the following reasons 3 1. It is a prime customer requirement since it ensures the purity and safety of the product. 2. It is a regulatory requirement in Active Pharmaceutical Ingredient product manufacture. 3. It also assures the quality of the process through an internal control and compliance. Types of contaminations 1. 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. In addition to the obvious problems posed by subjecting consumers or patients to unintended contaminants, potential clinically significant synergistic interactions between pharmacologically active chemicals are a real concern. 2. Contamination with unintended materials or compounds While inert ingredients used in drug products are generally recognised as safe or have been shown to be safe for human consumption, the routine use, maintenance and cleaning of equipments provide the potential contamination with such items as equipment parts, lubricants, chemical cleaning agents and pieces of cleaning tools such as brushes and rags. 3. Microbiological contamination Maintenance, cleaning and storage conditions may provide adventitious micro organisms with the opportunity to proliferate within the processing equipment. FDA requirements 4 1. FDA expects firms to have written standard operating procedures (SOP) detailing the cleaning process used for various pieces of equipment. 2. If firms have a specific cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, FDA expects the written procedures to address these different scenarios. 3. If firms have one process for removing water-soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is followed. 4. It is required by the FDA, in the general validation procedure, that the personnel responsible for performing and approving the study should comply with the acceptance criteria and the revalidation data. 5. FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. Minimizing equipment downtime has the potential to impact the efficiency and economics of pharmaceutical production. The main purpose of cleaning validation is to prove the effectiveness and consistency of cleaning in a given pharmaceutical production equipment to prevent cross contamination and adulteration of drug products with other active ingredients like unintended compounds or microbiological contamination, leads to prevent several serious problems and also useful in related studies like packaging component cleaning validation. So it is necessary to validate the cleaning procedures to ensure safety, efficacy, quality of the subsequent batches of drug product and regulatory requirements in Active Pharmaceutical Ingredients (API) product manufacture. The benefits due to cleaning validation are compliance with federal regulations, identification and correction of potential problems, previously unsuspected which could compromise the safety and efficacy of drug products. In this article cleaning, validation and importance are discussed in brief. Article

Cleaning Validation and Its Importance in Pharmaceutical Industry

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Page 1: Cleaning Validation and Its Importance in Pharmaceutical Industry

Pharma Times - Vol 42 - No. 07 - July 2010 21

* E-mail:[email protected]

IntroductionCleaning validation is a documented

process that proves the effectiveness andconsistency in cleaning a pharmaceuticalproduction equipment1. Validations ofequipment cleaning procedures are mainlyused in pharmaceutical industries to preventcross contamination and adulteration of drugproducts hence is critically important2. Theprime purpose of validating a cleaningprocess is to ensure compliance with federaland other standard regulations. The mostimportant benefit of conducting such avalidation work is the identification andcorrection of potential problems previouslyunsuspected, which could compromise thesafety, efficacy or quality of subsequentbatches of drug product produced within theequipment. This paper provides a review ofthe current trends in cleaning validation andits related importance.

ObjectiveThe objectives of equipment cleaning

and cleaning validation in an ActivePharmaceutical Ingredient (API) area aresame as those in pharmaceutical productionarea. In both these areas efforts arenecessary to prevent contamination of afuture batch with the previous batch material.The cleaning of 'difficult to reach' surface isone of the most important consideration inequipment cleaning validation. Equipmentcleaning validation in an API facility isextremely important as cross contaminationin one of the pharmaceutical dosage forms,will multiply the problem. Therefore, it is

Cleaning Validation and its importance inPharmaceutical IndustryS. Lakshmana Prabu1*, T.N.K. Suriyaprakash2

1 Dept. of Pharm. Technology, Anna University-Tiruchirappalli, Tiruchirappalli - 620 024.2 Dept. of Pharmaceutics, Periyar College of Pharmaceutical Sciences for Girls, Tiruchirappalli-620 021.

important to do a step-by-step evaluation ofAPI process to determine the most practicaland efficient way to monitor the effectivenessof the cleaning process.

It is necessary to validate cleaningprocedures for the following reasons3

1. It is a prime customer requirement sinceit ensures the purity and safety of theproduct.

2. It is a regulatory requirement in ActivePharmaceutical Ingredient productmanufacture.

3. It also assures the quality of the processthrough an internal control andcompliance.

Types of contaminations1. Cross contamination with active

ingredients

Contamination of one batch of productwith significant levels of residual activeingredients from a previous batch cannot betolerated. In addition to the obviousproblems posed by subjecting consumers orpatients to unintended contaminants,potential clinically significant synergisticinteractions between pharmacologicallyactive chemicals are a real concern.

2. Contamination with unintendedmaterials or compounds

While inert ingredients used in drugproducts are generally recognised as safeor have been shown to be safe for humanconsumption, the routine use, maintenanceand cleaning of equipments provide thepotential contamination with such items as

equipment parts, lubricants, chemicalcleaning agents and pieces of cleaning toolssuch as brushes and rags.

3. Microbiological contamination

Maintenance, cleaning and storageconditions may provide adventitious microorganisms with the opportunity to proliferatewithin the processing equipment.

FDA requirements4

1. FDA expects firms to have writtenstandard operating procedures (SOP)detailing the cleaning process used forvarious pieces of equipment.

2. If firms have a specific cleaning processfor cleaning between different batchesof the same product and use a differentprocess for cleaning between productchanges, FDA expects the writtenprocedures to address these differentscenarios.

3. If firms have one process for removingwater-soluble residues and anotherprocess for non-water soluble residues,the written procedure should addressboth scenarios and make it clear whena given procedure is followed.

4. It is required by the FDA, in the generalvalidation procedure, that the personnelresponsible for performing andapproving the study should comply withthe acceptance criteria and therevalidation data.

5. FDA expects firms to prepare specificwritten validation protocols in advancefor the studies to be performed on eachmanufacturing system or piece of

Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. Minimizingequipment downtime has the potential to impact the efficiency and economics of pharmaceutical production. The main purpose ofcleaning validation is to prove the effectiveness and consistency of cleaning in a given pharmaceutical production equipment toprevent cross contamination and adulteration of drug products with other active ingredients like unintended compounds ormicrobiological contamination, leads to prevent several serious problems and also useful in related studies like packaging componentcleaning validation. So it is necessary to validate the cleaning procedures to ensure safety, efficacy, quality of the subsequentbatches of drug product and regulatory requirements in Active Pharmaceutical Ingredients (API) product manufacture. The benefitsdue to cleaning validation are compliance with federal regulations, identification and correction of potential problems, previouslyunsuspected which could compromise the safety and efficacy of drug products. In this article cleaning, validation and importanceare discussed in brief.

Article

Page 2: Cleaning Validation and Its Importance in Pharmaceutical Industry

Pharma Times - Vol 42 - No. 07 - July 201022

equipment which should address suchissues as sampling procedures, andanalytical methods to be used includingthe sensitivity of those methods.

6. It is expected that firms conduct thevalidation studies in accordance withthe protocols and document the resultof studies.

7. Final validation report is to be approvedby the regulatory board which stateswhether or not the cleaning process isvalid.

Current approaches indetermining theacceptance limits forcleaning validation6-8

Acceptance limits for pharmaceuticalmanufacturing operation1. Approach 1 (Dose criterion)

Not more than 0.001 of minimumdaily dose of any product will appear in themaximum daily dose of another product.

Milligrams of active ingredient = I x K x Min product A permitted per J x L4 inch2 swab area I = 0.001 of the smallest strength of

product A manufactured per dayexpressed as mg/day and based onthe number of milligrams of activeingredient.

J = Maximum number of dosage units ofproduct B per day

K = Number of dosage units per batch offinal mixture of product B

L = Equipment surface in common betweenproduct A & B expressed as squareinches.

M= 4 inch2/swab.

2. Approach 2 (10 ppm criterion)Any active ingredient can be present in

a subsequently manufactured product at amaximum level of 10 ppm.

Milligrams of active ingredient = R x S x Uin product A permitted per T4 inch2 swab area R = 10mg active ingredient of product A in

one kg of product BS = Number of kilograms per batch of final

mixture of product BT = Equipment surface in common between

product A & B expressed as squareinches.

U = 4 inch2/swab.

3. Approach 3 (Visually clean criterion)No quantity of residue should be visible

on the equipment after cleaning proceduresare performed.

Cleaning ProceduresStandard cleaning procedures for each

piece of equipment and process should beprepared. It is vital that the equipment designis evaluated in detail in conjunction with the

product residues which are to be removed,the available cleaning agents and cleaningtechniques, when determining the optimumcleaning procedure for the equipment.

Cleaning procedures should besufficiently detailed to remove the possibilityof any inconsistencies during the cleaningprocess. Following parameters are to beconsidered during cleaning procedures.

A. Equipment Parameters to be evaluated

1. Identification of the equipment to becleaned

2. 'Difficult to clean' areas3. Property of materials4. Ease of disassembly5. Mobility

B. Residues to be cleaned

1. Cleaning limits2. Solubility of the residues3. Length of campaigns

C. Cleaning agent parameters to beevaluated

1. Preferable materials that arenormally used in the process

2. Detergents available (as a generalguide, minimal use of detergentsrecommended unless absolutelyrequired)

3. Solubility properties4. Environmental considerations5. Health and safety considerations

D. Cleaning techniques to be evaluated

1. Manual cleaning2. CIP (Clean-in-place)3. COP (Clean-out-of-place)4. Semi automatic procedures5. Automatic procedures6. Time considerations7. Number of cleaning cycles

Sampling Technique9-15

Generally there are two types ofsampling that are accepted. The mostdesirable is the direct method of samplingthe surface of the equipment, anothermethod being the use of rinse sampling.1. Direct surface sampling

It involves the determination of the typeof sampling material used and its impact onthe test data to check the interference of thesampling material with the test. Therefore,early in the validation programme, it is crucialto assure the sampling medium and solventif they are satisfactory and be readily used.

Advantages of direct sampling are that,areas hardest to clean and which arereasonably accessible can be evaluated,leading to establishing a level ofcontamination or residue per given surfacearea. Additionally, residues that are "driedout" or are insoluble can be sampled byphysical removal.

2. Swab samplingAfter cleaning the equipment, product

contact surfaces could be swabbed toevaluate surface cleanliness. Swabs used

should be compatible with the activeingredients and should not interfere with theassay. They should not cause anydegradation of the compound. The solventused for swabbing should provide goodsolubility for the compound and should notencourage degradation.

3. Rinse samplingSampling and testing of rinse samples

for residual active ingredient is a commonlyadopted method to evaluate cleaniness. Thisis a fairly convenient method in many casesand requires control over the solvent usedfor rinsing, the contact time and the mixinginvolved. The solvent used should beselected based on the solubility of the activeingredient and should either simulate asubsequent batch of product or at leastprovide adequate solubility.

A disadvantage of rinse samples is thatthe residue or contaminant may not besoluble or may be physically occluded in theequipment. An analogy that can be used isthe "dirty pot." In the evaluation of cleaningof a dirty pot, particularly with dried outresidue, one does not look at the rinse waterto see that it is clean; one looks at the pot.

Testing methodsThe basic requirements of the analytical

methods should have the following criteria.

1. Testing method should have the abilityto detect target substances at levelsconsistent with the acceptance criteria.

2. Testing method should have the abilityto detect target substances in thepresence of other materials that mayalso be present in the sample.

3. The testing analytical method shouldinclude a calculation to convert theamount of residue detected in thesample to 100% if the recovery datagenerated indicates a recovery outsidethe allowed range.

Analysing cleaningvalidation samples

There are many analytical techniquesavailable that can be used in cleaningvalidation24. But choosing the appropriateanalytical tool depends on a variety offactors15-17. The most important factor is todetermine the specifications or parametersto be measured18. The limit should alwaysbe established prior to the selection of theanalytical tool19-20.

Specific and non-specificmethods

A specific method detects uniquecompounds in the presence of potentialcontaminants. Ex: HPLC. Non-specificmethods are those methods that detect anycompound that produces a certain responseEx: Total Organic Carbon (TOC), pH andconductivity.

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Pharma Times - Vol 42 - No. 07 - July 2010 23

High performance liquidchromatography

Almost every pharmaceuticalcompany has an HPLC instrument, utilisinga variety of detectors. These include UV,fluorescence, electrochemical, refractiveindex, conductivity, Evaporate light scatteringdetector (ELSD) and many others. The vastmajority of techniques described in theliterature are for the determination ofsurfactants in concentrated products21-22.Therefore, the limits of quantitation and thelimit of detection are rather high. Analysis ofanionic and cationic surfactants is done byHPLC and Capillary electrophoresis (CE),where as amphoteric surfactants areanalysed by HPLC, CD and ELSD23-25.

Capillary electrophoresisCapillary electrophoresis can be used

for many different types of analysis, viz;separation, detection and determination ofsodium lauryl sulphate in cationic, anionicand non-ionic surfactants26-28. Anothertechnique known as Micellar electro kineticcapillary chromatography is used for theseparation of non-ionic alkyl phenol polyoxyethylene type surfactants29.

Total organic carbon (TOC)Presently total organic carbon is used

widely in the pharmaceutical industries forvarious purposes30-32. TOC is determinedby the oxidation of an organic compound intocarbon dioxide. The oxidation can occurthrough a number of mechanisms dependingon the instrument being used. TOC is usedfor the analysis of detergents, endotoxins,biological media and poly ethylene glycol33.

Ion chromatographyIon chromatography can be used for the

analysis of inorganic, organic and surfactantspresent in the cleaners34-39. Most cleanerscontain sodium and/or potassium. The ionchromatography detection technique ofsuppressed conductivity is more sensitive topotassium ions than to sodium ions. Verylow levels of cleaning agents can be detectedby using this technique.

Others 40-44

1. Thin layer chromatography (TLC): TLCis widely used for the qualitativedetermination of surfactants.

2. Atomic absorption spectroscopy (AAS):AAS is used for the determination ofinorganic contaminants.

3. Bioluminescence: It is useful forbiologicals. This type of analysis usuallyuses ATP-bioluminescence.

4. Optically simulated electronemission (OSEE)In some cases the limits of residue are

very less that they can't be detected byconventional methods. OSEE is a verysensitive method that can be used for both

qualitative and quantitative manner in thisregard.

5. Portable mass spectrometer Portable mass spectrometer can be

used to detect ultra sensitive measurementsand identification of the residue.

Additional techniquesApart from the above mentioned

techniques the biopharmaceutical industryutilises a wide variety of techniques45. Theseinclude Enzyme-Linked Immuno SorbentAssay (ELISA)46 and Limulus amaebocytelysate (LAL) technique.

Method validationIt is very important to scientifically

establish the residue limit prior to choosingthe method of analysis. This includes thelimit in the analytical sample and the limit inthe next product. This will ensure the abilityof the chosen method to detect andquantitate the limit present. Once thetechnique for analysis has been chosen, itis very important to validate the methodused47-50. The validation of a method is verydifferent from validation of recovery. Avalidated method is one that is rugged androbust enough to measure the residue limitestablished. Whereas, the validation of arecovery helps to determine the amount thatcan be recovered from a surface.

Data analysis forestimating possiblecontamination51-52

To support the cleaning validation study,an appropriate analytical method must bedeveloped to produce a sensitivity level, atleast equal to that of the acceptable residuallevel. For each analytical method, valuesdefined as 'minimum quantifiable quantity'(MQQ) and 'non-detectable' (ND) areapplied. A test result greater than or equalto the MQQ is considered reliable, whereasif it l ies between ND and MQQ it isconsidered unreliable. Therefore valuesreported as ND or between ND and MQQcan be manipulated to apply for the possiblecontamination.

Validation reportA validation report is necessary to

present the results and conclusions andsecure approval of the study. The reportshould include the following information:

1. References to all the proceduresfollowed to clean the samples and tests.

2. Physical and analytical test results orreferences for the same, as well as anypertinent observations.

3. Conclusions regarding the acceptabilityof the results, and the status of theprocedures being validated.

4. Any recommendations based on theresults or relevant information obtainedduring the study including revalidation

practices if applicable.5. Review of any deviations from the

protocol.6. When it is unlikely that further batches

of the product will be manufactured fora period of time, it is advisable togenerate reports on a batch by batchbasis until such time.

7. The report should conclude anappropriate level of verif icationsubsequent to validation.

An effective cleaningvalidation maintenanceprogramme5, 53

When a minimum of three cleaningvalidation runs get completed and if theresults meet the acceptance criteria, then thecleaning procedures would be demonstratedsufficiently and consistently to removechemical and detergent residues fromequipment surfaces during the study in orderto meet the pre-established criteria.However, overtime and certain other factorscan decrease the efficiency and consistencyof the cleaning program. They are,

1. Operator variability2. Equipment aging and repair

3. Potential non representative results andmonitoring programmes

4. Changes to the product, equipment andprocess.

Operator variabilityAdditional questions to be asked when

evaluating the cleaning process:1. Does the equipment have to be

scrubbed by hand?2. What is accomplished by hand

scrubbing as opposed to just a solventwash?

3. How variable are manual cleaningprocess from batch to batch andproduct to product?

These questions are all related tomanual cleaning. The last question focuseson sources of variation associated with amanual cleaning process that is operatorvariability. Many companies rellay onintensive training programme to reduceoperator variability. These programmes trainoperators on equipment disassemblyprocedure, detergent preparation, step-by-step cleaning procedures and dryingprocesses. It is difficult to train an operatorto perform certain elements, the same eachtime, such as strength applied, adherenceto detailed instructions on the correctscrubbing procedure (up and down or sideto side) and scrubbing time. It is even moredifficult to train different operators to performthese functions the same. Hence, theproblems of within operator variability andoperator-to-operator variability are to berectified by sufficient training programmes.

Page 4: Cleaning Validation and Its Importance in Pharmaceutical Industry

Pharma Times - Vol 42 - No. 07 - July 201024

Equipment aging andrepair

Through normal use, the smoothnessand structural integrity of the equipmentsurfaces can change over time. As thesurface becomes rougher, it is more difficultto clean because it has a greater contact areathat can adsorb and could trap morechemical residues. Repairing a piece ofequipment or installing new parts couldcreate new stress centres, leading to difficultyin cleaning the surfaces. To make anequipment maintenance programme, thefollowing points could be considered1. Enforcement of standard operating

procedures (SOPs).2. A routine functionality check.3. Mechanical maintenance.4. A cleanability evaluation programme for

equipment repair.

Potential non-respectiveresults and monitoringprogramme

However, cleaning validationresulting from three runs does not provide ahigh degree of confidence, especially formanual cleaning procedures. Operators mayintroduce a bias in their cleaning duringcleaning validation process. To confirm thevalidity of extrapolating validation results tofuture operations, a monitoring programmecan be implemented to ensure a consistentcleaning capability after the cleaningvalidation has been completed.

Monitoring programme can be done ineither of the following two ways.

1. Difficulty in cleaning the equipment2. Difficulty in cleaning the product and

equipment.

Difficulty in cleaning theequipment

The most 'difficult to clean' pieces ofequipment require the most intensivemonitoring schedule. 'Easier to clean' piecesrequire a moderate monitoring schedule.'Easiest to clean' pieces of equipment requireonly a periodic monitoring schedule.

Difficulty in cleaning the product andequipment:

It is divided into three groups based onthe degree of difficulty in cleaning the productand equipment.

1. Most 'difficult to clean' product andequipment requires the most intensivemonitoring schedule.

2. 'Easier to clean' product and equipmentthat requires a moderate monitoringschedule.

3. 'Easiest to clean' product andequipment that requires only periodicmonitoring.

The monitoring programme provides amechanism to verify the capability of thecleaning procedures, the efficiency of thetraining programme and the effectiveness ofthe equipment maintenance programme.

Changes to the products, equipment &process

When new products and equipmentsare added to the cleaning validationprogramme, revalidation of the acceptancelimits for all of the products and equipmentsinvolved in the original cleaning validationstudy may be necessary. The acceptancelimits for a cleaning validation programmeusually take into account parameters viz; theproduct, equipment matrix, potency, dailydose and batch size. A well designedcleaning validation expansion programmeprovides a scientific and systematic processfor managing new product, new equipmentand changes in manufacturing process andbatch sizes after the cleaning validation studyhas been completed.

Conclusions/SummaryA cleaning validation programme should

contain the assessment of equipment andproducts, assessment of the impact of aprocess on routine process, determinationof an appropriate cleaning agent andmethod, determination of acceptance criteriafor the residues, determination of a degreeof evaluation required to validate theprocedure, decisive on the residues to betested based on solubility and toxicity,development of sampling and analyticalmethods for recovery and detection ofresidues. acceptance criteria for thevalidation, compilation and approval of thevalidation protocol, scope for the validationstudies to be performed in accordance withthe protocol, compilation and approvals ofvalidation reports, documented studies,conclusions, recommendations andrevalidation policy.

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Appeal forAppeal forAppeal forAppeal forAppeal forIPA Building

FundProposed IPA Building

The President of Indian Pharmaceutical Association (IPA)appeals to all members of IPA to contribute

minimum of Rs. 1000/- towards the proposed IPA building at Mumbai.

Kindly send your contribution through D/D or local cheque in favour of “IPA Building Fund”on the following address.

Executive Secretary,

Indian Pharmaceutical AssociationC/o. Bombay College of Pharmacy, Kalina,

Santacruz (E), Mumbai 400098.

All donations towards this fund will get taxexemption u/s 80G of Income Tax Act.