Professional Documents
Culture Documents
Pharmaceutical Industry
By Mowafak Nassani, Ph.D.
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 published a guidance document: the 2004 FDA Guide to Inspections Validation
of Cleaning Processes.
The FDAs 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
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4.
5.
6.
7.
8.
OBJECTIVES
The objectives of this article are to establish a broad basis for cleaning
validation policy and programs, and to determine the requirements, procedures, acceptance limits, and working papers needed to support this vitally
important activity.
Cleaning Validation Protocol
Cleaning validation protocols should be developed, approved, and executed 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 Methodologies
This section should typically include a step-by-step explanation of sampling techniques and requirements, as well as the specific analytical procedures 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.
Cleaning Validation
39
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.
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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 resultant 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, samplers 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 included 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 techniques, reagents, equipment, and containers appropriate to the
type of testing to be performed. Only trained personnel should perform the collection of these samples.
Cleaning Validation
41
Sampling Methods
The sampling method selection for cleaners, involves choosing
between rinse water sampling, swabbing surfaces, coupon sampling, or placebo sampling. Rinse water sampling involves taking a
sample of an equilibrated post-final rinse that has been re-circulated 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 surfaces of equipment parts. Also, the most difficult to clean or worstcase 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 in
total daily unit
dose of next
product
A
B
C
*
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Residue Detection
Selecting a method to detect cleaner residues can involve specific
methods for specific cleaner ingredients such as: High Performance
Liquid Chromatography (HPLC), ion selective electrodes, flame photometry, 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 acceptance criteria.
Total number
of units dose
per day
Unit dose
weight
Number of
doses made
by one batch
Highest daily
dose
Cleaning Validation
Residual limit
compared to
worst-case
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All equipment that comes in contact directly with raw material intermediate as well as final product - must be considered for inclusion, because of its potential to act as a possible source for microbiological 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 throughout 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 production.
It is important to determine the type of organism present. It is necessary 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 microbiological 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
Cleaning Validation
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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 investigation (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 (contaminated): 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 cm 2: S
Thus, the residual limit in the cleaned equipment of active (contaminant)
mg / cm2 is calculated as follows:
R mg / cm2 = L / D x B / C x S / T
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
Cleaning Validation
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R mg / ml = L / D x B / C x 1 / V
Cleaning Validation
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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 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 numbering, and expiration dating.
Training records of operators should be shown for each cleaning procedure.
When a validated, automated cleaning procedure is in place, which produces a validated printout of critical processing stages, a triple check of critical stages should be performed.
The validation review or re-validation status should be re-assessed
based upon any changes to the operating situation, equipment replacement, 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-validation 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 sur50
face of production equipment would be suitable for the validation of the analytical 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 important to prove the effectiveness of the swabbing method and the swab materials 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) g per cm2,
or g 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 following 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 standard 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
Cleaning Validation
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Calculations
Residual Limit of active (contaminant) A in mg / cm2 of cleaned equipment or the concentration of active (contaminant) A carried over to unit
dose of product B (contaminated) is calculated.
Conclusion
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Figure 2
Equipment Parts Schema
Cleaning Validation
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Figure 3
Products Type Matrix
Figure 4
Contamination Acceptance Criteria Matrix
Cleaning Validation
55
No
Establishing
a rationale for the
cleaning validation
program
Cleaning
Procedure
Identification
OK ?
Yes
e
Cleaning validation
program is identified
2
2
No
Define objectives,
contamination
limit approach, equipment and
products group
Preparation
of Cleaning
Procedure
(SOP)
Yes
OK ?
Cleaning procedure
ready to be validated
3
3
Preparation
of Analytical
Method
Establish
acceptance criteria
Define sampling method
Define analytical technique
Establish acceptance
criteria matrix
No
Yes
OK ?
Analytical method
is validated
4
4
No
Cleaning
Procedure
Validation
Procedure
consistently meets
acceptance criteria.
Three consecutive,
successful results.
OK ?
Yes
Cleaning procedure
is validated
ReValidation
Required
Yes
Is Change
Critical ?
No
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Change
Control
Routine
Cleaning
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 active
product 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 program to maintain a validated state. Cleaning validation activity should cover
active residue identification, active residue detection method selection, sampling 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 cleaning validation program.
Cleaning Validation
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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.
Originally published in the August 2005 issue of the Journal of Validation Technology
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