GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES
Note: This document is reference material for investigators and other FDA
personnel. The document does not bind FDA, and does no confer any rights,
privileges, benefits, or immunities for or on any person(s).
I. INTRODUCTION
Validation of cleaning procedures has generated considerable discussion
since agency documents, including the Inspection Guide for Bulk
Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have
briefly addressed this issue. These Agency documents clearly establish the
expectation that cleaning procedures (processes) be validated.
This guide is designed to establish inspection consistency and uniformity by
discussing practices that have been found acceptable (or unacceptable).
Simultaneously, one must recognize that for cleaning validation, as with
validation of other processes, there may be more than one way to validate a
process. In the end, the test of any validation process is whether
scientific data shows that the system consistently does as expected and
produces a result that consistently meets predetermined specifications.
This guide is intended to cover equipment cleaning for chemical residues
only.
II. BACKGROUND
For FDA to require that equipment be clean prior to use is nothing new, the
1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shall be
maintained in a clean and orderly manner ***." A very similar section on
equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of
course, the main rationale for requiring clean equipment is to prevent
contamination or adulteration of drug products. Historically, FDA
investigators have looked for gross insanitation due to inadequate cleaning
and maintenance of equipment and/or poor dust control systems. Also,
historically speaking, FDA was more concerned about the contamination of
nonpenicillin drug products with penicillins or the cross-contamination of
drug products with potent steroids or hormones. A number of products have
been recalled over the past decade due to actual or potential penicillin
cross-contamination.
One event which increased FDA awareness of the potential for cross
contamination due to inadequate procedures was the 1988 recall of a finished
drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical
used to produce the product had become contaminated with low levels of
intermediates and degradants from the production of agricultural pesticides.
The cross-contamination in that case is believed to have been due to the
reuse of recovered solvents. The recovered solvents had been contaminated
because of a lack of control over the reuse of solvent drums. Drums that had
been used to store recovered solvents from a pesticide production process
were later used to store recovered solvents used for the resin manufacturing
process. The firm did not have adequate controls over these solvent drums,
did not do adequate testing of drummed solvents, and did not have validated
cleaning procedures for the drums.
Some shipments of this pesticide contaminated bulk pharmaceutical were
supplied to a second facility at a different location for finishing. This
resulted in the contamination of the bags used in that facility's fluid bed
dryers with pesticide contamination. This in turn led to cross contamination
of lots produced at that site, a site where no pesticides were normally
produced.
FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical
manufacturer which manufactured potent steroid products as well as
non-steroidal products using common equipment. This firm was a multi-use
bulk pharmaceutical facility. FDA considered the potential for
cross-contamination to be significant and to pose a serious health risk to
the public. The firm had only recently started a cleaning validation program
at the time of the inspection and it was considered inadequate by FDA. One
of the reasons it was considered inadequate was that the firm was only
looking for evidence of the absence of the previous compound. The firm had
evidence, from TLC tests on the rinse water, of the presence of residues of
reaction byproducts and degradants from the previous process.
III. GENERAL REQUIREMENTS
FDA expects firms to have written procedures (SOP's) detailing the cleaning
processes used for various pieces of equipment. If firms have one cleaning
process for cleaning between different batches of the same product and use a
different process for cleaning between product changes, we expect the
written procedures to address these different scenario. Similarly, if firms
have one process for removing water soluble residues and another process for
non-water soluble residues, the written procedure should address both
scenarios and make it clear when a given procedure is to be followed. Bulk
pharmaceutical firms may decide to dedicate certain equipment for certain
chemical manufacturing process steps that produce tarry or gummy residues
that are difficult to remove from the equipment. Fluid bed dryer bags are
another example of equipment that is difficult to clean and is often
dedicated to a specific product. Any residues from the cleaning process
itself (detergents, solvents, etc.) also have to be removed from the
equipment.
FDA expects firms to have written general procedures on how cleaning
processes will be validated.
FDA expects the general validation procedures to address who is responsible
for performing and approving the validation study, the acceptance criteria,
and when revalidation will be required.
FDA expects firms to prepare specific written validation protocols in
advance for the studies to be performed on each manufacturing system or
piece of equipment which should address such issues as sampling procedures,
and analytical methods to be used including the sensitivity of those
methods.
FDA expects firms to conduct the validation studies in accordance with the
protocols and to document the results of studies.
FDA expects a final validation report which is approved by management and
which states whether or not the cleaning process is valid. The data should
support a conclusion that residues have been reduced to an "acceptable
level."
IV. EVALUATION OF CLEANING VALIDATION
The first step is to focus on the objective of the validation process, and
we have seen that some companies have failed to develop such objectives. It
is not unusual to see manufacturers use extensive sampling and testing
programs following the cleaning process without ever really evaluating the
effectiveness of the steps used to clean the equipment. Several questions
need to be addressed when evaluating the cleaning process. For example, at
what point does a piece of equipment or system become clean? Does it have to
be scrubbed by hand? What is accomplished by hand scrubbing rather than just
a solvent wash? How variable are manual cleaning processes from batch to
batch and product to product? The answers to these questions are obviously
important to the inspection and evaluation of the cleaning process since one
must determine the overall effectiveness of the process. Answers to these
questions may also identify steps that can be eliminated for more effective
measures and result in resource savings for the company.
Determine the number of cleaning processes for each piece of equipment.
Ideally, a piece of equipment or system will have one process for cleaning,
however this will depend on the products being produced and whether the
cleanup occurs between batches of the same product (as in a large campaign)
or between batches of different products. When the cleaning process is used
only between batches of the same product (or different lots of the same
intermediate in a bulk process) the firm need only meet a criteria of,
"visibly clean" for the equipment. Such between batch cleaning processes do
not require validation.
1. Equipment Design
Examine the design of equipment, particularly in those large systems that
may employ semi-automatic or fully automatic clean-in-place (CIP) systems
since they represent significant concern. For example, sanitary type piping
without ball valves should be used. When such nonsanitary ball valves are
used, as is common in the bulk drug industry, the cleaning process is more
difficult.
When such systems are identified, it is important that operators performing
cleaning operations be aware of problems and have special training in
cleaning these systems and valves. Determine whether the cleaning operators
have knowledge of these systems and the level of training and experience in
cleaning these systems. Also check the written and validated cleaning
process to determine if these systems have been properly identified and
validated.
In larger systems, such as those employing long transfer lines or piping,
check the flow charts and piping diagrams for the identification of valves
and written cleaning procedures. Piping and valves should be tagged and
easily identifiable by the operator performing the cleaning function.
Sometimes, inadequately identified valves, both on prints and physically,
have led to incorrect cleaning practices.
Always check for the presence of an often critical element in the
documentation of the cleaning processes; identifying and controlling the
length of time between the end of processing and each cleaning step. This is
especially important for topicals, suspensions, and bulk drug operations. In
such operations, the drying of residues will directly affect the efficiency
of a cleaning process.
Whether or not CIP systems are used for cleaning of processing equipment,
microbiological aspects of equipment cleaning should be considered. This
consists largely of preventive measures rather than removal of contamination
once it has occurred. There should be some evidence that routine cleaning
and storage of equipment does not allow microbial proliferation. For
example, equipment should be dried before storage, and under no
circumstances should stagnant water be allowed to remain in equipment
subsequent to cleaning operations.
Subsequent to the cleaning process, equipment may be subjected to
sterilization or sanitization procedures where such equipment is used for
sterile processing, or for nonsterile processing where the products may
support microbial growth. While such sterilization or sanitization
procedures are beyond the scope of this guide, it is important to note that
control of the bioburden through adequate cleaning and storage of equipment
is important to ensure that subsequent sterilization or sanitization
procedures achieve the necessary assurance of sterility. This is also
particularly important from the standpoint of the control of pyrogens in
sterile processing since equipment sterilization processes may not be
adequate to achieve significant inactivation or removal of pyrogens.
2. Cleaning Process Written Procedure and Documentation
Examine the detail and specificity of the procedure for the (cleaning)
process being validated, and the amount of documentation required. We have
seen general SOPs, while others use a batch record or log sheet system that
requires some type of specific documentation for performing each step.
Depending upon the complexity of the system and cleaning process and the
ability and training of operators, the amount of documentation necessary for
executing various cleaning steps or procedures will vary.
When more complex cleaning procedures are required, it is important to
document the critical cleaning steps (for example certain bulk drug
synthesis processes). In this regard, specific documentation on the
equipment itself which includes information about who cleaned it and when is
valuable. However, for relatively simple cleaning operations, the mere
documentation that the overall cleaning process was performed might be
sufficient.
Other factors such as history of cleaning, residue levels found after
cleaning, and variability of test results may also dictate the amount of
documentation required. For example, when variable residue levels are
detected following cleaning, particularly for a process that is believed to
be acceptable, one must establish the effectiveness of the process and
operator performance. Appropriate evaluations must be made and when operator
performance is deemed a problem, more extensive documentation (guidance) and
training may be required.
3. Analytical Methods
Determine the specificity and sensitivity of the analytical method used to
detect residuals or contaminants. With advances in analytical technology,
residues from the manufacturing and cleaning processes can be detected at
very low levels. If levels of contamination or residual are not detected, it
does not mean that there is no residual contaminant present after cleaning.
It only means that levels of contaminant greater than the sensitivity or
detection limit of the analytical method are not present in the sample. 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, i.e. 50% recovery, 90%, etc. This is necessary
before any conclusions can be made based on the sample results. A negative
test may also be the result of poor sampling technique (see below).
4. Sampling
There are two general types of sampling that have been found acceptable. The
most desirable is the direct method of sampling the surface of the
equipment. Another method is the use of rinse solutions.
a. Direct Surface Sampling - Determine the type of sampling material used
and its impact on the test data since the sampling material may interfere
with the test. For example, the adhesive used in swabs has been found to
interfere with the analysis of samples. Therefore, early in the validation
program, it is important to assure that the sampling medium and solvent
(used for extraction from the medium) are satisfactory and can be readily
used.
Advantages of direct sampling are that areas hardest to clean and which are
reasonably accessible can be evaluated, leading to establishing a level of
contamination or residue per given surface area. Additionally, residues that
are "dried out" or are insoluble can be sampled by physical removal.
b. Rinse Samples - Two advantages of using rinse samples are that a larger
surface area may be sampled, and inaccessible systems or ones that cannot be
routinely disassembled can be sampled and evaluated.
A disadvantage of rinse samples is that the residue or contaminant may not
be soluble or may be physically occluded in the equipment. An analogy that
can be used is the "dirty pot." In the evaluation of cleaning of a dirty
pot, particularly with dried out residue, one does not look at the rinse
water to see that it is clean; one looks at the pot.
Check to see that a direct measurement of the residue or contaminant has
been made for the rinse water when it is used to validate the cleaning
process. For example, it is not acceptable to simply test rinse water for
water quality (does it meet the compendia tests) rather than test it for
potential contaminates.
c. Routine Production In-Process Control
Monitoring - Indirect testing, such as conductivity testing, may be of some
value for routine monitoring once a cleaning process has been validated.
This would be particularly true for the bulk drug substance manufacturer
where reactors and centrifuges and piping between such large equipment can
be sampled only using rinse solution samples. Any indirect test method must
have been shown to correlate with the condition of the equipment. During
validation, the firm should document that testing the uncleaned equipment
gives a not acceptable result for the indirect test.
V. ESTABLISHMENT OF LIMITS
FDA does not intend to set acceptance specifications or methods for
determining whether a cleaning process is validated. It is impractical for
FDA to do so due to the wide variation in equipment and products used
throughout the bulk and finished dosage form industries. The firm's
rationale for the residue limits established should be logical based on the
manufacturer's knowledge of the materials involved and be practical,
achievable, and verifiable. It is important to define the sensitivity of the
analytical methods in order to set reasonable limits. Some limits that have
been mentioned by industry representatives in the literature or in
presentations include analytical detection levels such as 10 PPM, biological
activity levels such as 1/1000 of the normal therapeutic dose, and
organoleptic levels such as no visible residue.
Check the manner in which limits are established. Unlike finished
pharmaceuticals where the chemical identity of residuals are known (i.e.,
from actives, inactives, detergents) bulk processes may have partial
reactants and unwanted by-products which may never have been chemically
identified. In establishing residual limits, it may not be adequate to focus
only on the principal reactant since other chemical variations may be more
difficult to remove. There are circumstances where TLC screening, in
addition to chemical analyses, may be needed. In a bulk process,
particularly for very potent chemicals such as some steroids, the issue of
by-products needs to be considered if equipment is not dedicated. The
objective of the inspection is to ensure that the basis for any limits is
scientifically justifiable.
VI. OTHER ISSUES
a. Placebo Product
In order to evaluate and validate cleaning processes some manufacturers have
processed a placebo batch in the equipment under essentially the same
operating parameters used for processing product. A sample of the placebo
batch is then tested for residual contamination. However, we have documented
several significant issues that need to be addressed when using placebo
product to validate cleaning processes.
One cannot assure that the contaminate will be uniformly distributed
throughout the system. For example, if the discharge valve or chute of a
blender are contaminated, the contaminant would probably not be uniformly
dispersed in the placebo; it would most likely be concentrated in the
initial discharge portion of the batch. Additionally, if the contaminant or
residue is of a larger particle size, it may not be uniformly dispersed in
the placebo.
Some firms have made the assumption that a residual contaminant would be
worn off the equipment surface uniformly; this is also an invalid
conclusion. Finally, the analytical power may be greatly reduced by dilution
of the contaminate. Because of such problems, rinse and/or swab samples
should be used in conjunction with the placebo method.
b. Detergent
If a detergent or soap is used for cleaning, determine and consider the
difficulty that may arise when attempting to test for residues. A common
problem associated with detergent use is its composition. Many detergent
suppliers will not provide specific composition, which makes it difficult
for the user to evaluate residues. As with product residues, it is important
and it is expected that the manufacturer evaluate the efficiency of the
cleaning process for the removal of residues. However, unlike product
residues, it is expected that no (or for ultra sensitive analytical test
methods - very low) detergent levels remain after cleaning. Detergents are
not part of the manufacturing process and are only added to facilitate
cleaning during the cleaning process. Thus, they should be easily removable.
Otherwise, a different detergent should be selected.
c. Test Until Clean
Examine and evaluate the level of testing and the retest results since
testing until clean is a concept utilized by some manufacturers. They test,
resample, and retest equipment or systems until an "acceptable" residue
level is attained. For the system or equipment with a validated cleaning
process, this practice of resampling should not be utilized and is
acceptable only in rare cases. Constant retesting and resampling can show
that the cleaning process is not validated since these retests actually
document the presence of unacceptable residue and contaminants from an
ineffective cleaning process.
VII. REFERENCES
1) J. Rodehamel, "Cleaning and Maintenance," Pgs 82-87, University of
Wisconsin's Control Procedures in Drug Production Seminar, July 17-22, 1966,
William Blockstein, Editor, Published by the University of Wisconsin,
L.O.C.#66-64234.
2) J.A. Constance, "Why Some Dust Control Exhaust Systems Don't Work,"
Pharm. Eng., January-February, 24-26 (1983).
3) S.W. Harder, "The Validation of Cleaning Procedures," Pharm. Technol. 8
(5), 29-34 (1984)
4) W.J. Mead, "Maintenance: Its Interrelationship with Drug Quality," Pharm.
Eng. 7(3), 29-33 (1987).
5) J.A. Smith, "A Modified Swabbing Technique for Validation of Detergent
Residues in Clean-in-Place Systems," Pharm. Technol. 16(1), 60-66 (1992).
6) Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation
Acceptance Limits for Pharmaceutical Manufacturing Operations," Pharm.
Technol. 17(4), 54-60 (1993).
7) McCormick, P.Y. and Cullen, L.F., in Pharmaceutical Process Validation,
2nd Ed., edited by I.R. Berry and R.A. Nash, 319-349 (1993)
There are no references from this document.
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