Dispelling the Myths of
Cleaning Validation
Destin A. LeBlanc
Cleaning Validation Technologies
Capital Chapter PDA
Gaithersburg, MD
October 30, 2002
1
CV myths
z “Things
the FDA doesn’t allow”
z Covers 8 myths
z Will discuss issues relating to
those myths
z Rationale: not unnecessarily
restrict scientifically justified
options
2
Myth #1
z “Regulatory
authorities don’t
like rinse water sampling”
z Fact: FDA and PIC/S guidance
documents says rinse water
sampling is one of two
acceptable sampling methods
3
Issues
z “Direct
measure” of target
residue
z Relating rinse water
concentration to potential
contamination
z Rinse recovery
z Adequate coverage of rinse
solution
4
Myth #2
z “You
must correlate rinse sampling
results with swab sampling results”
z Fact: Rinse and swab measure two
different things; don’t expect
correlation
5
Issues
z Swabs
focus on small area
z Rinses focus on larger area
z Swab measures worst case
z Rinse measures average
6
Issues
z If
both done correctly on same
surfaces, may pass on rinse but
fail swab
z If both done correctly on same
surface, if swabs pass, rinse
should also pass
7
Myth #3
z
“You can’t use non-specific
analytical methods”
z Fact: Non-specific methods
such as TOC are widely used
and are accepted by regulators
8
Issues
z TOC
limit set on dose based
calculations, not PW/WFI specs
z Calculate
and express limit as active
z Convert analytical TOC value to
active
z Compare measured value to limit
9
Issues
z Assume
worst case,all TOC due
to target residue
z Note: Correctly applied, TOC is
more stringent than specific
method for target residue
10
FDA support
z Human
Drug CGMP Notes --
“We think TOC or TC can be
an acceptable method for
monitoring residues routinely
and for cleaning validation.”
11
Myth #4
z “If
you use TOC, you must
correlate it with HPLC”
z Fact: As long as TOC is
validated with appropriate
standards, do not need to
“correlate” with HPLC
12
Issues
z What’s
point of running both
TOC and HPLC on same
standard for correlation?
z Method validation of TOC with
target analyte is adequate and
sufficient
13
Issues
z In
CV protocols, TOC will never
correlate with HPLC results
z TOC
is subject to interferences
z Can’t express exactly how much
target residue present, but can
assure is at or below measured
amount
z As long as interference increase
TOC, will be worst case
14
Myth #5
z “Any
residue is unacceptable”
z Fact: With newer methods or
with TOC, will always find some
residue
15
Issues
z Detection
limits of analytical
methods achieve lower levels
z Issue is whether residue is
medically safe and whether it
affect product quality
z But, any visible residue is
generally unacceptable
16
FDA support
z Human
Drug CGMP Notes -“Should equipment be as clean
as the best possible method of
residue detection or
quantification?”
ANSWER: “No…”
17
Myth #6
z “Dose-based
(MAC) limits
calculations are unacceptable”
z Fact: Are referenced in FDA
and PIC/S guidance documents
18
Issues
z Have
been misused
z Safeguards against
unreasonably high limits
z Consider
cumulative residues from
equipment train
z Default limits (such as 10 ppm)
z Visually clean criterion
z Reasonable “safety” factors
19
Issues
z Are
defaults arbitrary?
z Yes, but so what?
z If medically safe limit is X
ppm, and I set my limit is
below that, from a regulatory
perspective, should there be a
concern?
20
Issues
z Consider
other medical or
safety concerns unrelated to
“dose”
z Allergenic
z Cytotoxicity
z Reproductive
z May
hazards
result in –
z Limits
= LOD of best method
z Dedicated equipment
21
Myth #7
z “Recovery
percentages at
different spiked levels should
be linear”
z Fact: Recovery percentages are
highly variable. It is not
reasonable to expect linear
response
22
Example
Spike
Recovery
1.0 µg/cm2
91%
2.0 µg/cm2
81%
3.0 µg/cm2
71%
23
Issues
z Swabbing
is a manual procedure
(analogy to manual cleaning)
z High variability in recoveries
recovery for one individual
z High variability in recoveries
among individuals
z As practical matter, will use
lowest
24
Myth #8
z “You
can’t validate manual
cleaning”
z Fact: You will validate manual
cleaning processes
25
Issues
z Manual
cleaning more variable
than automated processes
z Consistency of manual cleaning
depends on adequate detail in
written procedure and adequate
training of operators
z Requires more attention to
validation maintenance
26
Origin of myths
z Probably
misinterpretation or
misapplication of 483’s
z Example:
“Your use of rinse water
sampling is inappropriate to….”
z Faulty conclusion: Can’t use rinse
water sampling
z Correct response: Use rinse
sampling correctly
27
Suggestions
Don’t chase latest 483
z Design a comprehensive, defendable
cleaning validation program
z Confirm (or disprove) “You can’t…”
statements by regulatory documents
(Human Drug CGMP Notes, Warning
Letters, Guidance Documents,
GMPs)
z
28
z Q&A
z Discussion
29