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INTRODUCTION

Cleaning validation in the pharmaceutical industry has been a topic of

ever-increasing interest and scrutiny in recent Food and Drug

Administration (FDA) inspections.The validation of procedures used to

clean the equipment employed during the various steps of a manufacturing

process is a clear requirement of current Good Manufacturing Practice

(cGMP). As such, FDA inspectors now expect to see a functioning cleaning

validation program with appropriate documentation in place during their

inspections.

The requirement that equipment be clean before being used is not a

new concept.The equally important requirement that it also be sanitary is

many 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 Validation

of Cleaning Processes .”

The FDA’s guide to inspections, which “intended to cover equipment

cleaning for chemical residues only,” includes:

1. “FDA expects firms to have written procedures [Standard

Operating Procedures (SOPs)] detailing the cleaning processes...”

2. “FDA expects firms to have written general procedures on how

cleaning processes will be validated.”

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

38 Institute of Validation Technology

Cleaning Validation in thePharmaceutical Industry

By Mowafak Nassani, Ph.D.


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and approving the validation study, the acceptance criteria, and

when 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 microbiological

aspects of equipment cleaning should be considered. This consists

largely of preventive measures…”

6. “Determine the specificity and sensitivity of the analytical method

used to detect residuals or contaminants.”

7. “The firm should challenge the analytical method in combination

with the sampling method(s) used to show that contaminants can

be recovered from the equipment surface and at what level...”

8. “Direct sampling (e.g., with swabs) is ‘most desirable,’ although

rinse sampling may be satisfactory.”

OBJECTIVES

The objectives of this article are to establish a broad basis for cleaning

validation policy and programs, and to determine the requirements, proce-

dures, acceptance limits, and working papers needed to support this vitally

important activity.

Cleaning Validation Protocol

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

cuted in accordance with the SOPs covering these activities in place at the

time. 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 cleaned

from the equipment, and the individual components of the product and

equipment under investigation.

➤ Sampling and Testing MethodologiesThis 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 which

laboratories are to be involved in the testing and any precautions to be

taken throughout the validation exercise.

Mowafak Nassani, Ph.D.

39Cleaning Val idat ion


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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 levels

of assurance concerning cleaning:

• Visual inspection

✓ Active product contact parts of the equipment are individually

examined (wherever possible) for cleanliness. This visual inspection

allows the early localization and identification of any inadequacies

in 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 are

that 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 Selection

Whenever possible, each piece of equipment should be dismantled

into its individual components after cleaning and each part should

be individually tested for cleanliness. In this manner, any inadequa-

cies in the cleaning process will be more readily identified and

localized.




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It may not be practical or desirable to dismantle large orClean–In–Place (CIP) equipment. Regardless, validation sampling

and testing should commence as soon as possible after the clean-

ing process is complete to reduce the chance for contamination by

outside sources. Equipment that has just been cleaned should be

covered immediately by appropriate means to protect it from any

contamination.

• Solvents

Aqueous 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 damage

to 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. Sterile

containers are suitable for this intended use. All validation samples

must be properly labeled with complete information regarding the

source of the sample, sampler’s name, sampling date, reference

number, product name, and the part of equipment from which the

sample 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 any

chemical or microbiological determination when required.

All types of samples, physical, chemical, or microbiological, should

be collected according to a written procedure and using tech-

niques, reagents, equipment, and containers appropriate to the

type of testing to be performed. Only trained personnel should per-

form the collection of these samples.

The environmental effectiveness of cleaning procedures should be

assessed 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.




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• Sampling Methods

The sampling method selection for cleaners, involves choosing

between rinse water sampling, swabbing surfaces, coupon sam-pling, or placebo sampling. Rinse water sampling involves taking a

sample of an equilibrated post-final rinse that has been re-circulat-

ed over all surfaces. Rinse samples should be correlated to a direct

measuring technique such as swabbing.

Swabbing involves using a wipe or swab that is moistened with

high purity water, such as Water-for-Injection (WFI) that is typically

wiped over a defined area in a systematic multi-pass way always

going from clean to dirty areas to avoid recontamination (e.g.: 10

cm side by side strokes vertically, 10 cm horizontally, and 10 cm

each with the flip side of the swab in each diagonal direction). For

TOC analysis, very clean swabs or wipes and sample vials should

be used. (All of these are commercially available). The amount of

residue 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 specifically

targeted for sampling whenever possible.



Figure 1

Worst-Case Determination Table

Product Active

Material Batch Size Solubility *Cleaning

Ease**

Maximum

allowable

daily amount

of active intotal daily unit

dose 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.


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• Residue Detection

Selecting a method to detect cleaner residues can involve specificmethods for specific cleaner ingredients such as: High Performance

Liquid Chromatography (HPLC), ion selective electrodes, flame pho-

tometry, derivative UltraViolet (UV) spectroscopy, Thin Layer

Chromatography, enzymatic detection, and titration. It can also

involve non-specific methods that detect the presence of a blend of

ingredients such as:TOC, pH, and conductivity. The FDA prefers

specific methods, but will accept non-specific methods with adequate

rationales for their use. For investigations of failures or action levels,

a specific method is usually preferable.

• Analytical Evaluation

Analytical validation of the cleaning procedure should be performed

after the approval of visual inspection (absence of stains or any

materiel residue). The specificity, sensitivity, and percentage of

recovery of the test method should be adequate to meet accept-

ance criteria.



Total number

of units doseper day

Unit dose

weight

Number of

doses made

by one batch

Highest daily

dose

Active materi-

al present inone batch

Residual limit

compared toworst-case


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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 / Standard

Concentration

The percentage recovery is important because it will be applied when

evaluating the final residual concentration according to the relation:

Percentage of actual amount of residual = Calculated Amount x

Percentage Recovery

It is very difficult to establish acceptable fixed limits for recovery percent-

age due to the individual difference in solubility of residues, the solvent

used, and the nature of the manufacturing surfaces.

The following three factors contribute to the difficulty of establishing fixed

limits 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 expect

an ideal percentage recovery that falls between 60% and 90%. It is very

important to continuously develop the sampling and swabbing methods and

reproducibility to improve percentage recovery values.

• Microbiological Cleaning Considerations




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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 considered

for the level of microbiological contamination appropriate to the area

classification.

Microbiological samples should be collected prior to and through-

out the cleaning procedure to assist in selection and confirmation

of the efficacy of disinfectants and detergents. Microbiological

cleanliness 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 organisms

such as, Escherichia coli, Salmonella spp, and Pseudomonas

aeroginosa , from all locations monitored. It is necessary, as well, to

ensure that high levels of other microbial flora do not mask these

organisms.

Within sterile production, attention must be paid to the number of

organisms 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 Determination

Worst-case determination of cleaning validation is a crucial step in

defining contamination limits and in cleaning procedure efficacy. A

worst-case determination study should be based on: active product

solubility; active product toxicity; smallest batch size that can be

manufactured using the equipment concerned; the maximum daily

dose of this product; the number of dosages that can be made

from next batch (contaminated); the product in its largest available

tables mass, or in case of ampoules or vials, the largest available

filling volume, and in both cases, the highest daily dose; the total

area with which the product comes into contact; the area of one

tablet or the volume of one individual fill; and the total amount of

residual contaminant (see Figure 1).

After completing the worst-case determination table, we can easily

identify the product representing this case (A, B, or C). The table




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should list all products to be manufactured in the same equipment

whatever the chemical and bioactivity types of actives.

➤ Acceptance Criteria

In 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. Acceptance

criteria are established by considering the contaminant type, the facility, and

the 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 which

items are to be removed by the cleaning process (e.g.: chemical intermedi-

ates, active ingredient, detergent, excipient, colour, flavour, degradation

product, micro-organism, endotoxin, particulates, lubricants, residual sol-

vents, moisture, etc.).

The equipment should demonstrate the absence of obvious liquid, liquid

and solid residues, and be free from any noticeable “off” odor.

A worst-case approach should be adopted and the cleaning procedure

should be validated for the least soluble and most difficult to clean active or

finished product as well as any residual cleaning agent. When more than

one 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 be

established based on product type. There may be a requirement for all or

certain 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 manufactured

in common equipment and then are to be applied to a selected reference

product. Adding a new product formulation to the existing product group may

act on the existing acceptance criteria. Also, if the product is less soluble

than the existing reference product, then the new product can become the

reference product and full cleaning validation must be performed. The new




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product should become a “stand alone” case when the cleaning method

required 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 the

next product should remain in the equipment after the cleaning procedure. A

list summarizing the batch size of products manufactured through the same

equipment 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 following

parameters:

• 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 cm 2: 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 Units

Batch size (smallest) in mg = 50 x 106

Concentration of active in unit dose of next product (contaminated) or

the number of total dose units manufactured = 200 mg



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


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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 volumes

are known, the following equation could be used taking into consideration the

total volume of final rinse in ml V:

The active (contaminant) carryover from product A to the next product

B (contaminated) per unit dose is calculated as follows:

For example, the concentration of active (contaminant) A per unit dose

is 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 the

lowest dosage form of the next product, we can say:

The limit of concentration of active A found in total (standard) daily dose

units 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 the

total product contacting parts of the equipment after cleaning is 9 mg (9000

µg). The next smallest batch size worst-case (contaminated) B is 100 Kg

and 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 contaminant

A 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 90

Contaminant µg / Unit dose B = 0.0081



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


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Contaminant µg / Total Daily dose B = 0.0081 x 3

Contaminant 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. It

considers that no more than 5 ppm from any active product can be left on

any part of equipment for potential carryover to next product.

This conservative limit could not be applied for all types of products of

pharmaceutical forms. An acceptance limit of 5 ppm could be applied for

products having a bioactivity or strength less than 10 mg per unit dose

“highly bioactive” or for products having a high level of toxicity. The main

inconvenience of the application of this limit is related to the analytical

method Limit of Detection (LoD or LD) and to equipment sensitivity in

detecting this value.

Detergent and cleaning agents should be treated by using the safety

factor of 1 / 1000 of LD50 value or less than 10 ppm, whichever is the lowest.

Another assessment of detergent residuals could be adopted such that

residues should not exceed the detection limit of the method of analysis for

the relevant active detergent substance.

The effective removal of residues having pharmacological or toxicologi-

cal activity is the primary concern in any cleaning procedure and validation

of 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 the

cleaning procedure must be considered.

Cleaning Standard Operating Procedure

The standard cleaning operation procedure should include the following

essential points:

➤ Objective

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

➤ Responsibility

Identification of who is responsible for performing the cleaning operations.




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➤ Procedure

Description of cleaning method to be used including cleaning agent;

concentration of the detergents surfactants, and sanitizing agents usedduring the cleaning procedure; temperature of the wash and rinse water or

other 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 to

assess cleanliness and dryness; and status labeling of equipment and

facility to ensure cleanliness status to all personnel.

➤ Other Items

Additional 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-assessed

based upon any changes to the operating situation, equipment replace-

ment, cleaning procedure changes, regulatory requirements, or adverse

market comments that are related to the cleaning validation. Re-validation

should 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 in

the initial validation or can be justified by some other means. Methods such

as drain water conductivity and TOC analysis may be employed.

➤ Analytical Method

The analytical method used to determine the residual amount of active

should be validated. A proper performance qualification protocol and report

should be appropriately established and approved prior to starting the

cleaning procedure.This demonstrates that the laboratory equipment and

techniques are capable of evaluating with precision, according to written

and 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-




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face of production equipment would be suitable for the validation of the ana-

lytical method. Serial dilutions of active standard preparations could be used

along with a placebo preparation containing the additives and excipients.These preparations would be suitable for simulating contamination during

this 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: active

product recovery percentage and active residual (contaminant) µg per cm2,

or µg of active residual (contaminant) per maximum daily dose units of next

product.

➤ Method

Description of analytical methods used: standard preparation, sample

preparation, analytical equipment used, analytical parameters, equipment

parameter, sample volume, materials used, and the determination of the fol-

lowing values (which are specific to the analytical method and are relative

for 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




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➤ 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 for

multi-product areas and equipment.This will help cleaning procedure devel-

opers to determine the worst-case and to calculate by the most efficient

method the limit of contamination.

➤ Equipment Parts Schema

Equipment 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 contains

equipment 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 Matrix

A table grouping the different active products according to their biological

activity, physical characteristics, and toxicity should be established. This

type of grouping gives an overview about the products’ manufacturing area

and equipment to be used. Products having the same characteristics may

require a dedicated facility or equipment. A product type matrix helps to

choose appropriate cleaning procedures for each group of products.

Based on this information, similar products should be gathered into one

group.




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Figure 2

Equipment Parts Schema


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Multi-Product Equipment Contamination Acceptance Criteria Matrix

Where equipment is used for multi-products manufacturing, it is useful to

establish a matrix listing the contamination acceptance limits of productscompared to the worst-case.This matrix gives a quick overview about the

maximum contaminant carryover per product (contaminant followed by con-

taminated).

A, B, C, D, and E are the different products manufactured using the

same 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 cleaned

according to the cleaning procedure then sampled (by swabs). Samples

after analysis give the result of 18 µg / cm2 as total residue of active product

D (contaminant) in all product contact parts of the equipment. If the next

product to be manufactured is B, the allowable limit of contamination figured

in 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.




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Figure 3

Products Type Matrix

* Given number to describe Biological Activity: 1, 2, 3, 4, …1 ismore 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 solublethan 2 in the same solvent, etc.

Figure 4

Contamination Acceptance Criteria Matrix


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Cleaning Procedure Flowchart

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



1

Cleaning

ProcedureIdentification

1

3

Preparationof Analytical

Method

No

Yes

No

Yese

4

CleaningProcedureValidation

4

No

Yes

2

Preparationof CleaningProcedure

SOP

No

Yes

No

YesRe-

ValidationRequired

2

Establishing

a rationale for thecleaning validation

program

Define objectives,contamination

limit approach, equipment andproducts group

Establish

acceptance criteria

• Define sampling method• Define analytical technique

• Establish acceptancecriteria matrix

Procedure

consistently meets

acceptance criteria.

Three consecutive,

successful results.

OK ?

OK ?

OK ?

OK ?

Is ChangeCritical ?

ChangeControl

RoutineCleaning

Cleaning validationprogram is identified

Cleaning procedureready to be validated

Analytical methodis validated

Cleaning procedureis validated

2

Figure 5

Cleaning Procedures Validation Flowchart


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CONCLUSION

It is practically impossible to prove that production equipment is “clean” at

the level of 100%. However, it is possible to prove that the traces of activeproduct remaining, spread through the equipment parts, are within an

acceptable limit and that we are capable of detecting and quantifying these

trace levels.

Cleaning validation provides a means of proving that the contamination

levels 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 cover

active 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 equipment

parts in direct contact with the product.

The good preparation and proper implementation of cleaning validation

tools (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. University

of Montpellier, France, in Analytical, Industrial Chemistry. He is the

General Director of Pharmaceutical Validation Services at PVS Canada.

He worked as a senior consultant in QA/QC, GMP, compliance, auditing

and validation for I.C.C.E, Brussels, Belgium. He has occupied the post

of 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]




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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 Unit

cGMP Current Good Manufacturing Practice

CIP Clean-In-Place

FDA Food and Drug Administration

HPLC High Performance Liquid

Chromatography

ICH International Conference on

Harmonization

LD/LoD Limit of Detection

LoQ Limit of Quantitation

ppm Parts per million

QA Quality AssuranceQC Quality Control

SOP Standard Operating Procedure

TOC Total Organic Carbon

UV Ultra Violet

WFI Water-For-Injection

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

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