Beruflich Dokumente
Kultur Dokumente
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.
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.
➤ 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.
Cleaning Validation 39
Mowafak Nassani, Ph.D.
• 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.
• 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.
Cleaning Validation 41
Mowafak Nassani, Ph.D.
• 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.
Figure 1
Worst-Case Determination Table
Maximum
allowable
daily amount
Active Cleaning
Product Batch Size Solubility * of active in
Material Ease**
total daily unit
dose of next
product
• 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 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.
Number of
Total number Active materi- Residual limit
Unit dose doses made Highest daily
of units dose al present in compared to
weight by one batch dose
per day one batch worst-case
Cleaning Validation 43
Mowafak Nassani, Ph.D.
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.
• 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).
Cleaning Validation 45
Mowafak Nassani, Ph.D.
➤ 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.
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 cm 2: S
R mg / cm2 = L / D x B / C x S / T
For example:
Concentration of active (contaminant) per dose unit = 30 mg
Cleaning Validation 47
Mowafak Nassani, Ph.D.
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:
R mg / ml = L / D x B / C x 1 / V
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.
➤ Objective
➤ Scope
Describing the range of application for the SOP, equipment, and products.
➤ Responsibility
Identification of who is responsible for performing the cleaning operations.
Cleaning Validation 49
Mowafak Nassani, Ph.D.
➤ 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 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-
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.
➤ 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
Cleaning Validation 51
Mowafak Nassani, Ph.D.
➤ Calculations
Residual Limit of active (contaminant) A in mg / cm2 of cleaned equip-
ment or the concentration of active (contaminant) A carried over to unit
dose of product B (contaminated) is calculated.
➤ Conclusion
Figure 2
Equipment Parts Schema
Cleaning Validation 53
Mowafak Nassani, Ph.D.
Figure 3
Products Type Matrix
Figure 4
Contamination Acceptance Criteria Matrix
Cleaning Validation 55
Mowafak Nassani, Ph.D.
Figure 5
Cleaning Procedures Validation Flowchart
1
1
No
Cleaning Establishing
Cleaning validation
Procedure a rationale for the
OK ? Yes
e program is identified
Identification cleaning validation
program
2
2
No
Define objectives,
Preparation contamination Cleaning procedure
of Cleaning limit approach, equipment and OK ? Yes ready to be validated
Procedure products group
(SOP)
3
3
Establish
No
acceptance criteria
Preparation • Define sampling method
of Analytical • Define analytical technique Analytical method
OK ? Yes is validated
Method • Establish acceptance
criteria matrix
4
4
No
Procedure
Cleaning consistently meets
Procedure acceptance criteria. OK ? Yes Cleaning procedure
Validation Three consecutive, is validated
successful results.
Routine
Re- Is Change Change Cleaning
Validation Yes Critical ? Control
Required
No
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 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. ❏
Cleaning Validation 57
Mowafak Nassani, Ph.D.
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