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Cleaning validation
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1Dispelling the Myths of Cleaning Validation
Destin A. LeBlancCleaning Validation Technologies
Capital Chapter PDA Gaithersburg, MDOctober 30, 2002
2CV myths
z Things the FDA doesnt allowz Covers 8 mythszWill discuss issues relating to those mythszRationale: not unnecessarily restrict scientifically justified options
3Myth #1
z Regulatory authorities dont like rinse water samplingz Fact: FDA and PIC/S guidance documents says rinse water sampling is one of two acceptable sampling methods
4Issues
z Direct measure of target residuezRelating rinse water concentration to potential contaminationzRinse recoveryzAdequate coverage of rinse solution
5Myth #2
z You must correlate rinse sampling results with swab sampling resultsz Fact: Rinse and swab measure two different things; dont expect correlation
6Issues
zSwabs focus on small areazRinses focus on larger areazSwab measures worst casezRinse measures average
7Issues
z If both done correctly on same surfaces, may pass on rinse but fail swabz If both done correctly on same surface, if swabs pass, rinse should also pass
8Myth #3
z You cant use non-specific analytical methodsz Fact: Non-specific methods such as TOC are widely used and are accepted by regulators
9Issues
zTOC limit set on dose based calculations, not PW/WFI specszCalculate and express limit as activezConvert analytical TOC value to activezCompare measured value to limit
10
Issues
zAssume worst case,all TOC due to target residuezNote: Correctly applied, TOC is more stringent than specific method for target residue
11
FDA support
zHuman Drug CGMP Notes --
We think TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation.
12
Myth #4
z If you use TOC, you must correlate it with HPLCz Fact: As long as TOC is validated with appropriate standards, do not need to correlate with HPLC
13
Issues
zWhats point of running both TOC and HPLC on same standard for correlation?zMethod validation of TOC with target analyte is adequate and sufficient
14
Issues
z In CV protocols, TOC will never correlate with HPLC resultszTOC is subject to interferenceszCant express exactly how much target residue present, but can assure is at or below measured amountzAs long as interference increase TOC, will be worst case
15
Myth #5
z Any residue is unacceptablez Fact: With newer methods or with TOC, will always find some residue
16
Issues
zDetection limits of analytical methods achieve lower levelsz Issue is whether residue is medically safe and whether it affect product qualityz But, any visible residue is generally unacceptable
17
FDA support
zHuman Drug CGMP Notes --Should equipment be as clean as the best possible method of residue detection or quantification?
ANSWER: No
18
Myth #6
z Dose-based (MAC) limits calculations are unacceptable z Fact: Are referenced in FDA and PIC/S guidance documents
19
Issues
zHave been misusedzSafeguards against unreasonably high limitszConsider cumulative residues from equipment train zDefault limits (such as 10 ppm)zVisually clean criterionzReasonable safety factors
20
Issues
zAre defaults arbitrary?zYes, 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?
21
Issuesz Consider other medical or safety concerns unrelated to dosezAllergeniczCytotoxicityzReproductive hazards
zMay result in zLimits = LOD of best methodzDedicated equipment
22
Myth #7
z Recovery percentages at different spiked levels should be linearz Fact: Recovery percentages are highly variable. It is not reasonable to expect linear response
23
Example
71%3.0 g/cm281%2.0 g/cm291%1.0 g/cm2
RecoverySpike
24
Issues
zSwabbing is a manual procedure (analogy to manual cleaning)zHigh variability in recoveries recovery for one individualzHigh variability in recoveries among individualszAs practical matter, will use lowest
25
Myth #8
z You cant validate manual cleaningz Fact: You will validate manual cleaning processes
26
Issues
zManual cleaning more variable than automated processesz Consistency of manual cleaning depends on adequate detail in written procedure and adequate training of operatorszRequires more attention to validation maintenance
27
Origin of myths
z Probably misinterpretation or misapplication of 483szExample: Your use of rinse water sampling is inappropriate to.zFaulty conclusion: Cant use rinse water samplingzCorrect response: Use rinse sampling correctly
28
Suggestions
z Dont chase latest 483z Design a comprehensive, defendable cleaning validation program
z Confirm (or disprove) You cant statements by regulatory documents (Human Drug CGMP Notes, Warning Letters, Guidance Documents, GMPs)
29
zQ&AzDiscussion