提出FDA清洁验证审计指南

2021年1月20日发(作者：冬凉夏暖)
Validation of Cleaning Processes
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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
be maintained in a clean and orderly manner ***.
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 equipme nt an d/or poor dust con trol systems. Also,
historically speak ing, FDA was more concerned about the con tam in ati on

of nonpenicillin drug products with penicillins or the cross-contamination of
drug products with pote nt steroids or horm on es. A nu mber of products
have bee n recalled over the past decade due to actual or pote ntial peni cilli
n cross-c on tam in ati on.
One eve nt which in creased FDA aware ness of the pote ntial for cross con
tam in ati on due to in adequate procedures was the 1988 recall of a
finished drug product, Cholestyramine Resin USP. The bulk pharmaceutical
chemical used to produce the product had become con tam in ated with low
levels of in termediates and degrada nts from the producti on of agricultural
pesticides. The cross-c on tam in ati on in that case is believed to have bee
n due to the reuse of recovered solve nts. The recovered solve nts had bee
n con tam in ated because of a lack of con trol over the reuse of solve nt
drums. Drums that had bee n used to store recovered solve nts from a
pesticide producti on process were later used to store recovered solve nts
used for the res in manu facturi ng process. The firm did not have adequate
con trols over these solve nt drums, did not do adequate testi ng of
drummed solve nts, and did not have validated clea ning procedures for the
drums.
Some shipme nts of this pesticide con tam in ated 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 no rmally produced.
FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical
manu facturer which manu factured pote nt steroid products as well as non-
steroidal products using com mon equipme nt. This firm was a multi- use
bulk pharmaceutical facility. FDA con sidered the pote ntial 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 in spect ion and it was con sidered in adequate by FDA. One
of the reas ons it was con sidered in adequate was that the firm was only
look ing for evide nee of the abse nee of the previous compo und. The firm
had evidenee, from TLC tests on the rinse water, of the presence of
residues of react ion byproducts and degrada nts from the previous process.
GENERAL REQUIREMENTS
FDA expects firms to have writte n procedures (SOP's) detaili ng the clea
ning processes used for various pieces of equipme nt. If firms have one clea
ning process for clea ning betwee n differe nt batches of the same product
and use a differe nt process for clea ning betwee n product cha nges, we
expect the written procedures to address these different scenario. Similarly,
if firms have one process for rem oving water soluble residues and ano ther
process for non-water soluble residues, the writte n procedure should
address both sce narios and make it clear whe n a give n procedure is to be
followed. Bulk
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III.


pharmaceutical firms may decide to dedicate certa in equipme nt for certa in
chemical manu facturi ng process steps that produce tarry or gummy
residues that are difficult to remove from the equipment. Fluid bed dryer
bags are ano ther example of equipme nt that is difficult to clea n and is ofte
n dedicated to a specific product. Any residues from the clea ning process
itself (detergents, solvents, etc.) also have to be removed from the equipme
nt.
FDA expects firms to have writte n gen eral procedures on how clea ning
processes will be validated.
FDA expects the gen eral validati on procedures to address who is resp on
sible for perform ing and appro ving the validati on study, the acceptance
criteria, and when revalidation will be required.
FDA expects firms to prepare specific writte n validati on protocols in adva
nce for the studies to be performed on each manu facturi ng system or piece
of equipme nt which should address such issues as sampli ng procedures,
and an alytical methods to be used in clud ing the sen sitivity of those
methods. FDA expects firms to con duct the validati on studies in accorda
nce with the protocols and to docume nt the results of studies.
FDA expects a final validati on report which is approved by man ageme nt
and which states whether or not the clea ning process is valid. The data
should support a con clusi on that residues have bee n reduced to an

EVALUATION OF CLEANING VALIDATION
The first step is to focus on the objective of the validation process, and we
have see n that some compa nies have failed to develop such objectives. It
is not unu sual to see manu facturers use exte nsive sampli ng and testi ng
programs follow ing the clea ning process without ever really evaluati ng the
effective ness of the steps used to clea n the equipme nt. Several questi ons
n eed to be addressed whe n evaluat ing the clea ning process. For
example, at what point does a piece of equipme nt or system become clea
n? Does it have to be scrubbed by hand? What is accomplished by hand
scrubb ing rather tha n just a solve nt wash? How variable are manual clea
ning processes from batch to batch and product to product? The an swers to
these questions are obviously important to the inspection and evaluation of
the clea ning process since one must determ ine the overall effective ness of
the process. An swers to these questi ons may also ide ntify steps that can
be elimi nated for more effective measures and result in resource sav ings
for the compa ny.
Determ ine the nu mber of clea ning processes for each piece of equipme nt.
Ideally, a piece of equipment or system will have one process for cleaning,
however this will depe nd on the products being produced and whether the
clea nup occurs betwee n batches of the same product (as in a large
campaig n) or betwee n batches of differe nt products. Whe n the clea ning
process is used only betwee n batches of the same product (or differe nt lots
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IV.

of the same in termediate in a bulk process) the firm n eed only meet a
criteria of,
processes do not require validati on.
1.
Equipme nt Desig n
Exam ine the desig n of equipme nt, particularly in those large systems
that may employ semi-automatic or fully automatic clean-in-place (CIP)
systems since they represe nt sig nifica nt concern. For example, san
itary type pip ing without ball valves should be used. Whe n such
nonsan itary ball valves are used, as is com mon in the bulk drug in
dustry, the clea ning process is more difficult.
When such systems are ide ntified, it is importa nt that operators
perform ing clea ning operatio ns be aware of problems and have
special trai ning in clea ning these systems and valves. Determ ine
whether the clea ning operators have kno wledge of these systems and
the level of training and experie nee in clea ning these systems. Also
check the writte n and validated clea ning process to determ ine if these
systems have been properly identified and validated.
In larger systems, such as those employi ng long tran sfer lines or pipi
ng, check the flow charts and pip ing diagrams for the ide ntificati on of
valves and writte n clea ning procedures. Pip ing and valves should be
tagged and easily identifiable by the operator performing the cleaning
function. Sometimes, in adequately ide ntified valves, both on prints and
physically, have led to in correct clea ning practices.
Always check for the prese nee of an ofte n critical eleme nt in the
docume ntati on of the clea ning processes; ide ntify ing and con troll ing
the len gth of time betwee n the end of process ing and each clea ning
step. This is especially importa nt for topicals, suspe nsions, and bulk
drug operations. In such operations, the drying of residues will directly
affect the efficie ncy of a clea ning process.
Whether or not CIP systems are used for clea ning of process ing
equipme nt, microbiological aspects of equipme nt clea ning should be
con sidered. This con sists largely of preve ntive measures rather tha n
removal of con tam in ati on once it has occurred. There should be
some evide nee that rout ine clea ning and storage of equipme nt does
not allow microbial proliferation. For example, equipment should be
dried before storage, and un der no circumsta nces should stag nant
water be allowed to rema in in equipme nt subseque nt to clea ning
operati ons.
Subseque nt to the clea ning process, equipme nt may be subjected to
sterilizati on or san itizati on procedures where such equipme nt is used
for sterile process ing, or for non sterile process ing where the products
may support microbial growth. While such sterilizatio n or san itizati on
procedures are bey ond the scope of this guide, it is importa nt to note
that con trol of the bioburde n through adequate clea ning and storage
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of equipme nt is importa nt to en sure that subseque nt sterilizati on or
sanitization procedures achieve the necessary assuranee of sterility.
This is also particularly important from the standpoint of the control of
pyroge ns in sterile process ing since equipme nt sterilizati on processes
may not be adequate to achieve sig nifica nt in activati on or removal of
pyroge ns.
2.
Clea ning Process Writte n
Procedure and Docume ntati on
Exam ine the detail and specificity of the procedure for the (clea ning)
process being validated, and the amount of docume ntati on required.
We have see n gen eral SOPs, while others use a batch record or log
sheet system that requires some type of specific docume ntati on for
perform ing each step. Depe nding upon the complexity of the system
and cleaning process and the ability and training of operators, the
amount of docume ntati on n ecessary for executi ng various clea ning
steps or procedures will vary.
When more complex clea ning procedures are required, it is importa nt
to docume nt the critical clea ning steps (for example certa in bulk drug
syn thesis processes). I n this regard, specific docume ntati on on the
equipme nt itself which in cludes in formati on about who clea ned it and
when is valuable. However, for relatively simple cleaning operations, the
mere docume ntati on that the overall clea ning process was performed
might be sufficie nt.
Other factors such as history of clea nin g, residue levels found after
cleaning, and variability of test results may also dictate the amount of
docume ntati on required. For example, whe n variable residue levels
are detected follow ing clea ning, particularly for a process that is
believed to be acceptable, one must establish the effective ness of the
process and operator performa nee. Appropriate evaluati ons must be
made and whe n operator performa nee is deemed a problem, more
exte nsive docume ntati on (guida nee) and training may be required.
3.
Analytical Methods
Determine the specificity and sensitivity of the analytical method used to
detect residuals or con tam inan ts. With adva nces in an alytical tech no
logy, residues from the manu facturi ng and clea ning 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 con tam inant prese
nt after clea nin g. It only means that levels of con tam inant 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 comb in ati on with the sampli ng method(s) used to show that con
tam inants can be recovered from the equipme nt surface and at what
level, i.e. 50% recovery, 90%, etc. This is n ecessary before any con
clusi ons can be made based on the sample results. A n egative test
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