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• Methods of Disassembling and Reassembling to ensure propercleaning and maintenance
As before
•• Protection of clean equipment from contamination prior to use
• Inspection of equipment for cleanliness immediately before use
• Records shall be kept of maintenance, cleaning, sanitizing, andinspection
Recordretention
Cleani ng & Use Log
13Cleaning Validation
Worldwide cGMPs (continued)
Equipment cleaning and use log 21 CFR 2 11 .1 82 EU 4.2 8 – 4.29
A written record of major equipment cleaning, maintenance anduse showing, for each batch processed:
• Date
• Time• Product
• Lot number
• Signature and date of person(s) performing
• Signature and date of person(s) double-checking
For dedicated equipment, the records of cleaning, maintenance,and use shall be part of the sequentially numbered batch record (ifno separate log is kept).
Evaluation of Cleaning Process• Examine objectives of the validation process,
written procedure and documentation
• Examine training and level ofexperience of the cleaning operators
• Examine allowed length of timebetween the end of processing andeach cleaning step and its potentialeffect on the cleaning process
• Examine ste s taken to revent microbiolo ical contamination
At wh at point does a piece of
equipment o r system become clean?Does it have to be scrubbed by
hand?What is accomplished by hand
scrubbing?How variable are manual cleaning
processes from batch t o batch and
product to product?
IQ / OQ Elements to Consider• Examine equipment design especially when using CIP
• Assure proper identification of process equipment to ensure correctimplementation of cleaning procedures
23Cleaning Validation
Guide to Inspections of Validation ofCleaning Processes (1993) (continued)
Scientific Design of Analysis
• eterm ne t e spec c ty an sens t v ty o t eanalytical method(s) used to detect residuals orcontaminants• Testing of rinse solutions should include testing for
residues or contaminants rather than for water quality
considered; there should be some evidence that routinecleaning and storage of equipment does not allowmicrobial proliferation; equipment should be dried beforestorage
• “When variable residue levels are detected followingcleaning, one must establish the effectiveness of theprocess and operator performance.”
• “Indirect testing, such as conductivity testing, may be ofsome value for routine monitoring once a cleaningprocess has been validated. … Any indirect test methodmust have been shown to correlate with the condition ofthe equipment.”
27Cleaning Validation
Guide to Inspections of Validation ofCleaning Processes (1993) (continued)
Other Important Statements:
“ found acceptable. The most desirable is the direct method ofsampling the surface of the equipment. Another method isthe use of rinse solutions.”
• “Rinse and/or swab samples should be used in conjunctionwith the placebo method” (when it is justified for use)
• “The firm should challenge the analytical method incom nat on w t t e samp ng met o s use to s ow t atcontaminants can be recovered from the equipment surfaceand at what level, i.e. 50% recovery, 90%, etc.”
Other Important Statements:• “In establishing residual limits, it may not be adequate to
focus only on the principal reactant since other chemicalvariations may be more difficult to remove…. the issue of by-products needs to be considered if equipment is notdedicated.”
• “When cleaning is between batches of the same product (ordifferent lots of the same intermediate in a bulk process) the
rm nee on y meet a cr ter a o , "v s y c ean" or t eequipment. Such between batch cleaning processes do notrequire validation.”
Not scientifically justif iable!!Does not consider by-pr oducts,cleaning agent, micro, the areain which the equipment iscleaned / stored, etc.
29Cleaning Validation
PIC/S, Canadian and WHOGuidance on Limits
Limits shall be logical, practical, achievable, verifiable; forexample, the most stringent of the following first three
• No more than 0.1% (1/1000th) of the normal therapeutic dose ofany product will appear in the maximum daily dose of thefollowing product
• No more than 10 ppm of any product will appear in anotherproduct
• No visible residue on the equipment after cleaning proceduresare performed *
*• Also, for certain allergenic ingredients, penicillins, cephalosporins
or potent steroids and cytotoxics, the limit should be below thelimit of detection by best available analytical methods (or mayrequire dedication)
manufacturing processes including, but not limited to,computerized systems that monitor and/or control themanufacturing process.
• The manufacturing process includes all manufacturingsteps in the creation of the finished product including,
, ,weighing, measuring, mixing, blending, compressing,filling, packaging, and labeling. Cleaning is not only considered a step in
the manufacturing process, but it is theFIRST step in gett ing ready for t he nextprocess.
31Cleaning Validation
US - May 1996 Proposed Revision to cGMPsBeing Revised as Part of Risk-Based GMPs
¶ 211.220 Process validation (continued)
• (b) Validation protocols that identify the product and productspec cat ons an spec y t e proce ures an acceptance cr ter afor the tests to be conducted and the data to be collected duringprocess validation shall be developed and approved.
• The protocol shall specify a sufficient number of replicate processruns to demonstrate reproducibility of the process and provide anaccurate measure of variability among successive runs
Number of runs to be j ustified.Rule of three typi cally applies.
• Validation documentation shall include evidence of the suitability ofmaterials and the performance and reliability of equipment andsystems. The manufacturer shall document execution of theprotocol and test results.
• c The manufacturer shall desi n or select e ui ment andprocesses to ensure that product specifications are consistentlyachieved.
• The manufacturer's determination of equipment suitability shallinclude testing to verify that the equipment is capable of operatingsatisfactorily within the operating limits required by the process.
• Parts of the process that may cause variability or otherwise affectproduct quality shall be tested.
Considerations for w orst-cases incleaning validation include:
• Maximum hold times• Maximum residue loads• Minimum process parameters
during validation
33Cleaning Validation
US - May 1996 Proposed Revision to cGMPsBeing Revised as Part of Risk-Based GMPs
¶ 211.220 Process validation (continued)
• d There shall be a ualit assurance s stem in lace which re uiresrevalidation whenever there are changes in packaging, componentcharacteristics, formulation, equipment, or processes, including reprocessing,that could affect product effectiveness or product characteristics, and
whenever changes are observed in product characteristics.
Change control considerations include:• Cleaning agent s• Cleaning pr ocess paramet ers• ean ng proce ures• Training procedures• Formulation• Equipment• Environments / storage locations for clean
equipment• I ntroduction of a new product (as it might
affect the limit for an existing product – seelimits section)
• Documented evidence that provides a high degree ofassurance that a cleaning process can reproducibly producea clean piece of equipment in accordance with thedesignated specifications
• Generally cleaning validation applies the “rule of”
• documented evidence that provides a high degreeof assurance that a single cleaning event canproduce a clean piece of equipment in accordancewith the designated specifications, suitable for thenext use
• Generall verification is used for develo ment batches
where three may not be made or for infrequentlymanufactured products; when three runs have beencompleted they may be summarized as a validation ifall conditions used in the three studies were the same
37Cleaning Validation
First, Some Definitions
• Certification – depending on the firm, certification often hasthe same meaning as verification; some companies
erent ate cert cat on as an expecte process t at woccur after each production event as a change over process,for example
• Monitoring – a routine evaluation of cleaning to determinewhether the original cleaning validation conditions are stillbeing achieved; may involve fewer samples or less invasivesam ling techni ues
• Engineering Trials – experimental cleaning trials that help toevaluate whether a cleaning process for a new / revisedproduct or process will be effective; still requires validated testmethods and sampling procedures
equipment which is used for themanufacture of one product only
Non-Dedicated Equipment -
• Potentially higher risk ofdegradant and impuritybuild-up, especially ifcampaigned
• Validation will be required
several products or processes
Remember the precautions statedearlier for the Guide to Inspection ofCleaning Validation Processes withregard to the pitfalls in not validatingthe cleaning of dedicated equipment.
or eac pro uc orrepresentative from agrouping / bracketing)
• May also be at risk fordegradants andimpurities if campaigningis observed
45Cleaning Validation
Types of Cleaning
Manual Cleaning - scrub brushesand high pressure hoses used by • Adaptable to varying soil loads
Attributes of Each Type
an opera or o remove pro ucresidue • Highly dependent upon training
Manual Cleaning - scrub brushesand high pressure hoses used by • Lack of inherent reproducibility may
re uire extensive monitorin over
Consequences of Each Type
residue
time
• Detailed procedures a must!Automated Cleaning (e.g., CIP –(Clean-In-Place) - cleaningperformed by a control system ormicroprocessor whichautomatically controls functions ofwash, rinse and dry
• Need to ensure that cleaningvalidation considers the worst-case soil loads or that productioncan adequately identify outliersfor study in the future
- e.g.,COP – Clean-Out-of-Place) -cleaning performed in a partswasher or sink; often requiresmanual intervention ordisassembly; may be automated
• Detailed procedures and loadmaps are typically required
• May require monitoring aswith manual above
47Cleaning Validation
Position / Role in ProcessAttributes of Each Position
ps ream – equ pmen ear y n emanufacturing process, for exampleprimary reactors, initial culture,initial blending
• ay ave unreac e s ar ngmaterials present on equipment
• In-process materials may still be“crude” in that they have not yet
undergone purification
Downstream – equipment usedlater in the manufacturing orfinishing process including such
• Residues are less likely to behomogeneously distributedthrou hout the batch as often
crystallization, purification or viralreduction, filling equipment ortableting equipment
there is limited mixing after theupstream processes
Upstream – equipment early in the • Additional residues may need to be
Consequences of Each Position
manu ac ur ng process, or examp eprimary reactors, initial culture,initial blending
considered for cleaning validation
Downstream – equipment usedlater in the manufacturing orfinishing process including suchprocess steps as finalcrystallization, purification or viralreduction fillin e ui ment or
• Sampling sites will have to be selectedhighly critically to ensure that non-homogeneous distribution of residuesdoes not adversely affect portions ofbatch
•
tableting equipment
conservative to accommodate thecritical nature of many sampling sites
• Be careful that purification processesdon’t concentrate contaminants
49Cleaning Validation
Precautions withPurification Processes
• Purification processes are generally intended toremove process-related impurities only
• Don’t falsely assume that residues from priorcleaning operations will be successfully removedby purification without validation
• Remember that cleaning validation affects the – ’
the residues from a prior process will becompatible with the next product or purificationprocess
If part of your rationale intends to use thepurification process as part of your basis for residueor limits selection, remember that FDA stated in
Human CGMP Notes that impurities are intended tocome from the starting materials or themanufacturing process itself and not from elementsleft over from the cleaning process
Source: The Certified Quality Manager Handbook, 2nd Ed., ASQ
WisdomWisdom
Wisdom is derived from t he collecti ve database ofknowledge, built from experience and values, by beingable to see the connectivity among seemingly disparate
KnowledgeKnowledge
InformationInformation
I nformation has meaning, but themeaning is based on theinterpretation of th e user of theinformation.
Knowledge is built t hrough the correlation andintegration of information w ith policies,procedures and regulations.
.
DataData
Data is meaningl ess unlesssomething is done with it .
53Cleaning Validation
Transformation of Data –For Cleaning Validation
You will achieve wisdom when you understand w hetheror not your policies, procedures and master plansadequately support t he complexity of your plant! Often
-
KnowledgeKnowledge
InformationInformation
Relate the various forms of data tounderstand the equipment, cleaningprocess and product residueinteractions.
Establish poli cies, procedures and m aster plansthat int egrate the information collected about
your plant.
are necessary t o become truly enligh tened!
DataDataCollect information aboutyour equipment, productsand processes.
• Introduction Objective and Scope - Goals of theMaster Plan and brief content insight as well asboundaries of the Validation Project and of theMaster Plan
Typical scope boundary elements:• Production areas included: marketed production,
Master Plan ContentsReferences - pertinent internal and external documents
Examples include:
• Scientific rationales, SOPs, risk analyses, literature supporting keyrationales or strategies
Avoid excessive generic references (e.g., GMPs)
Responsibilities – high level overview of key project participants – sufficient detail here may supercede the need to continue toreiterate responsibilities in protocols
Depart ment Responsibilit ies
Recovery StudiesAnalysis of Samples
Engineer ing Sur face Ar ea Calculat ionsMaterials of Construction I D
Validat ion Prot ocol and Report Preparat ionOper at ions Cleaning in accor dance wit h SOPs
Collecting samples
63Cleaning Validation
Master Plan Contents (continued)
Validation Approach – highlight the key elements of thevalidation program
• Scientific rationales (see next slide) – the basis for the selection ofthe validation testing and trade-offs
• Basis for the selection of validation priorities (e.g., New product
introductions, worst-case products, multi-purpose equipment, etc.)• Project management overview of the responsibilities for the
oversight of the cleaning validation program
• Inventory of validations to be accomplished or alreadyaccomplished in support of the plan
Cleaning Validation is as much about what you choose not to do as it is about what you choose to
do. Ensure your scientific rationales defend both!
• Analytical approach (specific / direct vs. non-specific/ indirect / screening)
• Sampling method selection
• Sampling site selection criteria
• Others? (e.g., disassembly philosophy, campaign or minor cleanstrategies, etc.)
Document these well as these will serve as the guideposts forfuture personnel or auditors navigating your cleaning validationprogram.
65Cleaning Validation
Master Plan Contents (continued)
Acceptance Criteria
For cleanin validation the acce tance criteria section typically refers to the way in which the acceptance criteriawill be calculated; if more than one criterion applies, theacceptance criteria section will need to define how theterms will be applied
Master Plan Contents (continued)Procedures & Format
Refers to Reference section for the rocedures and formats to be followed; in some cases samples of specificdocumentation samples or outlines of document headingsmay be included
Scope – Products and Procedures
Equipment Boundaries / Train Definition
Pre-Requisites (e.g., methods validation,
recovery studies, IQ, OQ of equipment, training, etc.)Validation Study Design
Sampling Plan
Acceptance Criteria
67Cleaning Validation
Master Plan Contents (continued)
• Risk / Hazard / Failure / Criticality / Impact Analysis – maybe provided here or in a separate document to substantiate
-, , , ,CTQs or critical parameters
• Planning & Scheduling – include or reference a projectschedule for major milestones; if referenced, ensure that itexists; if included, remember the audience and keep it highlevel
• Appendices – sample flow diagrams for key processes,specimen documentation formats, supportingdocumentation for the approach, data tables of key productattributes, tables including product-specific limits, etc.
Equipment Design and ConstructionProduction equipment and facilities should be designed to be cleanableand maintainable in accordance with CGMPs – other critical attributesmay apply depending on the nature of your production process
• Coved corners
• Welded seams
• Sealed joints or crevices, when necessary(with temperature / chemical resistant caulk or sealant)
• Sanitary clamp type connections
• Minimize dead leg opportunities(not only length of T but also orientation of lines)
• os ve s ope(typically minimum for long runs of 1/8 th in/ft or 10.4mm/m)
• Free-draining
• Non-additive, non-reactive, non-absorptive materials of construction
• Smooth, polished finishes (ex: 20 – 25 µin or 0.5 – 0.625 µm Ra on316L SS)
77Cleaning Validation
Existing Equipment Design Survey
• Survey the equipment (see example of potential tool on the nextslide)
•
• Identify risks associated with the weaknesses
• Mitigate as possible
When ranking, it may alsobe helpful to rank eachsection of thee ui ment b the
Product Contact ?
Yes No
Non-Crit ical orIncidental
Critical Site(i.e., location likely to be
-
nature of itsproduct contact:
on acdistributed in next bat ch orlocation w hich is l ikely to bein contact w ith highlyconcentrated active)
Special Considerations for Sanitizationor Disinfection Procedures
• Cleaning steps must be specified prior to the
• Contact time with chemical sanitant is critical
• Method of application may need to bedemonstrated to reliably leave sufficient “liquid”on the surface to effect the sanitization
• Ex iration dates for formulated sanitizers are
particularly important• Aseptic techniques should be taught and
practiced
105Cleaning Validation
Special Considerations for Sanitizationor Disinfection Procedures
• Other validation considerations:
•presence of known residues from processingor cleaning at the levels that are typicallypresent after an effective cleaning procedure;ensure the cleaning agent residues don’tinactivate the sanitant
• Re-use of a sanitizing solution must bevalidated as they often lose efficacy quicklywhen contaminated with residues / debris
Challenges in Creating Effective SOPs• Too tight v. Too loose control limits
• Excessive investigations
• Limited re roducibilit
• Too much v. Too little detail• Using clockwise 50cm circular motions and the amount of pressure that
it takes to see if a pineapple is ripe, wipe the white, lint-free wipe 25times then reverse to a counter-clockwise motion in the same positionfor an additional 25 circles. When complete, move 50cm to the left,repeat, it will take 125 - 50cm circles to clean the full circumference atthe top level, when the full circumference has been wiped in thismanner, move down 50cm and repeat for the next row …
• Rinse, wash, rinse• Defining scope and applicability of SOP
• Determining extent of cross-referencing v. includingdocuments / forms
107Cleaning Validation
Tips for Evaluating Existing SOPs
• Witness process
• Review the actual cleaning performed against the SOP
• Are all tools / steps identified?
• Ensure critical process control steps have a measurable
or observable parameter• Consider how the parameter is assured -- is
documentation the answer?
cleaning tasks - look for variability in current practices
• Potency, dosage or min. pharm. effect levels will
required to elicit a pharmacologic response
• Allergenic limits are common for products whichhave a well-established allergenic history for
roducts where the aller enic res onse is below
the therapeutic response
127Cleaning Validation
The Nature TermWhy Select One Over The Other?
• Toxicity limits are often difficult to apply as they- ,
have a lot of value for products which have notherapeutic or dose-based index (e.g., cleaning
agents) -- industry needs good guidance on thesafety factors to apply to these limits -- usuallyused in a NOEL or ADI (Acceptable Daily Intake)approach
Other Considerations (continued)When reviewing the equation, other considerations of use may drivethe selection of specific terms:
Position / role of theindividual pieces ofequipment in theprocess *
More conservative value selectionand/or higher safety factors themore pure the product becomes orthe closer it gets to finished dosage(or the more likely contaminants willbecome concentrated) *
* (upstream v. downstream, critical sites,
homogeneous v. non-homogeneous distribution, etc.)
Critical sites such as fillers and tablet presses (see next slide)
API drying trains esp. at the discharge valves
UF / DF skids in biopharmaceutical processing
141Cleaning Validation
Other Considerations (continued)
• Critical sites offer the opportunity forall residual contamination to bedistributed to a single dose or singleportion of the next batch
• Limits can be calculated that take this
possibility into account, as follows:
Single or limit ed dosesOther approaches include:
NatureJC x BatchNP 1x
Size x DoseNP SFop t
Surf ace area of crit ical sites
• ncreas ng e sa e y ac or orthese locations
Or
• Justifying the routine limitsthrough the understanding ofmaterial consumed at start-up
Result x Rinse or Diluent VolumeNatureJC x BatchNP 1x
NP o t
Limits for Cleaning
>ur ace rea x ecovery ec ma
Sampled
• In this case both sides of the equation yield a result that isexpressed as mass per unit surface area.
• In the box, you can see highlighted several terms that areconsidered the Maximum Allowable Carryover or MAC.
• ecen cr c sms o approac an e r va y …• If we were to use the MAC as our limit, we would need to
move the equipment train term over into the result as thenumerator.
Commonly Asked QuestionQ: If we calculate our limit based on a train based approach, doesn’t
that prohibit us from releasing equipment on a piece by piecebasis?
NatureJC x BatchNP 1x
A: No! We can still release on a piece by piece basis – the ratioformed by the equipment train and the surface area sampled is allwe need! By forming this ratio, we can ensure that no unit of
surface area has more than the MAC.
Size x Result x Rinse or Dil. Vol.
>ose
Also sometimes called MAC orMaximum Allowable Carryover
Sampled
As we can see, in either equationform, the equipment train surfacearea and the surface area sampledforms a ratio of the fraction ofsurface area that was sampled towhat is available
By dividing the allowablecarryover by the equipmentsurface area, we are determininghow much residue every squareunit of surface area of theequipment is permitted to have.
When we interpret our results,we divide by the amount ofsurface area sampled in order tocompare mass per unit surfacearea to mass per unit surfacearea.
This approach assumes uniform contamination, which we know is not always true,however we are conservative by picking those locations that we know are hard toclean and likely to have the highest concentration of residue.
In this approach every sample must pass the limit. It is inappropriate to average orfactor the results.
147Cleaning Validation
Limits for Cleaning Agents
• Cleaning agents constituents do not have a therapeutic index
• To determine safety for cleaning agents, companies often turn tothe only available information with regard to activity, the LD50
• LD50 are specific to an animal model (e.g., rat, guinea pig, mice,etc.) and to the route of administration (e.g., oral, topical, i.v., i.p.,s.c., etc.)
• Because we want to ensure that the carryover quantity is safe forthe person receiving the next dose, we can’t use the LD50 directlyin the nature term
• Instead, most firms first calculate either an ADI or Acceptable DailyIntake or a No Observed Effect Level
• The form for the NOEL or ADI equation is the same as thepharmacologic properties limits
What Microbiological Residues ShouldBe Considered And When?
Bioburden and endotoxin are typically included in
contaminants are required to be limited in yourfinal product based on your product specifications
• Bioburden includes bacteria, yeast and molds that arepresent in your water system and environment and can becontributed by your raw materials, equipment and
• Endotoxin is a lipopolysaccharide present in the cellmembranes of the gram negative microorganisms; it isreleased when the organisms die and can cause a feverin patients when introduced to the blood stream
• Bioburden is living and endotoxin is derivedfrom living systems therefore pyroburden andbioburden levels will be heavily dependentupon environmental conditions• Is equipment dry, covered and closed?
• Is the environment aseptic or at least a cleanmanufacturing area that limits viable and non-
viable particulate levels, temperature and relativehumidity? (both for manufacturing and cleanequipment storage)
• How drastically do environmental conditionschange based on season of the year?
169Cleaning Validation
What are the Characteristics ofMicrobiological and EndotoxinContamination?
• Like environmental monitoring, bioburden andpyroburden assessments are not one-timeactivities
• It is recommended that the levels be subjectto routine monitoring with alert and action
Precautions With Microbiological AndEndotoxin Contamination
• Several mechanisms can be employed for the
removal (e.g., flushing, wiping) and destruction / inactivation (e.g., chemical treatment, dry heat)
• Destruction of microbiological contaminationcan increase the possibility of endotoxin
methodology is also an effectivedepyrogenation process (e.g., dry heat)
171Cleaning Validation
Precautions With Microbiological AndEndotoxin Contamination
• Cleaning and sanitization / disinfection cannot
• Residues will inhibit the penetration of chemicalagents
• Rinsing, such as that typically following cleaningprocedures, may introduce additional bioburden
• Agents typically used for sanitization / disinfectionare typically poor cleaning agents as detergency isgenerally not optimal for the designated residues
Sampling Techniques for Microbial andEndotoxin Residues
• As with chemical residues, the sampling techniquesfor microbial bioburden and endotoxin roburden mustbe qualified to ensure that there is no interference and toensure that the technique recovers the residuesappropriately.
• Common surface sampling techniques include:• Swab - applicable to both micro and endotoxin (although not as common
for endotoxin); ensure that you determine recovery
• Rinse - applicable to both micro and endotoxin, however large volumescan make this undesirable for sensitivity; can be filtered for micro purposes
• RODAC - applicable to micro only, direct surface measurement throughmedia press-plates, requires scrupulous cleaning after sampling
177Cleaning Validation
Other Tips on Micro Programs
• Time between sanitization and sampling should bestandardized in order to get a consistent picture of
o ur en
• Consideration should be given to measuringbioburden both after cleaning and after storage,before use
• Keep chemical cleaning and bioburden / endotoxinreduction programs under separate protocols
• Chemical cleaning programs can then be concludedwhile monitoring continues for bioburden andendotoxin
• Assay methods are preferred to be specific to the analyte
• Screenin methods e. ., non-s ecific ma be usedprovided that all analyte identified is attributed to theworst case residue limit
• Assay methods most commonly employed are thosewhich the company already have in their laboratory
• Assa methods and sam lin methods must bedemonstrated to be suitable through methods validationin conjunction with the sampling method / extractionsystem and through recovery studies
• Demonstration that a test method is predictable (e.g.,linear, accurate, precise, specific, rugged) across therange of interest
• Demonstration that the sample preparation, instrumentand method instructions are all appropriate for use andreproducible
Goals of Test Method Transfer
• To demonstrate that a test method can be re roduced
reliably by a different laboratory on differentinstrumentation often with different personnel prior to firstuse official use
181Cleaning Validation
Elements and Acceptance Criteria forMethods Validation
• Industry standard practice for methods validation is taken fromUSP and ICH guidance on methods validation
• These guidances often focus on traditional analysis methodssuch as chromatography and spectroscopy, yet you may be
using more novel methods such as direct surface analysisusing an IR probe or Ion Mobility Spectrometry (IMS) thereforemodified approaches may be called for
,procedures for methods validation (which are typically writtenfor product release or stability methods), remember that yourpolicy or protocols should contain the rationale for theselection of the approach and the acceptance criteria
What Other Elements Are There?• System Suitability is a key for complex methodswhere you want to assure that there is sufficientcontrol over the anal tical s stem beforeinterpreting your results
• Sensitivity can be interpreted from the linearitydetermination, and, when required can bedetermined more specifically throughexperimentation
• Let’s discuss each attribute in more detail
187Cleaning Validation
Elements of Test Method Validation
Accuracy The closeness of test results obtained by the method to the true oraccepted value. It provides an indication of any systematic erroror bias in the method and should be determined across the
’me o s range. yp c a accep ance cr er on o < s app e orchemical analysis.
e a s i n g r e s p o n s
e
o r b a n c e , p p m C , e t c . )
Theoretical
Resp. vs. Conc.ActualResp. vs. Conc.
Accuracy may be assessed with 3replicates at each of minimum of 3
concentrations representing +20% ofpoint of interest (e.g., 80%, 100% and120%). With 100% representing yourcleaning limit. Samples are prepared byspiking active in matrix, although this
increasing concentration of analyte
i n c r
( e . g . , a b s
with active only.
A Y-Intercept of 0 (or close to 0) can alsohelp to confirm that the method is notsuffering from significant bias.
Accuracy’s Role In Cleaning Validation• It is a common approach for stability-indicating methods to
establish accuracy in the presence of degradants
•procedure as well (e.g., heat, contact with water andcleaning agent), therefore forced degradation may be aconsideration for your cleaning methods validation
• For protein-based products, for example, it is common toconsider validating the method using a degraded samplethat includes both native and denatured proteins, or
perhaps entirely denatured proteins• Consider this attribute, as critical to your analytical system
and the known degradation properties of your residue
189Cleaning Validation
Elements of Test Method Validation
Precision(Repeatability)
A measure of the repeatability of the method. Determination isthrough the distribution of data about a mean value over repeatedanalysis of a homogeneous sample. It provides an indication ofthe random errors in the method. (For intermediate precision, see
s i n g r e s p o n s e
b a n c e , p p m C ,
e t c . )
ActualResp. vs. Conc.
e e n on or rugge ness.
increasing concentration of analyte
i n c r e a
( e . g . , a b s o r
Typically 6 to 7 replicates of the samesample are tested at one or more pointsacross the range. Using statistics, canalso be calculated across duplicateinjections across a full range. < 2% RSD isgenerally acceptable with <15 or 20% forbiological assays. 190Cleaning Validation
The degree of reproducibility of test results obtained by theanalysis of the same samples under a variety of expectedconditions, such as different analysts, different instruments,different lots of reagents, different days, different laboratories, etc.
e a s i n g r e s p o n s e
o r b a n c e , p p m C , e t c . )
ActualResp. vs. Conc.
Oper.#1Inst.#1Lab#1
Oper.#1Inst.#1Lab#2
Oper.#2Inst.#1Lab#2
Oper.#1Inst.#2Lab#1
Oper.#2Inst.#1Lab#1
Oper.#1Inst.#1Lab#1
increasing concentration of analyte
i n c
r
( e . g . , a b
s
Not all combinations will be required for allassays. Generally more than one operator andmore than one day are tested with at least twoconcentrations (typically twelve data points).Results are expected to be similar to thosedemonstrated during Precision, but may beslightly higher (e.g., <5%). 191
Elements of Test Method ValidationSpecificity(Selectivity)
Demonstration that there is no significant interference caused bythe sample matrix, related impurities, degradant products or thediluent.
Stock SolutionActive Only
Stock Solution
Matrix, Impurities,and/or Diluent Alone
Plus Matrix, Impuritiesand/or Diluent, etc.
Ideally, ensure that there is good separation between any peaks of interest and thoseassociated with the matrix or diluent. For cleaning we may also consider
x diluent or rinse volumesurface area sampled x recovery
Limit? >
>=LOQ
.
OK
This presumes limit andresult of this equation willboth be expressed asmass per unit surface area
195Cleaning Validation
• Limits of quantitation should be less than the cleaning limit• Limits of quantitation should take into consideration the dilution, as well. See the
What Are AppropriateLimits Of Quantitation?
o ow ng examp e:
You established a total cleaning limit of 20 mg in the equipment train for a newproduct. When the testing is carried out on rinse samples, the following is reported
by the analytical lab for a 1mL test volume:Residue Total Rinse Vol.
Manufacturing Tank BLOQ 2,000 mL
Holding Tank BLOQ 2,000 mL
Transfer Hoses BLOQ 1,000 mL
Filler Equipment BLOQ 500 mL
If the limit of quantitation of the analytical method is 0.01 mg/mL, did the test resultsmeet the acceptance criteria?
LinearityA method’s ability to obtain test results directlyproportional to the concentration (amount) of
Five to seven data points are typically selected to demonstrate linearity in a rangethat represents at least 50 - 150% of target concentrations. For methodsvalidation for cleaning, often this can represent the same + 20% around the 100%point of interest that was used for the Accuracy determination.
analyte in the sample over a given range.
Methods validation will require that you report the equation for the line as well asthe r2 value (the coefficient of determination – the proportion of variation in y thatis explained by the best-fit linear equation). The r2 should be > 0.995 in mostcases (>0.98 for trace analytes such as in cleaning validation may beappropriate).
197Cleaning Validation
Elements of Test Method Validation
Range The interval between the upper and lower levelsof analyte (inclusive) over which the linearity,
validated. Typically this will correspond to therange used in the recovery studies.
Range does not have any “acceptance criteria”, ratherrange for the assay is “reported”. It is expected, howeverthat a minimum ran e of 80% to 120% will be achieved.
You may have noticed, that if planned properly, therequirements of linearity, accuracy, precision and rangecan all be ascertained from a single experiment.
Consider measuring the specificity and accuracy in multipleconcentrations of placebo or diluent (e.g., 1X and 10X) to getboth a real and a “magnified” view of possible interference / bias
Stability Consider including evaluations of stability of: samples, reagentsolutions, and/or standards both on-instrument and in storageas part of the determination of method robustness andruggedness. This can be accomplished through the hold-overand testing of standards and samples during the ruggednessevaluation for different days.
Sensitivity The smallest difference in the amount of analyte which canreliably be detected over the validated range. In accordancewith USP, the slope of the line is the “sensitivity”. If methodrequires close differentiation of analyte concentrations, considerincluding sensitivity in your methods validation.
201Cleaning Validation
Considerations for Methods Validation:
Methods and Sampling Go Hand in Hand!
Include the following in the methods validation:
• Specify components and solvents in either sampling SOPor in analytical method
• Sample / standard stability (time of sampling to timeof test)• Refrigeration
• Light
• Extracted / unextracted (for swabs)
If thought out properly, these can be included in yourruggedness evaluation of day to day differences in yourassay and its performance
Validation Plan for Methods Transfer• Create formal protocols for methods transfer
• Create two sets of 3 – 10 samples each representing 3 – 5 levels ofanal te or at a minimum select 3 or more sam les that re resent range of variation of actual samples
• Measure the following on one or more instruments with onetechnician in both the receiving and sending laboratory:
• Linearity
• Precision
• Accuracy
• Quantitation and Detection Limit
• Values to be assessed for both within lab and between laboratoryperformance
205Cleaning Validation
What are Recovery Studies?
• Recovery studies determine the amount of product that is“recoverable” from a surface each time you sample that surface
• or examp e, t ere was 100 g on a sur ace an you swa eand analyzed it, you may find that you “recovered” only 50 g ofthe material – a recovery of 50%.
100 g 100 g
50 g
50 gSpike surface oftypical MOC, allowto dry / heat, etc.
Swab / rinseaccording toprescribedprocedure
Take swab, extract andanalyze; for rinseanalysis may be direct
Identify the percentageof what was “recovered”vs. what was “spiked”
Recovery Study For Swabbing?• In some cases, the material releases from the surface but resists
extraction from the swab.
• o e erm ne s s po en a y w y your recovery s ow, you canstudy the analytical extraction by spiking the swab directly andassessing whether changes in swab type, diluent, pH, duration ofextraction, mechanical action (e.g., vortex, sonication) will help inincreasing the recovery.
8 g in test tube for analysis
10 g 10 g 2 g on swab unrecovered
207Cleaning Validation
What Else Should Be Included In AllRecovery Studies For Both Swab AndRinse?• Direct analysis of spiking solution to ensure that the theoretical spiking
quantity is accurate
• Understand whether or not you have volatile constituents in yourproduct – in these cases, your theoretical spiking quantity and theamount available on the dried surface will not match
• In these cases, consider a “loss on drying” experiment
• Blank coupon analysis as a control to show that there is nointerference / enhancement from the MOC of the surface or sample kit(or from the cleaning / preparation of them)
• Blank swab analysis as a control for the swab – note that the swab isincluded in the blank coupon analysis above, but if you want to seethe individual contributions from the sample kit components this mayhelp you to “qualify” your sampling system
• All companies swear by their personal swab sampling pattern
• Ensure that your pattern provides you with ease of training and ensurethat the necessary recovery and is demonstrated with adequatere roducibilit between ersonnel and da s
• More than one swab can be used, but be sure to extract it in the samesample tube in order to avoid increasing the error term in yourmeasurement through the inclusion of “background” from multiple
Studies• Consider spiking more than one concentration
to check for “linearit ” of the recover e. . 50%, 100% and 150% of the limit)
• Samples should be tested in duplicate ortriplicate to ensure a valid test, only validatedtest methods with appropriate run controlsshould be em lo ed
• Replicate coupons should be tested to confirmthe accuracy of the recovery; consider usingmore than one person or more than one day inthe study
215Cleaning Validation
Qualifying Sampling Personnel
• Swab sampling is highly technique dependent
• Rinse sampling is less technique dependent, but somemethods of collection are clearl more com lex
• Sampling personnel should be qualified to collectsamples
• Typically this qualification includes:• Review of methods and techniques
• Witnessing methods and techniques
• rac ce n me o s an ec n ques
• Analysis of results through a mock-recovery with a well-characterized and/or worst-case compound
• Optionally, periodic recertification is employed
Discuss the Following:• What is the consequence of using a coupon in your recovery
studies that is smaller than your routine sample size?
• What is the consequence of using a coupon in your recoverystudies that is larger than your routine sample size?
• What are the possible considerations when recovery is lowfor a compound?
• What do you investigate when individuals don’t get the samerecover for a com ound one o erator to the next?
• What do you investigate if a single individual doesn’t get thesame recovery sample to sample? Would your answerchange if multiple personnel suffered the same failure?
219Cleaning Validation
Methods Validation and RecoveryStudies
• Testing and acceptance criteria must bedefined in a rotocol
• The protocol for the method and therecovery study may be one documentprovided that all criteria are included
• If no SOP draft exists, protocol must define thecritical method arameters / method set-u ;method must include:• Instrumentation and instrumentation operating parameters
• Specifications for standardization or calibration of method
• Instructions for how to prepare sampling kits
• Instructions for how to sample (if not already included in a stand-alone procedure)
• Conditions of storage and test of samples• Calculation / reporting of results
221Cleaning Validation
Methods Validation and RecoveryStudies-continued
• Results must be collected and reported inrotocol or bound laborator notebook; ood
documentation practices apply
• Summary report should be prepared whichinterprets the results and reports key valuessuch a LOQ recover
• methods that can uniquely identify an analyte; becareful as not all s ecific methods are effective at quantifying analytes; all method validationconsiderations to this point should be considered
• Non-Specific / Indirect / Screening methods• while linearity, accuracy and precision apply, generally
specificity does not as a screening method is one thatdoes not t icall uni uel identif the anal te s e. .
TOC)
223Cleaning Validation
Types of Test Methods
• Biological assays• due to the lack of complete characterization of many
biolo ical residuals, their ro ensit to denature ordegrade in the presence of cleaning conditions,biological materials often have more relaxed limitsassociated with methods validation; the key is to
ensure adequate reproducibility to ensure a valid test• Microbiological tests
• because the materials being measured are livingorganisms, their behavior is less predictable thanconventional chemical assays; keys here include theverification that competitive, inhibitory or enhancingmaterials do not influence the results achieved
Specific / Direct Methods Non-Specific / Indirect Methods
Chromatography (HPLC)
Gas Chromatography (GC) Conductivity
Atomic Absorption (AA) Total Organic Carbon (TOC)
Inductively Coupled Plasma(ICP)
Gravimetric Analysis
pectrop otometry , s, ,Near-IR, Mid-IR, FTIR) oto e ectron em ss on
Ion Mobility Spectroscopy (IMS) Visual
Specific or Direct Methods
Specific / direct methods are often seen as being moredesirable due to their ability to uniquely identify thecontaminant – however, this may also limit their usefulness!!
• They are often unable to screen for a wide variety ofcompounds such as those that might be present in a
complex solution (e.G., Media in a fermentation process)• Can be expensive to develop; especially if the current“product release method” isn’t effectively modified for traceanalytes
•residues which may prohibit identification of the targetanalyte
• Ability to identify an analyte uniquely does not alwayscorrespond with the ability to “quantify” an analyte!
FD483 Observation“Equipment cleaning validation consisted of only testing PurifiedWater rinses for pH and conductivity. It was not tested for chemicalcleaning agents or product.”
This 483 points out the concernof the FDA that non-specific techniquesdo not provide assurance that products
can be detected by the non-specific methods
Some residues however, are detected effectively and sensitively by,
• Here it is assumed that the “action” is constant for yoursystem.
• If you only are varying two parameters (e.g., your water isonly available at a single temperature), your experimentaldesign will be cut in half
Gathering and Analyzing Results
• Engineering studies are a potential good use ofscreening methods – especially if you aren’t trying toachieve a limit, but rather understand therelationship of one result to another
• Use analysis of variance (ANOVA) techniques toexamine results
•influential in achieving a “clean” system and whichfactors are most influential on each other(dependent variables) based on their interactions
Understand Your ObjectivesTake stock of your decisions to this point:
• What equipment is the subject of your study and whatboundaries will be observed?
• What residues will you be assessing? Can you assess themin a single trial or will multiple trials be required?
• Active / Excipient
• Micro
• Particulate
• What groupings / bracketings of equipment / products have
rationale?
• What analytical methods / sampling methods will be in use?Make sure you identify them clearly for each analyte alongwith the procedure(s) to be followed.
245Cleaning Validation
Understand Your Objectives
Take stock of your decisions to this point:• What locations on the equipment will be sampled? Do you have
• What key parameters will you be studying / observing (T.A.C.T.)?• Will you simply be monitoring them or do you intend to challenge
them?
• Will you need to have multiple operators / shifts performing thecleaning procedures?
• Will you be witnessing the cleaning?
• How will your equipment be soiled?• Routine production – single batch
• Routine production – campaign (# of days / # of batches)
• Intentional worst-case soiling – is a justification available for this beingworst-case
Understand Your ObjectivesTake stock of your decisions to this point:
• What is the maximum time after use before cleaning? Will
• What are your limits? Do you have a clear list of allcalculations that need to be included for the interpretation ofyour results?
• What documentation of cleaning will be included as part ofthe validation record?
• Will your study include an equipment expiration study or will
• What is the time after cleaning before next use?
• What are the conditions of storage? (covers, environment, etc.)
247Cleaning Validation
Worst-Case Conditions toChallenge In Validation Studies
• Worst-case conditions are typically includedin validation
• Worst-case conditions can help us assure
that our procedures / process are robust• By demonstrating robustness, we are
including an inherent safety factor that willhelp to assure that if we see minor changesin soil load, or person to person differencesthat our process will still be successful
• Residues may dry on surfacesor, if hygroscopic may pick up
• Personnel / Shifts
• Process parameters
• May provide representative datawith regard to person-to-personor shift-to-shift robustness
• Reducing process parameters(e.g., 5 minutes less wash time)will ensure that full parameter is
• Starting soil conditions such asmaximum campaign lengthand/or maximum batch size
a ways success u
• Will ensure that any conditionthat is less severe in terms ofsoil load will be successful
249Cleaning Validation
Typical Cleaning PQ Protocol Contents
• Scope / Purpose• define the equipment, procedures, practices to be
challenged; be sure to include references to anygroupings / bracketing of equipment / products thatwill also be considered validated based on asuccessful outcome
• Responsibilities• participants in the validation and their roles in the
studies
• ac groun• optional section to describe any pre-work leading to
this point; references may be included to cycledevelopment, prior trials or linked validation studies
• Validation Procedure – details of each datasheet to be executed and attached to thevalidation, including all documentation to becompleted and attached
• Acceptance Criteria – include limits (or theirsource) and all calculations required for theinterpretation of results
253Cleaning Validation
Typical Cleaning PQ Protocol Contents
• Revalidation conditions / parameters
• Monitoring conditions / parameters
• Data sheets for execution
1. Instrument and Calibration Checklist
2. Equipment Boundaries (if to be field verified)
3. Standard Operating Procedures / Training
4. Methods Validation / Recovery Studies (if to be field verified)
5. Witnessing of Cleaning
6. Rinse Samples
7. Visual AssessmentOrder of theseactivities is cleaning
Meaning of Consecutive Successful• Validation guidelines often refer to FDA’s requirement for
“consecutive successful trials”
• Consecutive successful in these cases means consecutivetrials without intervening failures – it does not mean withoutintervening production
• Defend the timing of your cleaning evaluations as part ofyour strategy
• When you have a failure, be sure you understand andinvestigate whether they are:• Extrinsic failures – not rocess related, therefore re eat only
the failed run (e.g., utility breakdown, failure to follow SOP,etc.)
• Intrinsic failures – process related, therefore repeat the entirevalidation
255Cleaning Validation
Issues with Campaign Manufacture
Batch# 1
Batch# 2
Batch# 3
When gettingready for submission
PV 1
CV 1
PV 2
CV 2
PV 3
CV 3
. . .
Batch# 1
Batch# 2
Batch# 3
In real life we . . . Batch# 4
Batch# . . . n
CleaningEvent
Validation should reflect real life. We also need to have data tosupport inspections such as the PAI. Consider collecting datalater as part of the life cycle under monitoring programs.
Time After Cleaning Before Use –Hold Time Studies or “Equipment Expiration”
• Equipment should be stored DRY and COVERED or
• Microbial propagation will depend upon:• Conditions of storage (e.g., Temperature and relative humidity
of environment, quality / cleanliness of covers, degree ofcleanliness and dryness of equipment)
• Location of storage (e.g.., Clean equipment storage room, inthe room in which cleaning is conducted or in a production roomthat is used for other purposes before equipment reuse)
Study Elements• Understand typical hold times for equipment
– -cleans prior to use – don’t try to validate to the absolute extremes, youare unlikely to be permitted to hold equipment that long!
• Ensure that routine (or intentional) interventions with equipment / storage areas, etc. will occur during study
Options / Considerations for Studies:• Justify that pre-use rinses will be sufficient to remove residues prior to
processing and eliminate the need for these studies entirely
•
fashions after cleaning and study representative members (e.g., closedvessels v. open tools)
• Because residues, especially bioburden, will change over time, keepthe equipment expiration studies as part of the routine bioburdenassessment (i.e., ongoing) rather than discrete validation studies (i.e.,3 runs)
• Confirm that all test methods required to support thevalidation have been validated or transferred with the appropriate ruggedness
• Ensure that there are clear references to the analyticalmethods and sampling methods in the validationprotocol
• If the method is sensitive and sample stability was,
appropriate procedures / tools are in place to properlyhandle the samples after collection and to record andcontrol the time between sampling and testing
263Cleaning Validation
Sampling
• For each analytical method, within theprotocol or in an appropriately detailed SOP or
,• Proper sampling technique
• Appropriate sampling container and tools
• Controls and standards to be sampled and testedalong with the “unknowns”
• Personnel / department qualified to collect sample
• oun samp ng p an a oes no as e resu sof one sample based upon the collection of another
Tools to Take to the FieldMaterials & resources needed for field execution
• Approved protocol on file
• Official copy of blank attachments / checklists
• Appropriate SOPs, sampling and analytical methods,sampling maps, etc.
• Trained operators to perform the cleaning
• Qualified sampling technicians
• Calibrated test instruments (if any)• Designated sampling containers and labels, supplies and
tools Training should be conducted in job-specific proceduresas well as general “clean” / aseptic practices
267Cleaning Validation
Field Execution –Good Execution Practices
• Prior to validation conclude and summarize experimentation – ensure that all systems are in good working order with currentcalibration and reventive maintenance
• Ensure that all supporting rationales are documented andapproved
• Ensure that protocol and monitoring conducted in the fielddemonstrate process control
• Take notes in the protocol in an identified comments section,not within a separate notebook
• Ensure that observations are recorded, initialled and dated incase of future investigation or review
Keep comprehensive notes – Others should be ableto follow the work and repeat it.
Add the timing requirements and assays called for on thesampling form or create a separate chain of custody to beissued with the sampling form.
To be com leted by Sam ling Personnel [A, B, C, D (E&F swabs only) at the time of container preparation; (E&F rinse only) G and H at the time of sample collection]
A B C DSample ID Equipment Location Sample Type
S–Swab; R-Rinse
Diluent Type Sample DiluentVolume (mL)
SampleSize (cm
2)
Sampling Technician
Initials / Date
273Cleaning Validation
Deviations in Field Execution
• Deviations do not mean that the validation is a failure
• Deviations require a formal investigation anddetermination of the impact to the validation as well asthe appropriateness of reusing the equipment for thenext process
• Extrinsic failures – not process related, therefore repeat only thefailed run (e.g., utility breakdown, failure to follow SOP, etc.)
• Intrinsic failures – process related, therefore repeat the entirevalidation
• Follow FDA’s guidance relative to conduct of failureinvestigations
• Approval Page - corresponding signatures to those approving theprotocol pre-implementation
• Purpose / Scope – reiterate the goals and boundaries of thevalidation; referencing supported groupings / bracketing may againbe appropriate
• Background – reiterate any pertinent relational information withregard to other studies
• Description – provide sufficient description of the system to ensurethat this document can stand alone as a summary to the executedprotocol
• Procedures / Test Methods / Equipment – define those elementsused to execute the protocol – remember that these now representthe validated operational / process state
Validation Reports• Results - provide a summary of results and state whether acceptance
criteria were met; use tables and graphs to present data effectively;
provide evidence of how the acceptance criteria were met
• Deviations – list the deviations and their resolutions, state the impact tothe validation and/or to follow-on production, if any
• Revalidation – state the conditions under which revalidation would berequired (e.g., change in key process parameter, change in cleaningagent, modification to equipment, formulation, etc.)
• Conclusion – state whether the initial goals of the protocol were met;
reiterate any groupings / bracketing that are supported by the validation;clearly state any procedure amendments or requirements as a result ofthe qualification
• Follow the summary with the executed protocol
279Cleaning Validation
Review and Approve Reports
• Ensure that all groups agree with the validity of the datacollected and the conclusions reached
• Ensure that all acce tance criteria have been met
• Ensure that all groups agree that the pertinent regulatoryand policy requirements have been met – especially if
there were any failure investigations as a result of OOSor deviations
• Ensure that all groups understand any directions forfuture production (e.g., procedures to be followed forcleaning, additional disassembly procedures,inspectional requirements, etc.)
Preventive Maintenance and CleaningFor automated systems, ensure that:
• Cleaning agent dispensing apparatus is functional andnot clogged
• Ensure spray balls / spray devices are not clogged andare freely rotating (as appropriate)
• Ensure valves are operating properly and are in goodrepair • Wear
•• Corrosion•
For manual systems, ensure that:
• Cleaning tools are routinely inspected and replaced asnecessary for:
. .,
283Cleaning Validation
Calibration Definition
• Testing (and adjustment if necessary) ofinstruments to ensure that they indicateaccurate y, n accor ance w t recogn zestandards, across their full or intended
operating range• Required for safety of product, equipment and
• Requires demonstration of traceability to appropriatecalibrated standards
• Before each operation, confirm calibration status of all
• Incidents which might affect the calibration should bereported to ensure that the calibration can be verifiedand / or repeated, as necessary
• Ensure that procedures are clear with regard to thenotification required when “adjustments” are necessary-- define the ermissible ran e carefull !
• IQ / OQ should verify that the instrument range andaccuracy are suitable to the process control capabilitydesired
285Cleaning Validation
Calibration and Cleaning
• Calibration is required for all instruments thatare assuring T.A.C.T.
• Consider whether sensors (e.g., proximitysensors on a dynamic spray ball) are part of
the calibration or PM program• Ensure that instruments that are used for bothprocess monitoring / control and cleaningmonitorin / control are suitable in accuracand range to both tasks
Change Control and CleaningConsider the necessity to review your cleaningapproach when any of the following change:
• Solvent or cleaning agent to be used for cleaning
• Batch size or dose size
• Formulation, pre-cursors or intermediates
• Processing conditions
• Process equipment
• Procedures for cleaning, sampling or testing• Campaign length
• Hold times / hold conditions
289Cleaning Validation
Monitoring Definition
Demonstrates consistency of initial cleaning resultsby reconfirming the results through intermittentsampling of equipment after cleaning validation iscomplete
• Most often applied for manual cleaning to confirm thecontinued good practices of the operators and toensure that there is no “drift” with time
•long campaign
• Biologics facilities often perform “verification” or“certification” activities for facilities change-over whichis really a form of monitoring
• Intent is to reconfirm initial validationresults
• Frequency / Motivation:
• Change based program
. .,
293Cleaning Validation
Revalidation Drivers
• Change control history
• reven ve ma n enance s ory
• Calibration records
• Process control results (esp. automatedsystems)
• Monitoring results / trending
Re-perform validation studies in whole or in part, asnecessary based on whether the data from the ongoingprocess and in-process controls demonstrates consistency
• May not be required if monitoring is frequent (in
• May not be required if automated cleaning systemshave in-line analysis (e.g., pH, TOC, conductivity, etc.)
• May be performed under different conditions than theoriginal validation such as different groupings / bracketin , different worst-case conditions, or
elimination of “easy” to clean systems / sampling sitesbased on original data analysis
API Active Pharmaceutical Ingredient (drug substance)
BPC Bulk Pharmaceutical Chemical (drug substance); term replaced byinternational term API
Bracketing See grouping
Campaign
Production
Production in which multiple batches of the same product are produced
sequentially; for the period of the campaign, the equipment is dedicatedto that product; depending on the product, cleaning between batchesmay be less extensive than at the end of the campaign
CAPA Corrective and Preventive Actions – actions to be taken upon theoccurrence of a failure in order to ensure that the immediate failure iscorrec e an o preven rom recurr ng
Change-Over (may also be termed Cleaning Certification or Cleaning Verification) Termused frequently in the biotechnology and API industries to indicate theend of a campaign when the production equipment is being cleaned andturned around for the next campaign and/or next product; while cleaningprocesses are typically validated, extensive testing is typically done atthe time of change over
CIP Clean-In-Place; refers to automated cleaning performed where the equipmentwas used with little disassembly
Cleaning Establishing documented evidence that an approved cleaning procedure willValidation consistently provide equipment (or other product or incidental-product
contact surface) which is suitable for processing pharmaceuticals,biopharmaceuticals or medical devices
CleaningVerification
Sometimes also called cleaning “certification”, a verification activity istypically a single cleaning run; the sampling and testing is often the sameintensity as a validation run, however this term is used when it is notexpected that multiple trials of the same formulation or process will beconducted, therefore a true “validation” may not be possible; if multiple runsare performed over time, a validation summary can be written after three
procedures
COP Clean-Out-Of-Place; generally refers to an automated or semi-automatedprocess such as an high flow or ultrasonic bath or parts washer
Critical Sites Locations that will disproportionately contribute residue to the next dose,next batch or portion of the next batch
Glossary of Cleaning Related Terms
Term or Acronym Definition
CTQ Critical to Quality –attr ibutes that are determined to be critical to the finalquality of the product or process
EU European Union
Family See grouping
Grouping A mechanism by which related equipment, products and/or procedures
may be collectively tested, generally through the evaluation of a worst-case representative from the grouping
HACCP Hazard Analysis and Critical Control Point – FDA risk-based methodemployed by food plants to look for carryover residues of highest riskand employ methods to control / eliminate them
o po oca ons a are cu o c ean on e equ pmen may or may noalso be a critical site)
LD50 Lethal Dose 50 – Amount of product required to kill 50% of ananimal population; LD50 are available for most materials without atherapeutic index; LD50 should always reference animal and routeof administration
LOD (or DL) Limit of Detection (or per ICH, Detection Limit)
LOQ (or QL) Limit of Quantitation (or per ICH, Quantitation Limit)
MOC Materials of Construction
NOEL No Observed Effect Level
OOS Out of S ecification
Organoleptic Of the five senses; generally means visual detection in thecleaning validation context
PAI Pre-Approval Inspection (FDA process prior to approval of a newdrug)
Glossary of Cleaning Related TermsTerm or
AcronymDefinition
PM Preventive maintenance – documented procedures which are performedperiodically to ensure the proper working condition of the equipmentfrequently including the replacement of its wear parts and andreplenishment of its lubricants
Ppm or ppb Parts per million or parts per billion
Protocol A written, approved test plan that describes the testing and analysis
required to demonstrate that a cleaning procedure is validQSIT Quality System Inspection Technique – US FDA Inspection Approach
based on Quality Subsystems throughout the factory
Ra Roughness average – measurement of the finish of metals, esp.stainless steel
Reengineering Activities performed to redesign equipment to better meet GMP orprocess requirements
RODAC Replicate Organism Detection and Counting – RODAC plates are acommon method to sample for microbial contamination on flat surfaces;RODAC plates contain agar which can be directly pressed against asurface for recovery