cleaning validation in pharmaceutical industry

INTRODUCTION

Cleaning validation in the pharmaceutical industry has been a topic ofever-increasing interest and scrutiny in recent Food and DrugAdministration (FDA) inspections. The validation of procedures used toclean the equipment employed during the various steps of a manufacturingprocess is a clear requirement of current Good Manufacturing Practice(cGMP). As such, FDA inspectors now expect to see a functioning cleaningvalidation program with appropriate documentation in place during theirinspections.

The requirement that equipment be clean before being used is not anew concept. The equally important requirement that it also be sanitary ismany times obfuscated by the word, clean.

In response to the often-asked question “what is clean,” the FDA pub-lished a guidance document: the 2004 FDA “Guide to Inspections Validationof Cleaning Processes.”

The FDA’s guide to inspections, which “intended to cover equipmentcleaning for chemical residues only,” includes:

1. “FDA expects firms to have written procedures [StandardOperating Procedures (SOPs)] detailing the cleaning processes...”

2. “FDA expects firms to have written general procedures on howcleaning processes will be validated.”

3. These procedures will “address who is responsible for performing

38 Institute of Validation Technology

Cleaning Validation in the Pharmaceutical Industry

By Mowafak Nassani, Ph.D.

and approving the validation study, the acceptance criteria, andwhen revalidation will be required.”

4. “FDA expects firms to conduct the validation studies in accordancewith the protocols and to document the results of studies.”

5. Besides assuring chemical cleanliness, “the microbiologicalaspects of equipment cleaning should be considered. This consistslargely of preventive measures…”

6. “Determine the specificity and sensitivity of the analytical methodused to detect residuals or contaminants.”

7. “The firm should challenge the analytical method in combinationwith the sampling method(s) used to show that contaminants canbe recovered from the equipment surface and at what level...”

8. “Direct sampling (e.g., with swabs) is ‘most desirable,’ althoughrinse sampling may be satisfactory.”

OBJECTIVES

The objectives of this article are to establish a broad basis for cleaningvalidation policy and programs, and to determine the requirements, proce-dures, acceptance limits, and working papers needed to support this vitallyimportant activity.

Cleaning Validation ProtocolCleaning validation protocols should be developed, approved, and exe-

cuted in accordance with the SOPs covering these activities in place at thetime. A typical cleaning validation protocol should consist of Objective,Sampling and Testing Methodologies, and Acceptance Criteria sections.

➤ Objective This section defines the intention and scope of the cleaning validation

exercise. Additionally, it will include information such as equipment names,identification numbers, the name(s) and type(s) of product being cleanedfrom the equipment, and the individual components of the product andequipment under investigation.

➤ Sampling and Testing Methodologies This section should typically include a step-by-step explanation of sam-

pling techniques and requirements, as well as the specific analytical proce-dures to be used in the analysis of those samples. It should specify whichlaboratories are to be involved in the testing and any precautions to betaken throughout the validation exercise.

Mowafak Nassani, Ph.D.

39Cleaning Val idat ion

A visual check should be incorporated into the cleaning assessment.The sampling technique chosen to evaluate the effectiveness of the clean-ing procedure should be swabbing, the fluid rinse of samples, or a combina-tion of both methods. The following sampling methods provide various levelsof assurance concerning cleaning:

• Visual inspection✓ Active product contact parts of the equipment are individually

examined (wherever possible) for cleanliness. This visual inspectionallows the early localization and identification of any inadequaciesin the cleaning procedure.

✓ Qualitative – dependent upon inspector and item sampled.✓ Subjective – dependent upon inspector and item sampled.

• Rinse water sampling and analysis✓ According to 2004 FDA “Guide to Inspections Validation of

Cleaning Processes:” “Two advantages of using rinse samples arethat a larger surface area may be sampled, and inaccessible sys-tems or ones that cannot be routinely disassembled can be sam-pled and evaluated.”

✓ Analysis can be quantitative, using pH, conductivity, particle count,microbial count, Total Organic Carbon (TOC) determination, spec-trophotometry, bioassays, or limulus amebocyte lysate for pyrogens.

✓ Recovery factor is uncertain; it involves dilution.

• Surface sampling and analysis✓ Removes adherent materials.✓ Analysis can be quantitative.✓ Precise definition of the area sampled is required.

• Surface sampling from coupons✓ Quantitative.✓ Depends on whether coupons are equivalent to the surface of

interest.✓ Requires removing coupons from the system.

• Method SelectionWhenever possible, each piece of equipment should be dismantledinto its individual components after cleaning and each part shouldbe individually tested for cleanliness. In this manner, any inadequa-cies in the cleaning process will be more readily identified andlocalized.



It may not be practical or desirable to dismantle large orClean–In–Place (CIP) equipment. Regardless, validation samplingand testing should commence as soon as possible after the clean-ing process is complete to reduce the chance for contamination byoutside sources. Equipment that has just been cleaned should becovered immediately by appropriate means to protect it from anycontamination.

• SolventsAqueous or organic solvents used in the cleaning procedure,should be sufficient to remove residues, and at the same time,should be minimized to reduce the risk of reaction with or damageto the equipment, or the over-dilution of the residue and the result-ant loss of analytical sensitivity.

Samples should be collected in clean or sterile containers. Sterilecontainers are suitable for this intended use. All validation samplesmust be properly labeled with complete information regarding thesource of the sample, sampler’s name, sampling date, referencenumber, product name, and the part of equipment from which thesample has been collected.

A sample of the rinse or swabbing solvent should always be includ-ed with the actual test samples to serve as a reagent blank for anychemical or microbiological determination when required.

All types of samples, physical, chemical, or microbiological, shouldbe collected according to a written procedure and using tech-niques, reagents, equipment, and containers appropriate to thetype of testing to be performed. Only trained personnel should per-form the collection of these samples.

The environmental effectiveness of cleaning procedures should beassessed by surface sampling of non-product contact surfaces(e.g.: floors, walls, air ducts, exterior equipment surfaces, etc.).Samples should be collected and analyzed for potential contamina-tion.



• Sampling MethodsThe sampling method selection for cleaners, involves choosingbetween rinse water sampling, swabbing surfaces, coupon sam-pling, or placebo sampling. Rinse water sampling involves taking asample of an equilibrated post-final rinse that has been re-circulat-ed over all surfaces. Rinse samples should be correlated to a directmeasuring technique such as swabbing.

Swabbing involves using a wipe or swab that is moistened withhigh purity water, such as Water-for-Injection (WFI) that is typicallywiped over a defined area in a systematic multi-pass way alwaysgoing from clean to dirty areas to avoid recontamination (e.g.: 10cm side by side strokes vertically, 10 cm horizontally, and 10 cmeach with the flip side of the swab in each diagonal direction). ForTOC analysis, very clean swabs or wipes and sample vials shouldbe used. (All of these are commercially available). The amount ofresidue is known to be uniformly distributed on the smooth sur-faces of equipment parts. Also, the most difficult to clean or “worst-case” areas of the equipment should be identified and specificallytargeted for sampling whenever possible.



Figure 1

Worst-Case Determination Table

ProductActive

MaterialBatch Size Solubility *

CleaningEase**

Maximum allowable

daily amountof active in

total daily unitdose of next

product

A

B

C

* Given number to describe solubility: 1, 2, 3, 4, …1 is more soluble than 2 in the same solvent, etc.

** Given number to describe cleaning ease: 1, 2, 3, 4, …1 is easier to clean than 2 under the same conditions and procedure, etc.

• Residue DetectionSelecting a method to detect cleaner residues can involve specificmethods for specific cleaner ingredients such as: High PerformanceLiquid Chromatography (HPLC), ion selective electrodes, flame pho-tometry, derivative UltraViolet (UV) spectroscopy, Thin LayerChromatography, enzymatic detection, and titration. It can alsoinvolve non-specific methods that detect the presence of a blend ofingredients such as: TOC, pH, and conductivity. The FDA prefersspecific methods, but will accept non-specific methods with adequaterationales for their use. For investigations of failures or action levels,a specific method is usually preferable.

• Analytical EvaluationAnalytical validation of the cleaning procedure should be performedafter the approval of visual inspection (absence of stains or anymateriel residue). The specificity, sensitivity, and percentage ofrecovery of the test method should be adequate to meet accept-ance criteria.



Total number of units dose

per day

Unit doseweight

Number ofdoses made by one batch

Highest dailydose

Active materi-al present inone batch

Residual limitcompared toworst-case

For the swab method it may be necessary to determine:✓ The percentage recovery of the swab extraction procedure.✓ The effectiveness of the swab at recovering residues from equip-

ment parts surface.✓ The interference of swab materials in the analysis.

For the rinse solution method it may be necessary to determine:✓ The percentage recovery of the rinse solution extraction procedure.✓ The effectiveness of the rinse solution at recovering residues from

equipment parts surfaces.✓ The interference of the rinse solution in the cleaning procedure and

analysis.✓ A correction for recovery efficiency in calculations for acceptable

residue levels.

Percentage Recovery = 100 x Sample Concentration / StandardConcentration

The percentage recovery is important because it will be applied whenevaluating the final residual concentration according to the relation:

Percentage of actual amount of residual = Calculated Amount xPercentage Recovery

It is very difficult to establish acceptable fixed limits for recovery percent-age due to the individual difference in solubility of residues, the solventused, and the nature of the manufacturing surfaces.

The following three factors contribute to the difficulty of establishing fixedlimits for the recovery percentage:

1. The residues behavior toward the solvent used.2. The solvent used.3. The nature of the manufacturing surfaces.

Some products such as proteins, for example, have a very low solubility,so the percentage recovery may be as low as 10–20%. For soluble residue,a higher percentage recovery should be expected. In general we can expectan ideal percentage recovery that falls between 60% and 90%. It is veryimportant to continuously develop the sampling and swabbing methods andreproducibility to improve percentage recovery values.

• Microbiological Cleaning Considerations



All equipment that comes in contact directly with raw material -intermediate as well as final product - must be considered for inclu-sion, because of its potential to act as a possible source for microbi-ological contamination. In addition, the facilities must be consideredfor the level of microbiological contamination appropriate to the areaclassification.

Microbiological samples should be collected prior to and through-out the cleaning procedure to assist in selection and confirmationof the efficacy of disinfectants and detergents. Microbiologicalcleanliness is assessed as < 200 cfu / 100 cm2 for non-sterile pro-duction.

It is important to determine the type of organism present. It is nec-essary to demonstrate the absence of pollution indicator organismssuch as, Escherichia coli, Salmonella spp, and Pseudomonasaeroginosa, from all locations monitored. It is necessary, as well, toensure that high levels of other microbial flora do not mask theseorganisms.

Within sterile production, attention must be paid to the number oforganisms present rather than their type. The level of microbiologi-cal contamination of the rinse water should be 10 cfu / 100 ml.Sampling is repeated three times during the validation.

• Worst-Case DeterminationWorst-case determination of cleaning validation is a crucial step indefining contamination limits and in cleaning procedure efficacy. Aworst-case determination study should be based on: active productsolubility; active product toxicity; smallest batch size that can bemanufactured using the equipment concerned; the maximum dailydose of this product; the number of dosages that can be madefrom next batch (contaminated); the product in its largest availabletables mass, or in case of ampoules or vials, the largest availablefilling volume, and in both cases, the highest daily dose; the totalarea with which the product comes into contact; the area of onetablet or the volume of one individual fill; and the total amount ofresidual contaminant (see Figure 1).

After completing the worst-case determination table, we can easilyidentify the product representing this case (A, B, or C). The table



should list all products to be manufactured in the same equipmentwhatever the chemical and bioactivity types of actives.

➤ Acceptance CriteriaIn determining the final acceptance criteria for a cleaning validation exer-

cise, the calculation of the acceptable level of contaminant in the next prod-uct maximum therapeutic patient dose is of primary importance. Acceptancecriteria are established by considering the contaminant type, the facility, andthe risk to the operator, product, and patient.

More stringent acceptance criteria are required in the case of highly bio-logically active materials compared to some excipients.

Facilities that produce product based on a single chemical entity (dedi-cated facility) shall not be subjected to as stringent a standard as multi-pur-pose facilities. Dedicated areas offer a low-risk potential, whereas a multi-product area tends toward a higher risk of contamination.

The use of automated cleaning process will tend toward more repro-ducible results when compared with manual systems.

When a number of materials are potential contaminants, consider whichitems are to be removed by the cleaning process (e.g.: chemical intermedi-ates, active ingredient, detergent, excipient, colour, flavour, degradationproduct, micro-organism, endotoxin, particulates, lubricants, residual sol-vents, moisture, etc.).

The equipment should demonstrate the absence of obvious liquid, liquidand solid residues, and be free from any noticeable “off” odor.

A worst-case approach should be adopted and the cleaning procedureshould be validated for the least soluble and most difficult to clean active orfinished product as well as any residual cleaning agent. When more thanone piece of equipment or stage is involved in the processing, the cumula-tive effect of each should be taken into consideration.

Microbiological acceptance criteria for cleaning procedures should beestablished based on product type. There may be a requirement for all orcertain specific microorganisms to be absent dependent upon product type.

Acceptance criteria should be justified in a rational, written, approved,document prior to the commencement of the validation exercise.

Worst-case criteria are to be calculated for a product group manufacturedin common equipment and then are to be applied to a selected referenceproduct. Adding a new product formulation to the existing product group mayact on the existing acceptance criteria. Also, if the product is less solublethan the existing reference product, then the new product can become thereference product and full cleaning validation must be performed. The new



product should become a “stand alone” case when the cleaning methodrequired is not suitable for other products.

A safety factor of not more than 1 / 1000 (0.1%) of the active under inves-tigation (contaminant) found in a single unit of the lowest dosage form of thenext product should remain in the equipment after the cleaning procedure. Alist summarizing the batch size of products manufactured through the sameequipment should be prepared in order to determine the smallest batch size.This is an important step to calculate the carryover limit.

The calculation of acceptance criteria should be based on the followingparameters:

• Residual limit of active (contaminant) expressed in mg / cm2: R• 1/ 1000 of concentration of active (contaminant) per dose units: L• Maximum allowable number of doses per day of next product (con-

taminated): D• Smallest batch size in mg: B• Concentration of active in unit dose of next product (contaminated)

or the number of total dose units manufactured: C• Total surface area of equipment parts in contact with the product

(contaminant) expressed in cm2: T• Surface swabbed in cm2: S

Thus, the residual limit in the cleaned equipment of active (contaminant)mg / cm2 is calculated as follows:

For example:Concentration of active (contaminant) per dose unit = 30 mg

Maximum allowable number of doses per day of next product (contaminated) = 4 UnitsBatch size (smallest) in mg = 50 x 106

Concentration of active in unit dose of next product (contaminated) orthe number of total dose units manufactured = 200 mg



R mg / cm2 = L / D x B / C x S / T

Total surface area of equipment parts in contact with the product (contaminant) expressed in cm2 = 45000 cm2

Surface swabbed in ccm2 = 100 cm2

Residual limit of active (contaminant) in mg / cm2 =30 x 1/1000 / 4 x 50 x 106 / 200 x100 / 45000

Residual limit of active (contaminant) in the equipment after cleaning =4.17 mg / cm2

For the automated systems and where rinse is used and rinse volumesare known, the following equation could be used taking into consideration thetotal volume of final rinse in ml V:

The active (contaminant) carryover from product A to the next productB (contaminated) per unit dose is calculated as follows:

For example, the concentration of active (contaminant) A per unit doseis 2 mg per day. Based on a safety factor of not more than 1 / 1000 (0.1%)of the active under investigation (contaminant) found in a single unit of thelowest dosage form of the next product, we can say:

The limit of concentration of active A found in total (standard) daily doseunits of next (contaminated) product B is:

1 / 1000 x 2 mg = 0.002 mg or 2 µg

Supposing that the total amount of contaminant product A found in thetotal product contacting parts of the equipment after cleaning is 9 mg (9000µg). The next smallest batch size worst-case (contaminated) B is 100 Kgand B unit dose weight (tablet weight for example) is 90 mg. The total allow-able daily dose of B is three doses. The concentration of active contaminantA carried over to unit dose of product B is calculated:

Contaminant µg / mg = 9000 µg / 100 x 106

Contaminant µg / mg = 9 x 10-5

Contaminant µg / Unit dose = 9 x 10-5 x 90Contaminant µg / Unit dose B = 0.0081



R mg / ml = L / D x B / C x 1 / V

Contaminant µg / Total Daily dose B = 0.0081 x 3Contaminant µg / Total Daily dose B = 0.0243

The active (contaminant) A carried over to total daily units dose of prod-uct B (contaminated) is inferior to the established limit of 2 µg.

Another more conservative acceptance criteria limit could be adopted. Itconsiders that no more than 5 ppm from any active product can be left onany part of equipment for potential carryover to next product.

This conservative limit could not be applied for all types of products ofpharmaceutical forms. An acceptance limit of 5 ppm could be applied forproducts having a bioactivity or strength less than 10 mg per unit dose“highly bioactive” or for products having a high level of toxicity. The maininconvenience of the application of this limit is related to the analyticalmethod Limit of Detection (LoD or LD) and to equipment sensitivity indetecting this value.

Detergent and cleaning agents should be treated by using the safetyfactor of 1 / 1000 of LD50 value or less than 10 ppm, whichever is the lowest.Another assessment of detergent residuals could be adopted such thatresidues should not exceed the detection limit of the method of analysis forthe relevant active detergent substance.

The effective removal of residues having pharmacological or toxicologi-cal activity is the primary concern in any cleaning procedure and validationof that procedure. In addition to chemical assay and microbiological testing,other tests, such as pH, TOC, and conductivity may be desirable.

Whenever there is a change in manufacturing process, product formula-tion, manufacturing equipment, or cleaning procedure, revalidation of thecleaning procedure must be considered.

Cleaning Standard Operating Procedure The standard cleaning operation procedure should include the following

essential points:

➤ Objective

➤ ScopeDescribing the range of application for the SOP, equipment, and products.

➤ ResponsibilityIdentification of who is responsible for performing the cleaning operations.



➤ Procedure Description of cleaning method to be used including cleaning agent;

concentration of the detergents surfactants, and sanitizing agents used during the cleaning procedure; temperature of the wash and rinse water orother solvent(s); flow rate and/or pressure at which the wash and rinse solvents are delivered; volume or amount of water or other solvents used to wash and rinse the equipment; diagrams describing the location of difficult to clean areas and “trap points:” inspection and/or testing regime toassess cleanliness and dryness; and status labeling of equipment and facility to ensure cleanliness status to all personnel.

➤ Other ItemsAdditional concerns that should be considered in the cleaning SOP

include the following:Where preparation of a cleaning solution is performed locally, it must be

against a procedure that includes manufacturer instructions, batch number-ing, and expiration dating.

Training records of operators should be shown for each cleaning proce-dure.

When a validated, automated cleaning procedure is in place, which pro-duces a validated printout of critical processing stages, a triple check of crit-ical stages should be performed.

The validation review or re-validation status should be re-assessedbased upon any changes to the operating situation, equipment replace-ment, cleaning procedure changes, regulatory requirements, or adversemarket comments that are related to the cleaning validation. Re-validationshould take place once a year at a minimum.

The use of non-specific test methods could be permissible for re-valida-tion exercises provided that the limits set can be related to a specific result inthe initial validation or can be justified by some other means. Methods suchas drain water conductivity and TOC analysis may be employed.

➤ Analytical MethodThe analytical method used to determine the residual amount of active

should be validated. A proper performance qualification protocol and reportshould be appropriately established and approved prior to starting thecleaning procedure. This demonstrates that the laboratory equipment andtechniques are capable of evaluating with precision, according to writtenand validated analytical methods, the small amount of residual contaminant(s) (active or others).

A simulation exercise using the active product and the same material sur-



face of production equipment would be suitable for the validation of the ana-lytical method. Serial dilutions of active standard preparations could be usedalong with a placebo preparation containing the additives and excipients.These preparations would be suitable for simulating contamination duringthis exercise.

Prior to the collection of samples from the cleaned equipment, it is impor-tant to prove the effectiveness of the swabbing method and the swab materi-als to be used.

Cleaning Analytical Method Validation The following sections should be included:

➤ Objective

➤ Scope Describe the active product (s) that could be evaluated by the method.

➤ Acceptance Criteria Describe the method followed to determine the acceptance criteria. The

major and critical acceptance criteria to be mentioned are as follows: activeproduct recovery percentage and active residual (contaminant) µg per cm2,or µg of active residual (contaminant) per maximum daily dose units of nextproduct.

➤ MethodDescription of analytical methods used: standard preparation, sample

preparation, analytical equipment used, analytical parameters, equipmentparameter, sample volume, materials used, and the determination of the fol-lowing values (which are specific to the analytical method and are relativefor each active product):

• Precision• Accuracy• Limit of Detection• Limit of Quantitation (LoQ)• Linearity (where appropriate, linearity of detector response for stan-

dard solution over a range of concentrations)• Recovery percentage• Absence of interference between swab materials and active product• Absence of interference between solvent and active product



➤ Calculations Residual Limit of active (contaminant) A in mg / cm2 of cleaned equip-

ment or the concentration of active (contaminant) A carried over to unitdose of product B (contaminated) is calculated.

➤ Conclusion

Cleaning Procedure Tools (Matrices)Tables, schemas, and matrices are the main tools used during the

preparation of cleaning validation protocol and procedure especially formulti-product areas and equipment. This will help cleaning procedure devel-opers to determine the worst-case and to calculate by the most efficientmethod the limit of contamination.

➤ Equipment Parts SchemaEquipment parts schema are useful to illustrate the different critical parts

of the equipment that are in direct contact with the product, parts area, loca-tion of difficult to clean areas or “trap points,” and swab locations. It containsequipment name, identification number (tag number), equipment location,name of each item, item surface, swab factor, and products to be manufac-tured in the machine.

➤ Products Type MatrixA table grouping the different active products according to their biological

activity, physical characteristics, and toxicity should be established. Thistype of grouping gives an overview about the products’ manufacturing areaand equipment to be used. Products having the same characteristics mayrequire a dedicated facility or equipment. A product type matrix helps tochoose appropriate cleaning procedures for each group of products.

Based on this information, similar products should be gathered into onegroup.





Figure 2

Equipment Parts Schema

Multi-Product Equipment Contamination Acceptance Criteria Matrix

Where equipment is used for multi-products manufacturing, it is useful toestablish a matrix listing the contamination acceptance limits of productscompared to the worst-case. This matrix gives a quick overview about themaximum contaminant carryover per product (contaminant followed by con-taminated).

A, B, C, D, and E are the different products manufactured using thesame equipment. Contaminant limit for each product expressed in µg / cm2

is determined during the active product carryover acceptance criteria deter-mination exercise. Values are reported properly in the matrix. For example,after manufacturing product D (contaminant), the equipment is cleanedaccording to the cleaning procedure then sampled (by swabs). Samplesafter analysis give the result of 18 µg / cm2 as total residue of active productD (contaminant) in all product contact parts of the equipment. If the nextproduct to be manufactured is B, the allowable limit of contamination figuredin the matrix for this case (D followed by B) is 25 µg / cm2. Consequently,the equipment will be declared “clean” and labeled accordingly.

Cleaning validation matrices should be reviewed and revalidated follow-ing any change of cleaning elements e.g., modification of cleaning proce-dure, use of new equipment, and equipment modification could result in sur-face change of product contact parts, changes in regulatory requirements,introduction of new product, etc.





Figure 3

Products Type Matrix

* Given number to describe Biological Activity: 1, 2, 3, 4, …1 is more bioactive than 2, etc.

** Given number to describe Toxicity: 1, 2, 3, 4, …1 is more toxic than 2, etc.

*** Given number to describe Solubility: 1, 2, 3, 4, …1 is more soluble than 2 in the same solvent, etc.

Figure 4

Contamination Acceptance Criteria Matrix

Cleaning Procedure Flowchart

Figure 5, summarizes the main steps of a cleaning procedure validation.



1

CleaningProcedure

Identification

1

3

Preparationof Analytical

Method

3

No

Yes

No

Yese

4

CleaningProcedureValidation

4

No

Yes

2

Preparationof CleaningProcedure

(SOP)

No

Yes

No

YesRe-

ValidationRequired

2

Establishing a rationale for the cleaning validation

program

Define objectives, contamination

limit approach, equipment and products group

Establish acceptance criteria

• Define sampling method• Define analytical technique

• Establish acceptance criteria matrix

Procedure consistently meets acceptance criteria. Three consecutive, successful results.

OK ?

OK ?

OK ?

OK ?

Is Change Critical ?

Change Control

Routine Cleaning

Cleaning validation program is identified

Cleaning procedure ready to be validated

Analytical method is validated

Cleaning procedure is validated

2

Figure 5

Cleaning Procedures Validation Flowchart

CONCLUSION

It is practically impossible to prove that production equipment is “clean” atthe level of 100%. However, it is possible to prove that the traces of activeproduct remaining, spread through the equipment parts, are within anacceptable limit and that we are capable of detecting and quantifying thesetrace levels.

Cleaning validation provides a means of proving that the contaminationlevels have been reduced below contamination acceptance limits.

The cleaning validation program should involve a rational monitoring pro-gram to maintain a validated state. Cleaning validation activity should coveractive residue identification, active residue detection method selection, sam-pling method selection, the establishment of residue acceptance criteria,methods validation, recovery studies, and the identification of equipmentparts in direct contact with the product.

The good preparation and proper implementation of cleaning validationtools (matrices and tables) is a determinant factor in the success of a clean-ing validation program. ❏

About the Author

Mowafak Nassani Ph.D. has a Doctoral degree from U.S.T.L. Universityof Montpellier, France, in Analytical, Industrial Chemistry. He is theGeneral Director of Pharmaceutical Validation Services at PVS Canada.He worked as a senior consultant in QA/QC, GMP, compliance, auditingand validation for I.C.C.E, Brussels, Belgium. He has occupied the postof QA/QC Manager in leading multinational pharmaceutical companies.

Dr. Nassani can be reach by phone at:+1 (514) 991-2494 or by e-mail at: [email protected]



REFERENCES

1. Guidance for Industry, “Non-clinical Studies for the Safety Evaluation of Pharmaceutical

Excipients,” 5/18/2005

2. FDA, “Guide to Inspection of Validation of Cleaning Processes,” July 2004.

3. International Conference on Harmonization (ICH), “Guidance for Industry: Q3A Impurities

in New Drug Substances,” 2/11/2003

4. Validation of Analytical Procedures: Methodology, FDA Guidance, December 1997.

5. FDA, “Guide to Inspection of Pharmaceutical Quality Control Laboratories,” July 1993.



Article Acronym Listing

cfu Colony Forming UnitcGMP Current Good Manufacturing PracticeCIP Clean-In-PlaceFDA Food and Drug AdministrationHPLC High Performance Liquid

ChromatographyICH International Conference on

HarmonizationLD/LoD Limit of DetectionLoQ Limit of Quantitationppm Parts per millionQA Quality AssuranceQC Quality ControlSOP Standard Operating ProcedureTOC Total Organic CarbonUV Ultra VioletWFI Water-For-Injection

Originally published in the August 2005 issue of the Journal of Validation Technology

cleaning validation in pharmaceutical industry

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