Limitarimis:
`
`Limitations:
`
`— longer sample turn—around time
`— relatively expensive
`
`Special Validation Concerns:
`
`4 recovery, specificity. detection limit
`
`7.5.10 Thin Layer Chromatography (TLC): Thin Layer
`Chromatography is a sensitive technique which uses very
`simple equipment and principles. TLC has been used for the
`analysis of residues of actives and cleaning agents.
`Advantages:
`
`— highly specific
`— moderate—to—high sensitivity
`- fairly inexpensive
`Limitations:
`
`— moderate-lo-high sensitivity
`visual endpoint detection is not quantitative
`— automatic readers are semi-quantitative
`— lengthy process to perform sample preparation
`
`Special Validation Carts‘lcleratinny:
`
`— recovery. specificity. detection limit
`
`7.5.11 Capillary Zone Electrophoresis (CZE): Also
`known as capillary electrophoresis (CE). this technique has
`been applied mostly to the biotechnology industry and is
`effective for evaluating residues of proteins. amino acids.
`and certain cleaning agents. The technique is highly specific
`and quite sensitive. lt's disadvantages are that only a single
`sample can be run at a time. thus a series of samples would
`require lengthy time periods and that most companies do not
`have this equipment
`in their
`labs
`requiring additional
`expenditures. CEZ works best for large bipolar molecules.
`Advantages:
`
`— highly specific
`— highly quantitative
`— sensitive
`
`Limitations:
`
`— expensive
`
`Special Validation Concerns:
`
`— recovery
`— specificity
`— detection limits
`
`7.5.12 Fourier Transform Infrared (FTIR): FTtR in-
`volves the application of advanced mathematical concepts to
`multiple infrared scans of a sample. The technique is both
`qualitative and quantitative. FTlR is suitable for residues of
`actives as well as cleaning agents and has good sensitivity.
`It's major drawback is that the equipment is quite expensive
`and a library of spectra must be developed for comparison
`purpOses.
`Advantages:
`
`— specific
`— qualitative
`A can be quantitative
`
`— expensive
`— requires extensive library of spectra
`
`lmmunosorbant Assay
`7.5.13 Enzyme Linked
`(ELISA): An ELISA assay is an antigen-antibody type
`reaction involving the use of specific chemicals developed
`especially for the residue involved. It is very specific. ELISA
`assays typically are used for analysis of protein residues
`resulting from manufacturing of biotechnology type prod—
`ucts. While these assays are very sensitive. they are also
`costly to develop and validate. It should also be noted that an
`ELISA method developed for a protein will not detect the
`same protein once it is denatured. Many proteins are easily
`denatured by the cleaning process. and the method would
`fail to detect significant amounts of protein in the denatured
`form.
`
`Advantages:
`
`— ultimately specific
`— very sensitive
`Limitations:
`
`i very expensive
`— difficult to develop and validate
`— labor intensive
`
`A may not provide accurate results if proteins are dena-
`tured
`
`7.5.14 Atomic Absorption/Ion Chromatography (AA!
`lCl: AAIIC is another fairly complex technique which has
`been applied. although rarely. to analysis ofeleaning samples.
`It has the advantage of being specific and very sensitive. but
`sull'ers the disadvantage of involving expensive equipment.
`AA/lC has a fairly narrow potential area of application in
`cleaning analysis: however. for the company manufacturing
`potent ionic or inorganic products it is a potentially useful
`application. For a company already having this equipment. it
`could also be readily applied to the analysis 01‘ residues of
`cleaning agents.
`Advantages:
`
`— very specific
`— sensitive
`
`Limitations:
`
`— generally only useful for metals. salts and metal com—
`plexes
`_ expensive
`
`7.5.15 Ultraviolet (UV) Spectrophotometry: Although
`UV has been applied to analysis of many products and raw
`materials. it often does not have the required sensitivity for
`pharmaceutical products. It is useful for those cases where
`the residue limits are high enough that an analytical tech-
`nique of moderate sensitivity will suffice.
`Advantages:
`
`A moderately to highly specific
`— high sensitivity
`— may be used as a screening method or for confirma-
`tory 1D
`
`Vol. 52, No. 6t November-December 1998. Supplement
`
`M
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`

`Limitations:
`
`— requires more technical expertise and more expensive
`equipment than some of the other methods.
`
`Special Validation Concerns:
`
`— recovery. specificity. linearity. detection limit. preci—
`sion
`
`7.6 Pass-Fail Testing Methods
`
`Pass-fail type testing. also known as “go-no go“ testing is
`used in many analytical situations and has been widely used
`over the years for detection of impurities in raw materials
`and products. In actual application to testing. the analyst is
`looking for a physical change such as a color change or
`development of a cloudy solution. The difficulty with the
`development of such tests for cleaning testing is in knowing
`the actual quantitative level of the transition. i.e.. the break
`point between success and failure. Often the transition point
`is a range. if this is the case. the range must be known and
`it‘s relationship to the limits must be established in the
`validation process. Another difficulty is in not knowing how
`close to the transition point your actual sample may be. The
`actual result. although passing. could have been very close
`to failure and with normal plus/minus variation it could fail
`on the next sample.
`
`7.7 Analytical Methods Validation
`
`The analytical methods used for testing cleaning satnples
`ntust be validated for accuracy. precision. linearity. rugged—
`ness. robustness. sensitivity and recovery. The reader is
`encouraged to refer to appropriate sources on analytical
`method validation (e.g.. lCH guidelines. etc.).
`
`7.8 Micmbiul and Errdomxt'rr Detection and Testing
`
`Testing; methods used to isolate. quantitatc. and speciate
`bacteria and associated endotoxins for cleaning studies are
`the same as those used routinely in the microbiology
`laboratory. Sterile swabs and samples from rinse solutions
`can be used as vehicles to generate samples for microbial
`testing. Alert levels and/or action levels should be estab-
`lished. In addition. cleaning agents should be checked to
`identify their level of bioburden.
`if any. Refer to the
`literature for more detail on endotosin detection methods
`including gel clot. chromogenic and turbidometric LAL
`methods or rabbit pyrogen.
`isolated microorganisms should be identified to an appro—
`priate level
`to determine whether they are of particular
`concern (pathogens. gram negative. etc.). Special cleaning
`and depyr'ogenation methods may be necessary depending
`on the nature of the bioburden.
`
`B. Limits Determination
`
`The determination of cleaning limits and acceptance
`criteria is a crucial element of a good cleaning validation
`program. A limit is an actual numerical value and is one of
`the requirements of the acceptance criteria of a cleaning
`validation protocol. Limits and acceptance criteria should be:
`
`-— practical
`— veriiiable
`
`— achievable
`
`— scientifically sound
`
`The limits should be practical in the sense that the limit
`chosen should be appropriate for the actual cleaning situa—
`tion to be validated. Also. the limits must be verifiable by
`some means of detection. In addition. the limits must be
`achievable by the analytical methodology available for the
`specific product. Most
`importantly.
`the company should
`develop a scientifically sound rationale for the limits chosen.
`
`8.] The Scientific Ratr‘urtrrlefltr Cleaning
`
`It is very important that cleaning limits not be selected
`arbitrarily but. rather. that there be a logical and scientific
`basis for the numerical lituil selected. The scientific rationale
`
`is normally included in the limits section of the protocol for
`the cleaning validation. The scientific rationale which sup-
`ports the actual limit should he logical. comprehensive. and
`easily understood.
`
`8.2 Contamination nfthr' Nerf Product
`
`Product residue remaining on equipment contaminates it
`subsequently manufactured product. Thus. it is important to
`have information about the potential contaminant as well as
`the product which could become contaminated.
`
`8.3 Considerationsflir Developing Lirttitx
`
`There are many areas that should be considered prior to
`establishing cleaning validation limits (see Table I). Once
`these areas have been considered. one can establish a risk
`assessment factor appropriate for use in detemrining limits.
`
`8.4 Lirm'tr Based on Medical or lennm‘ologicul Pfll'l’llt‘)‘
`oftlte Product
`
`One basis of establishing limits is a mathematical calcula-
`tion which allows a certain fraction of the therapeutic dose to
`carry over into each dosage unit of the following product.
`Passihlc approaches to safety factor determination are
`discussed in Sections 8.5 and 8.6. below. The fraction of
`dose reduction is a measure of the risk itwolvcd and should
`
`be assessed by the company depending on the actual
`manufacturing situation.
`
`8.5 The Brisisfor Quantitative Limits
`
`Actual numerical limits are usually based on one of the
`following:
`
`—— the medical or pharmacological potency of the prod-
`uct
`
`TABLE ill
`Safety Factor
`
`Approach
`”10'“ to lllOfl'l‘ ot'a
`non'naI daily dose
`”Hill“ to llltlllil'l‘ oi'a
`normal daily dose
`lllllilil"'lo |llil.lliiil"‘of
`a normal daily dose
`lll0.l)lli)"‘ to Illili).()00lh
`of a normal daily dose
`
`Approach Typically Applicable To
`
`topical products
`
`oral products
`
`injcctions. ophthalmic products
`
`research. investigational products
`
`18
`
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`— the toxicity of the residue
`f the analytical limit of detection
`
`Dilierent manufacturing and cleaning situations may
`require different approaches and each approach will be
`discussed individually.
`It
`is also important
`to factor the
`following product to be manufactured in the same equip
`ment into the limit calculation. Factors such as the batch size
`
`of the following product. the route of administration. and the
`largest daily dose of subsequent product which might be
`administered are important in the calculation.
`All of these factors mentioned previously are usually
`summarized in an equation which may take the following
`general form:
`
`TDXBSXSF
`
`MAC =
`
`LDD
`
`where:
`
`MAC : the maximum allowable carryover
`TD = a single therapeutic dose
`BS = the batch size of the next product to be manufac-
`tured in the same equipment
`SF = the safety factor
`LDD = the largest daily dose of the next product to be
`manufactured in the same equipment
`
`This mathematical equation shows that the batch size of the
`next product as well as the largest daily dose of the next
`product are required for the calculation. if the next product
`to be manufactured is not known, then the smallest batch
`size of any product manufactured previously in the equip-
`ment can he used. When a new worst case is to be
`
`manufactured in the equipment. then this would be evalu-
`ated by the change control process and new Limits could be
`imposed on the cleaning for the equipment.
`limit.
`As an example of the calculation of an overall
`consider the case of a product A having a single therapeutic
`dose of 100 mg. Assume that the product is given by the oral
`route of administration. Let's also assume that
`the next
`
`product to be manufactured in the same equipment has a
`batch size of IO Kg. and a largest daily dose of 800 mg. Use
`a safety factor (SF) of ll‘llltlt). In this case. the calculation
`would be:
`
`TD X BS X SF
`MAC : ——
`LDD
`
`100 mg >< |(l.t)ll(l.000 mg X [/1000
`=———— = 1250 mg
`800 mg
`
`This is the total limit for all residues on all equipment used to
`manufacture the product.
`
`8.6 Limits Based on the Trtt’icitr nf'tt'te Residue
`
`Using the therapeutic dose as the basis of limits calcula-
`tions is appropriate for situations where the material is an
`active ingredient and therapeutic dosage levels are known.
`There are other situations. however. where the material is
`
`not medically used and there are no known therapeutic dose
`data available. Examples are precursors and intermediates
`used in chemical synthesis ti.e., manufacture of active
`
`tAPls)). and cleaning agents.
`ingredient
`pharmaceutical
`These materials have no quantitative therapeutic dosage
`levels. Yet. they may have a medical or toxic effect in the
`body.
`In these cases.
`it
`is necessary to base the limits
`calculations on the toxicity of the material.
`This can be done by using the method described above for
`pharmacological activity with substitution ofthe toxic dose.
`Altematively. where toxicity is expressed as LD50,
`the
`following methodology can be used.
`
`NOEL = L05“ >< emperieal factor
`
`ADI f NOEL >< AAW X SF
`
`where:
`
`NOEL = no observed effect level
`
`LD50 : lethal dose for 50% of animal popula-
`tion in study
`empirical factor = derived from animal model developed
`by Layton. et. al.
`ADI : acceptable daily intake
`AAW = average adult weight
`SF : a safety factor
`
`This equation can be applied to a pharmaceutical cleaning
`validation study for the purpose of calculating a limit. The
`result would be as follows:
`
`MAC =
`
`ADI X B
`R
`
`where:
`
`MAC : maximum allowable carryover
`B = smallest batch size of any subsequent product
`R 2 largest daily dose of any product made in the
`same equipment
`
`The only changes made to the equation are those represent-
`ing the batch size and the largest daily dose of the
`subsequent product. The basic value of this approach is. as
`indicated previously.
`that a limit can be calculated for
`cleaning validation purposes based solely on the toxicity of
`the material. It is important that the LDSU be from the same
`route of administration as the product for which the limit is
`calculated. For example. if the product is an oral product.
`then the LD;., should be from the oral route of administra—
`tion. Likewise.
`if the product is an intravenous injection.
`then the Lan should also be by the intravenous route of
`administration.
`
`ll 7 Limits Based on the Analytical Limitations
`
`These approaches to establishing limits are based on the
`cleaning limit being the limit of analytical detectability. In
`some cases. where the danger of contamination and the
`consequences are of a critical nature, this may be a viable
`approach. However.
`in the great majority of cleaning
`situations. this extreme degree of cleaning is neither neces-
`sary nor justified. When carried to extremes the cost of
`cleaning can easily surpass the cost of the product. The key
`to selecting this approach is the nature of the product (i.e.. its
`
`15
`
`Vol. 52. No. 6} November—December 1996. Supplement
`
`2
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`toxicity and stabilityl and the nature and use of other
`products made in the same equipment. A further problem
`with using these approaches is that constant advances in
`analytical technology means that more sensitive analytical
`procedures are constantly being developed.
`
`8.8 The Meaning of "None Detected"
`
`The use of the term "none detected" is very common in
`the laboratory.
`It
`is important.
`to correctly interpret
`the
`meaning of this term. especially where cleaning samples are
`involved. "None detected" does not equal zero. i.e.. it does
`not mean there was no residue present. All that can be stated
`about such results is that the level of residue was below the
`
`detection capability of the analytical technique or instru-
`ment. often referred to as the sensitivity of the method. The
`sensitivity parameter is one of the most important param-
`eters of an analytical method and sensitivity must be
`validated as a pan of the analytical methods validation.
`The sensitivity of an analytical method is often expressed
`as either the limit of detection or the limit of quantitation.
`The sensitivity of the analytical method may be used to
`establish the actual cleaning limits.
`In cases where the
`cleaning validation study results in "none detected" the
`sensitivity of the analytical method could be used to
`calculate the maximum amount of residue which could be
`present.
`
`8.9 Dividing a Limit/timing Various Pieces quqnipmenl
`
`In order to evaluate a processing operation composed of
`several unit operations.
`it
`is
`important
`to consider the
`accumulated residue from each piece of process equipment.
`This is the sum of all residues which were present on the
`various pieces of manufacturing and packaging equipment.
`The total residue is equal to the sum of all residues in the
`manufacturing “train" as represented in the following
`diagram:
`
`could be transferred to an individual dosage unit (e.g.. tablet
`press. encapsulating machine. tablet filler).
`Prior to the dose forming step the allowable residue may
`be distributed across the equipment. The dose forming step
`(compression. filling) tnust use a different. tighter limit to
`restrict potential carryover to a single product dose.
`
`9. Ongoing Verification of Cleaning
`
`9. I Verifii'oiimi officiating
`
`Verification of cleaning involves the performance of
`testing which confirms that
`the cleaning method is ad-
`equately removing substances to established levels. The
`CGMP regulations require inspection of each piece of
`equipment immediately before use to ensure its cleanliness.
`However. additional verification may be necessary depend-
`ing on the complexity of the equipment.
`
`9.2 Monitoring quutmnurir mu! Monmit’ Cleaning
`
`For automatic cleaning methods. ongoing verification
`may not be required. if the automated system is designed.
`ittstallcd and validated appropriately and the process repro-
`ducibility is confirmed. no further verification should be
`necessary. For semi-automated processes. a determination
`must be made about
`the predicted reproducibility of the
`process over time.
`Manual cleaning generally requires periodic verification.
`Verification should confirm the ongoing appropriateness of
`the training program as well as tltc operator's ability to
`perform the cleaning process.
`One way in which corporations provide for the ability to
`perfomt ongoing or occasional verification is to correlate
`rinse results to other
`residual data. Once this data is
`
`levels
`is possible to conlirrn that the residual
`coilected. it
`meet the predetermined requirements. it may be used as an
`adjunct to cleaning validation or in a clinical supply setting
`where consistency of cleaning may not have been estab-
`lished.
`
`Equipment A
`
`Equipment 8
`Equipment C
`Figure '1
`
`Equipment D
`
`10. Change Control
`
`Equipment A could be. for example. a powder blender:
`equipment B could be a granulator: equipment C could be a
`compressing machine: and equipment D might represent a
`packaging filler fora solid dosage form such as a tablet. For
`a liquid product. equipment A could be a mixing tank:
`equipment B could be a holding tank; equipment C could be
`transfer piping to the packaging department: and equipment
`D might be the liquid filling equipment.
`in many manufacturing operations each piece of equip-
`ment
`is a discrete unit. Since the equipment pieces are
`usually separate stand-alone units. it is necessary to deter-
`mine limits t'or each individual equipment piece.
`An equipment train should be tleiineated to separate those
`portions in which the residue would be evenly distributed
`(cg. blender. granulatorl from those in which the residue
`
`20
`
`All aspects ofcleaning should fall under the auspices of a
`change control policy. Cleaning standard operating proce~
`dares. assay methods. equipment. detergents. product formu—
`lations. batching methods and the like should all hr: docu-
`mented at the time of the validation effort. Changes to these
`items will
`require format documentation and approval.
`Typically. corporate change control policies are in existence
`which will govern the review and approval of these changes.
`lfa firm chooses not to pursue the verification ofcleaning
`on a periodic or occasional basis. changes performed under
`the change control program will require reconfirmalion of
`the cleaning validation results. or verification. If the change
`is deemed to be fundamental to either the grouping philoso—
`phy on which the validation was founded. or to the cleaning
`method. the change may require revalidation.
`Revalidation. in contrast to verification. may require that
`portions of the initial cleaning validation program be
`repeated. Revalidation may differ from verification only by
`
`nnA I... ......t .4 nh_-__..-...:_,.o D..:.......-. ‘ Technology
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`the amount or type of sampling that is perfonned. Typically
`the sampling and testing that are peri‘onned during revalida—
`tion are more stringent than that performed during routine or
`occasional monitoring. Revalidalion ol'cleaning may incur»
`porate aspects of both validation and verification, but in
`
`accordance with a firm's internal policies may be restricted
`to one or the other.
`
`The careful planning and execution of the revalidation
`program will allow for compliance in the ongoing operations
`of the facility.
`
`11. APPENDICES
`11.1 Glossary of Terms
`
`acceptable daily intake
`
`analyte
`AP]
`automated cleaning
`
`batch production
`
`blank
`
`bulk pharmaceutical
`
`campaign
`
`CGM P
`change Control
`
`change-over
`clean t H
`
`cleant lincssl tadj.)
`
`clean-in-place (Cll’)
`CIP system
`clean—out-of—placc ((‘f )Pl
`COP system
`
`cleaning agent
`cleaning validation
`
`contaminant
`continuous process
`
`control parameters
`coverage
`critical site
`
`dead leg
`dedicated equipment
`degradation
`dcpyrogenalion
`detergent
`disinfection
`
`endolos‘ilt
`equipment grouping
`equipment train
`final rinse
`hot spot
`impingement
`impurity
`LDm
`largest daily dose
`limit
`
`an amount of a substance administered or consumed on a daily basis that will not produce a pharmaco-
`logical or toxic response
`substance for which an analysis is being performed
`active pharmaceutical ingredient
`a cleaning procedure which relies on a sequence of programmed. reproducible steps (usually via
`mechanical and/or electronic devices)
`a series of unit operations performed according to a single manufacturing order during the same cycle of
`manufacture to produce a specific quantity of a drug having uniform character and quality within
`specified limits
`analytical method control sample used to establish it baseline for the result. e.g.. as in a titration where
`one or two drops of the titrant must be added to the blank to cause an indicator color change
`generally known as bulk pharmaceutical chemicals; also called primary pharmaceuticals or active phar-
`Inacculical ingredients
`processing of more than one product in the same facility andfor equipment in a sequential manner: only
`one product is present in any one manufacturing area of the facility at a time
`Current Good Manufacturing Practices
`a documented system for reviewing proposed or actual changes that mi ght affect a validated system or
`process: change control includes the determination of any corrective action required to ensure that the
`system remains in a validated stale
`actions required for switching multi-product equipment and facilities from one product to another
`the implementation of procedures to render a piece of equipment. or a system. free ot'adultcrants and
`contaminants
`visually clean—absence ot’matcrials which would adulterate a product when inspected with the eyes
`delectbly clean—absence of materials which would adulterate a product down to the level of detection
`chemically clean—absence of all chemicals Which would adulterate a product
`cleaning without the need to disassemble equipment (may be either automatic or manualt
`a system. usually automatic. used to clean equipment in place
`the cleaning performed. usually manually. after disassembly of equipment or a system
`a system which may be automatic. semiautomatic or manual. used to clean equipment out of place. e.g..
`a parts washer
`usually a detergent or surfactant that reduces the surface tension of a solvent to increase its effectiveness
`demonstrating that cleaning results are consistent and reproducible. usually by sampling critical and rep—
`resentative sites on the equipment after cleaning
`extraneous substance that exists in a product
`a series of operations performed according to a manufacturing order so as to provide a steady stream of a
`drug having uniform character and quality within specified limits
`those operating variables that can be assigned values that are used to regulate a process
`the exposure of equipment surface area to the cleaning process
`area of a piece ot‘equipment on which residual materials are trapped or concentrated tc.g.. because of
`location. surface or equipment design) and which is liltely to contribute all of the contamination to a
`single dose ti.e.. "hot spot")
`a pipe with restricted flow or agitation exceeding the length of six pipe diameters
`equipment that is to be utilized for a single product or product family
`breakdown of material during manufacture or after exposure to the cleaning process
`removal or destructirm of pyrogens
`a synthetic wetting agent and emulsifier that can be added to a solvent to improve its cleaning efficiency
`to adequately treat equipment. containers. or utensils by a process that is effective in destroying vegeta—
`tive cells of microorganisms of public health significance. and in substantially reducing numbers of
`other undesirable microorganisms
`lipopolysaccharide. Usually from gram negative bacteria
`equipment closely related by design. as to be considered the same for the purposes ol'clealting
`the sequence of equipment through which a product is produced or processed
`the last rinse ot' a piece ol'equipmcrtt during the cleaning procedure (see rinse)
`see critical site
`to cause to strike
`any extraneous substance or contaminant present in the drug substance or drug product
`the dose resulting in a fifty percent mortality of the test animal
`maximum daily time ofthc next product to be produced in the equipment train
`a prescribed maximum and/or minimum tolerance
`
`Vol. 52. No. 61' November—December 1998. Supplement
`————_—
`
`4
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`

`11. APPENDICES
`(continued)
`
`the lowest concentration of analyte in a sample that can be detected. but not necessarily quantituted.
`under the stated experimental conditions
`the lowest concentration of analyte in a sample that can be determined with acceptable precision and
`accuracy under lltc stated experimental conditions
`any process equipment which is uniquely identified within the drug product batch record (cg. auto—
`clavc. hatch tank. blender. cncapsulutor. tiller. luhlel pm“)
`a cleaning procedure requiring operator performed critical steps te.g.. scrubbing with a brush or rinsing
`with a hose!
`the maximum amount of carryover from one product to the next that will not produce a therapeutic dose.
`corrected for a safety factor te.g.. ”1000)
`the minimum dose required to elicit a response in vitro or in vivo
`
`the minimum dose that will produce a pharmacological response as derived by medical criteria
`ancillary equipment (e.g.. dispensing containers. utensils. scoops) associated with a drug product manu-
`facturing process
`to bring into colloidal solution. esp. proteins
`inen material or l'onnulation
`use of an inert material to mechanically displace and dilute residuals
`
`establishing documented evidence which provides a high degree of assurance that a specific process will
`consistently produce a product meeting its predetermined specifications and quality attributes
`a group of closely formulated products with the same active ingredientts)
`establishing documented evidence that a system validation does what it is supposed to do. based on
`information generated before actual implementation of the process
`a documented with agreed upon set of standards and tests
`use of a representative drug product andlor piece of equipment to demonstrate a cleaning procedure can
`achieve adequate levels of cleanliness for similar product andtor equipment families
`a material which elicits a pyrogenic response (fever)
`to cleanse or treat an equipment as part of a cleaning procedure
`a predetermined value (cg... ”mom used to minimize the uncertainty ol'u calculated limit
`to make physically clean and to remove and destroy. to the maximum degree that is practical. agents
`injurious to health
`a system controlled partly by mechanicalfelectronic devices. but requiring some manual intervention
`cleaning performed in the midst of a production campaign: serial cleaning is usually less intensive than
`the procedure used between different products
`an absorptive device used to remove a sample front a surface
`an amount ol'drug that will produce a pharmacologial response
`see “no—elTect"
`the minimum dose required to produce a harmful. poisonous effect
`absence of visible contaminants
`the highest or lowest value of a given control parameter. maximum system load. or maximum or
`minimum environmental conditions actually evaluated in a validation exercise
`
`limit of detection
`
`limit of quantitation
`
`major equipment
`
`manual cleaning
`
`maximum allowable
`carryover
`minimum phanna—
`cological dose
`minimum therapeutic dose
`minor equipment
`
`pcptizing
`placebo
`placebo scrubbing
`(or solid washing)
`process validation
`
`product family
`prospective
`
`protoCol
`prototyping
`
`pyrogcn
`rinse (achouanonaqtit-ousi
`safety factor
`sanitize
`
`semi—automated
`serial cleaning
`
`swab
`therapeutic dose
`threshold dose
`toxic dose
`visually clean
`worst case
`
`H. 2 Suggested Reading
`
`Journal Articles
`
`.1. Agalloco. “ “Points to Consider' in the Validation of Equipment Cleaning
`Procedures." Journal of Parenteral Science and Technology. Vol. 46. No. 5.
`Septembcrfleloher l992.
`S..I.Ainswor1h. "Snaps and Detergents." Chemical and Engineering News.
`January N92.
`H. L. Avullone. "Manufacture of Clinical Products.“ Pharmaceutical Tech-
`nology. September IQQfl.
`H. L. Avullone. "Drug Substance Manufacture and Control." Phartnaeeutiv
`cal Engineering. March/April l989.
`H. L. Avallone. "CC-MP Inspection of New Drug Products." Pharmaceutical
`Technology. October. I989.
`R. Bal'l't. ct al.. FDA Questionnaire, July 1 1. I988. “A Total Organic Carbon
`Analysis Method for Validating Cleaning Between Products in Biopharmu-
`comical Manufacturing." Journal of Parenteral Science and Technology.
`JanuaryIFcbruary. [991.
`H. J. Basentan. "StP/CiP Validation—The validation and use ot‘SlP/CIP
`systems." Pharmaceutical Engineering. March/April 1992.
`E. J. Bigwood. "The Acceptable Daily intake of Food Additives." CRL'
`Critical Reviews in Toxicology. June NT}.
`T. Cairns. "Confin‘nation of Trace Level Residues in the Food Supply."
`Crit. Rev. Food Science Nutrition. Vol. 30. No. N4. pp. 397402. 1991.
`
`22
`
`5. W. Harder. "The Validation of Cleaning Procedures." Pharmaceutical
`Technology. May 198-3.
`P. Layman. "Henkcl-[icolah New Force in Cleaning Market." Chemical
`Engineering News. October i‘J'JI.
`I). W. Layton. cl at. ”Denying Allowable Daily Intakes for Systemic
`’I‘oxicunts Lacking ('hronic Toxicity Data." Regulatory Toxicology and
`Plntrntacology 7. 9!» I
`I 2. 1987.
`Ii. Mats. J. Howard. "(T-C Altemalive Cleaning Systems.” Journal of the
`If-lS.Hept/(Ict 19‘“.
`S. Mazumdar. "Octuctliylporphyrinatc Heme Complexes Encapsulated
`Inside Aqueous Detergent Mieelles—A Spectroscopic Study." J. Chem.
`Soc. Dalton Trans" N8. pp. 2091—2096. 1991.
`I). W. Mcndcnhall. "Cleaning Validation." Drug Development and IndusA
`trial Pharmacy. I989.
`J. Moschclla. B. Kusse. J. Longfellow. J. Olson. "An Intense Lithiumi
`Ion~Heam Source Using Vacuum Baking and Discharge Cleaning Tech‘
`niques." Journal oprplicd Physics. Vol. 70. No. 7, October I991.
`R. Nash. C. Helling. S. Ragone. A. Leslie. "Ground Water Residue-
`Sampling.” American Chemi 'al Society. l99l.
`Puhlix Supermarkets. "Dairy Processor Clean—Up with Cl? Monitor. Pubiix
`Sat-es Money Controlling Wash and Rinse Cycles." Dairy Foods. Septem»
`her. 199".
`J. V, Rodricks. "Risk Assessment and Animal Drug Residues." Drug
`Metabolism Review. Vol. 22. No No—li. p. 601. 1990.
`E. Sargent. el al.. “Establishing Airhome Exposure Control Limits in the
`
`it Technology
`
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`Pharmaceutical Industry." American Industrial Hygiene Association Jour-
`nal. 49(6). 309 t l988).
`J. M. Smith. “A Modified Swahhing Technique for Validation of Detergent
`Residues in CIP Systems." Phan'oaceutical Technology. January 1992.
`S. A. Taylor. Gerald Chapman. “Cle