PHARMACY LIBRARY
`
`MAR O 4 1999
`
`< ·•
`
`• • 1) O!AM!:'.:=l.Ll'I HALL
`:.:nE, s· ..UJJ: so~.·,·, s~, c
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`FRESENIUS EXHIBIT 1075
`Page 1 of 26
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`

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`Points to Consider for
`Cleaning Validation
`
`Technical Report No. 29
`PDA
`
`PHARMACY'.... :1,,-\i=<Y
`
`2130 CHAl.l?::"L' .., .,, L
`~5 "I. CHARTE'- ~- -r;-_ -- , " ' 5;!706
`
`August 1998
`
`FRESENIUS EXHIBIT 1075
`Page 2 of 26
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`PD A Journal of
`Pharmaceutical Science and Technology
`
`iupplement, November- December 1998
`EDITOR:
`
`Joseph B. Schwartz
`
`Volume 52
`
`'R OFFICERS AND DIRECTORS
`
`Joyce H. Ayd leu
`,lllirman:
`baim1an-Elcc1: Rohen B. Myers
`Floyd Benjamin
`<eretary:
`R. Michael Enz.inger. Ph.D.
`'reasurcr:
`.nmediate Past
`Chairman:
`
`Raymond Shaw, J r., Ph.D.
`
`~ne; E. Akers. Ph.D.
`<imieAllcwell
`liyce L. De Young, Ph.D.
`~ephanie R. Gray
`Frederick A. Gust:ifs1111
`Hartin W. I knlcy
`'llenry K. Kwan. Ph.D.
`Nikki V. Me hringer
`iobcrt F. Morrissey, Ph.D.
`Terry E. Munson
`Toshiaki Nishiha ta, Ph.D.
`Glenn E. Wright
`
`?resident: Edmuml M . rry
`
`PDA Journal or Pharmm:e utical Science & Technology (ISSN
`l076-397X) is puhlished bimonthly hy lhe PDA, lnc., 7500 Old
`Georgetown Rd., Suite 620. Bethesda. MD 20814.
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`Journal of Pharmaceutical Scie nce & Technology, 7500 Old
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`
`Fom1erly the
`--Journal of Parenteral Science and Technology"
`
`Copyrighr- PDA, Inc. 1998
`ISSN 1076-397X
`
`FRESENIUS EXHIBIT 1075
`Page 3 of 26
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`1. Introduction
`
`I .I Bac/.:gmwrd
`
`In recent years. cleaning has achieved a pos111on of
`incn!a:,,ing importance in the pharm:iceutic:il indu try The
`current gootl manufacturing practices (CGMP) regulations
`recog:ni1e lhat cleani ng is a critical i~sue IO ensure prnducr
`quality. Vinually every aspect of manufacturing ill\,olves
`cleaning. rrom thl! initial Mages of bulk production to the
`li nal dosuge fonn,
`The CGMPs in the United Stale~. Euroix and other puns
`of t~e world have provided Lhc phamiaccuticul industry with
`genl!ral guidance for cleaning requiremen1s. For example. in
`the U.S .. ~ection 211.67 of pa11 2 1 of the Code of federal
`Regulations (CFR) st mes 1ha1 " Equipment anti utensib ,hall
`be deaned. maintained, and sanitized at appropriate imcr(cid:173)
`vab to prevent malfu11ction~ or contamination that would
`alter the ,af'cty. identity. strength. quulity. or purity of the
`drug product beyond the official or other e,tabli~ed require(cid:173)
`mcnu,.'' Scc1ion '.2 11. 18'.! of pan 2 1 of the CFR identifie~ that
`cleaning procedures must be documented appropriately, und
`that a cleaning and u:,,e log ~hould he e\tablished. In addition
`10 CGMP,. variou~ inspectionnl guideline document~ pub(cid:173)
`li~hcd by the FDA contain cxpcl:tations regarding cleaning
`in the pharmaceutical industry. Cleaning is also .iclclres-;ed in
`the PIC rccnmmendat1ons on cleaning validation and in the
`SFSTP Comnfr;sion report "'Validation des procedes de
`ncuoyuge."
`It ha~ alwuy, been the responsibility of the regulated
`industry and the regulatory agencies 10 in1crprct 1he CGMPs
`and 10 crea1e programs and policies which e:-tahlhh 1he
`general requirement~ ai- specitic practict:s. Recognizing the
`importance of the rcla1ion!>hip hct,~een dcanin~ and product
`quality. regula1ory agenc:ies are demanding greulcr evidence
`of cleaning. cffcctivcm:ss through validation or vcrific.,tion,
`
`1.2 Purpose
`
`The purpose of this publicmion is to identify and discuss
`the many lal:tors involved in the design, validation. imple(cid:173)
`mentation and control nf' cleaning program~ for the phanna(cid:173)
`ceutical Industry.
`The document doe~ not attempt to in1crpret CGMPs but
`provide~ guidance for establishing a deaning, v:,lidation
`program. It identities the many factors 10 be considered for
`all segments of the phann;iceutic:.il indu~lry. It nlso identities
`,pccific poinb 10 be considered by dosage form manufactur(cid:173)
`ers. manufacturers of clinical Lrial materials (CTMs) an
`manufacturers of butt... pharmm:eutical chemicals and bio(cid:173)
`chemicab. The report covers the different approaches which
`may be appropriate for the different stages of produc1
`development from the e,Hly re~earch stage:.. to the commer(cid:173)
`cially marketed product.
`
`/.3 Scope
`
`Thi~ paper applies to biopharmnceutical. hulk pharmact.:u•
`tical and finished dosagt: form operations: liquid. dry. solid
`and semi--;olid dosage forms arc rnvered in both s1crile and
`non-stcnle pre~entations. Both clinical and marketed prod(cid:173)
`uct cleaning validation pmgram:, ure identified.
`
`Vot 52. No. 6 / November-December 1998, SUpplement
`
`Th.: manufacture of mod~m pharmaccu1icals is a complex
`process involving highly technical personnel, complex equip(cid:173)
`ment. sophisticated faci lities anti complicated proces~c~.
`Individuals respon. ible for all aspects of the production.
`approval and validation of products. ~uch a:.. quality control,
`quality assurance, engi neering, validation. production. re(cid:173)
`search and development. contrnctors and vendors and regu(cid:173)
`latory affairs personnel may use this document a:,, a rcsounx
`for esl,ablishing or reviewing the cleaning programs within
`their faci lities,
`The validation programs dest.:ribed herein assume thut :111
`overall valida1ion prugram with appropriate controls j:,,
`already in place for the fac il ity. utililil!s. equipment and
`procc:,:,,C:-., Th~ cleaning of the environment is not specifi(cid:173)
`cally covered. however many of the same concern~ that are
`considered for the cleaning of proccs, equipment al'-0
`impac t 1he cleaning of the environment, The monitoring of
`microbiological and endotoxin conLamination and ~leps for
`their elimina1ion are mentioned in several sections and
`shouJd be pan or the cleaning validarion program. However
`this documenl is not intended to be n comprehensive treatise
`on mkrobiological control. or endoroxin limitation, Other
`document~ have addressed microbiologic.1I progrJms and
`methods for the environmental monitoring which can be
`:ipplied to deaning.
`
`1.4 ffrporr Orga11i::.mio11
`
`Each or the major Lopics of 1hii; document starts with a
`general section which applies Lo all segments of the pharma(cid:173)
`industry. Points to be considered for i.pecific
`tcutical
`industry segment:,, such as h1opharmaceu11caJs. bulk pharma(cid:173)
`ceutical chemicals. clinical products may vary, depending on
`the spcd tk product type. A glossary is provided al the end of
`the report.
`Finished Pharmace uticals: Finished pharmuc.:uticals
`represent :-olid fnrmulatio11s. semi-solid fom1ulations. liquid
`and aero~nl fom1Ulation,; with variou:,, routes of administra(cid:173)
`tion. Over-the-counter and prescription pharmaceu1iculs for
`hnLh humun and ve1crinary use are included in this ca1egory.
`The common characteri'1ics shared by finished ph,trmaceu(cid:173)
`ticals arc their manufacture by combining raw materials and
`activ,e ingredients to create the fina l dosage fom1.
`Pham,accutical manufacwrers often make a large number
`of product types in one facility: o ften there are several
`diffe1rent strengths prepared or the same product. The
`cleaning problems indudc the large number or processes
`and product types manufactured within one facility. The
`number of cleaning methods. ai.,ays and type:.. of equipment
`11) be· tested are often staggering, This is complicated by lhe
`i:..!>uc:s 1>u1rounding the use of non-dedicated equipment.
`Thus.. the e~tablishment of a cleaning validation policy
`whic h i-; upplicablc tu all products is often very difficu lt.
`Bi.opharmaceuticaJs: Bioprocess manufacturing. starting
`with microhial. animal or in~ec1 cells. or DNA derived host
`cells or other cell~ modifictl to make a ~peeialized prodi;ct.
`can be performed in several ways. Indeed. new me1hod~ for
`bioprocc~sing arc constantly being developed. The mos!
`common method is lhrough large scale fennentation (such as
`bac11.:rial cell culture or mammalian cell culture) followed by
`highly specific purilication s1ep~. Other method~ include the
`
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`development of an antibody in hoM animals (such as
`ascites ). cloni11g of cells o r tissues. or transgenic generation
`of cellular components. namely. proteins. Many in the
`biophurmaccuiical industry consider the stages or fermenta(cid:173)
`tion to be similar to other pharmaceutical industry processes.
`For example. the initial stages o f the large scale fermentation
`have a striking similarity to bulk pharmaceutical chcmicnl
`production. Later. harvest and purilication steps fi nd more in
`common with pharmaceutical processes. It is important to
`remember however. that other bioproces~ing method ~ used
`in the biophannaccutical industry differ greatl y from tradi(cid:173)
`tional pharmaceutical processes.
`Cleaning for biopharmaceuticals presents special con(cid:173)
`cerns due to the large nu mber of impurities such a~ cellular
`debris. waste products of cellular me1abolism. media constitu(cid:173)
`ents and buffer salts generated or added during manufacture
`which must bccliminmed from the eq uipment. In the case of
`mammalian cell cultures, due to the nature of the source
`material. microbial contamination is of great concern. Iden(cid:173)
`tification of the re~idues is often quite difficult because they
`may vary fro m batch to batch. The large variety of protein(cid:173)
`aceous materials present in the residue make d ifferentiation
`of the contami nan Ls from one another a challenge.
`Due to the nature of lhe biophannaceutical production.
`multi-product fac il ities represent an area o f regulatory
`concern. In order to control the production within a multi(cid:173)
`product faci lit·y, it is necessary to ensure that s pecia l
`precautions are taken which preclude produc1 to product
`carryover. C leaning is an integral part of the strategies
`designed to ensure that there is no cross-contamination in
`these facilities. The terms c leaning and cleaning validation
`in multi-product fac ilities often include the facility itself.
`and therefore empbasii: is placed on changeover validation.
`C leaning for biotechnology products ha, been described
`in "Cleaning and Cleaning Validation: A Biotechno logy
`Perspective," PDA. Bethesda, MD, 1996.
`Bulk PharmaceuticaJ Chemicals: Bulk pharmaceutical
`chemical processes are typically biochemical or chemical
`syntheses carried out o n a relatively large scale. The bulk
`pbannaceutical chemicals may be provided to pharmaceuti(cid:173)
`cal manufacturers as active or inactive ingredients for
`eventual inc lusion in a fi nished dosage form pharmaceutical.
`The bulk pharmaceutical chemical manufacturing process
`for active ingredients ii- typically enclosed in large tanks
`with direct Lransfer of materials from tank 10 tank after a
`particular chemical reaction has occurred. The initial stages
`of the bulk pharmaceutical chemical drug development are
`reminiscent o f the chemical indusLry. At some point during
`the process. the manufacturer must. in accordance with
`CGM Pi; have identified a process step after which the
`proel!s:s will strictly comply with the CGMPs.
`Bulk pharmaceutical chemical production, due in large
`part tl1 lhe sc ale of manufacture and its use of strong reagents
`and c hemic al:,;, is o ften perfonned in c losed systems which
`may use auto mated or semi-automated Clean-In- Place tech(cid:173)
`no logies. T he difficulties in the validation of cleaning
`processes often stem from the inaccessibility of many areas
`to direct sampling. The contami nants to be removed include
`precursor mo lecule~. intennediatcs. byproducts. impurities
`
`or other physical forms s uch as isomers or polymorpbs.
`which exist from early stages in the process.
`Clinical Products: l n this document, clinical products
`identify those products which are currently registered as an
`investigational starus due to their involvement in c linical
`trials. The Clinical Products category id!!ntifies the special
`care that must be taken with these products which may not
`he as fully characterized as marketed materials. Bo th
`pharmm.:cutical and biopham1aceu1ical drug products and
`tlrug substances are Lncluded in this category.
`C leaning in a clinical manufacturing setti ng is often
`complicated by the use o f smaH sca le manually c leaned
`equipment. Clinical manufacturing may represent a period
`during which process improveme nts are made, and therefore
`the same equipment may not be used each lime the product
`i~ made. Also. since clinical products are often manufactured
`in development facilities, the subscqucnl products may not
`be known. T he next materials manufactured may be research
`products , development products, placebo products or o ther
`clinicaJ prod uc ts. Our intent is to addreS!> c leani ng o f
`1.XjUipment in Pha~e III and later. but it may be appropriate to
`CllllSidcr the same approaches in earlier pha~es as well.
`Typically, assays fo r low level detection of the acti ve
`ingredient and its exc ipients will need to be developed and
`validated. Verification o r cleaning effectiveness. as opposed
`tc, Lraditional validation. is prevalent s ince infom1alion on
`the material is not readil y available.
`
`2. The Cleaning Continuum
`
`The subject of cleaning validation is one which the
`pharmaceutical and biotechnology industries have struggled
`with. Progress w a consensus in approach in the induMry has
`been slowed by the number and complexity of is:,;ue:-.
`surrounding the cleaning process and the variety of facili·
`ties, products a nd equipment in use. The development of a
`universal approach to cleaning validation is unlike ly given
`these variations.
`
`2.1 Use of the Cfrw1ing Co11ti1111u111
`
`The intent of this sett ion is 10 describe the limits of the
`cleaning continuum (see Table I). These limits represent the
`extremes in the range o f operating differences found within
`the industry which preclude a uniform approac h. At each end
`o f 1he continuum, the cleaning validation requisi 1e:s ure
`either simple or complex. Recognition that there are ma ny of
`these coupled limits. and that each cleaning process has a
`unique place within each level o f the continuum. explains
`why specific industry-wide approaches have been so c.lifli(cid:173)
`cult to develop.
`The cleaning continuum provides some of the primary
`points to consider in any cleaning validation program. The
`continuum helps firms to establish the parameters whic h are
`critical fac tors for individua.l products, thereby e nabling
`them to set priorities, develop grouping philosophies and
`establish the "scientific rationale'' which will govern the
`cleaning program. The contin uum will assist in determining
`which processes, equipment and products represen t the
`greatest concerns and may help to establish the criticality of
`cleaning limits and methods. The continuum should be used
`
`2
`
`PDA Journal of Pharmaceutical Science & Technology
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`FRESENIUS EXHIBIT 1075
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`during the initial phases of defining a cleaning validation
`program or during new product developmenl.
`The cleaning continuum includes: cleaning program crite(cid:173)
`ria, equipment characteristics. quality attributes of equip(cid:173)
`ment design, formulation/prO<iuct attributes. analytical meth(cid:173)
`odology and manufacturing/process attributes. All of the
`factors in the continuum di rectly affect the ability to clean:
`however, their relative importance and criticality may be
`different from one company to another.
`
`2.2 Cfea11i12M Program Crireria
`
`When establishing a cleaning validation program. it is
`important to first characterize the types of cleaning that are
`used in the facility. The cleaning methods that are used in a
`facihty can reveal important factors with regard 10 process
`control. procesl> reproducibility. the best ways in which to
`challenge the process, the best ways in which to col lect
`s.imples and the best ways in which 10 monitor cleaning
`effectiveness during routine cleaning.
`Automated Cleaning-Manual Cleaning: Automated
`cleaning will usually provide reproducible rewlts. Process
`control is inherent in automated systems and process moni(cid:173)
`toring is frequently integral with the control system. Auto(cid:173)
`mated systems may not adjust to present conditions. The
`validation of an automated system requires that the cycle is
`proven to be rugged and will provide reproducible results
`under a given range of operating conditions. Control system
`validation is a large part of the validation of an automated
`cleaning system.
`Manual cleaning is a universal practice within the pharma(cid:173)
`ceutical industry. There are many pieces of equipment and
`portions thereof for which construction and/or configuration
`make manual cleaning a necessity. The control of manual
`cleaning is accomplished by operator training. well defined
`cle.ining procedures. visual examination of equipment after
`use and prior to the next use. and well-defined change
`control programs. It may be desirable to identify worst case
`cleaning situations (in terms of operntor experience and/or
`cleaning methodology) for validation purposes. With manual
`cleaning. concern must also be given 10 the ruggedness of
`the method. Successful reproducibil ity is a funct ion of strict
`adherence to written prcx:cdures.
`Clean-In-Place (CIP)-Clean-Out--0f-Place (COP): The
`cleaning of large pieces of equipment m,1y be performed in
`
`TABLE 1
`The Cleaning Continuum
`
`Manual ....................................................... Automated Cleaning
`Clean-out-of-Place (COP) ......................... Clean-in-Place (CIP)
`Dedicated Equipment ...................... Nnn-Dedicated Equipment
`Product Contact Surfaces ........... Non-Product Contnct Surfaces
`Non-Critical Site ..................................................... Critical Site
`Minor Equipment .............. , ............................ Major Equipment
`Low Risk Drugs .................... , .......................... High Risk Drugs
`Hjghly Characterized ................................ Poorly Characterized
`Sterile ....................................................................... Non-Sterile
`Solid Formulations ....................... ........... Liquid Formulations
`Soluble ...................................... ................................... Insoluble
`Single Product Facility ....................... Multiple Product Facility
`Campaigned Production .............. Non-Campaigned Production
`Simple Equipment Train .................. Complex Equipment Train
`
`the equipment'i- permanent location. general ly in a configu(cid:173)
`ration very similar to that in which it is utilized for
`production. This procedure is widely known as Clean-ln(cid:173)
`Place (CIP). Smaller equipment items arc frequently trans(cid:173)
`ported to a designated cleaning or wash area where the
`cleaning procedure is performed. This practice i~ known as
`Clean-Out-of-Place (COP). but the tern, is not as prevak111
`as its counterpart.
`The additional activities involved with tramport of equip(cid:173)
`ment to and from the wash room. component idenrification,
`the elimination of cross-contamination potential during
`transfer. and cleaning and storage prior to use make the
`validation of COP procedures somewhat more difficult than
`the comparable CJP activity. The need for manual manipula(cid:173)
`tion is an integral part of many COP procedures and requires
`detailed procedures and training. The manual manipulation
`makes COP concerns similar to those of manual cleani ng in
`place.
`The use of automated washing machines to COP smaller
`items is an important part of many COP systems. The use of
`these systems reduces the differences between CJP and COP
`significantly. These systems are considered to be highly
`reproducible in their cleaning performance and are gaini ng
`wide acceptance.
`
`2.J Equipmenr Characteristics/Materials of Construction.
`
`Equipment usage during production is another important
`aspect to consider in establishing a cleaning validation
`program. 1L is important to understand not only the range of
`products that are likely to come into contact with the various
`equipment surfaces, but also the role that the equipment
`plays in the production train. This will help to establish the
`contamination and cross-contamination potentials of the
`equipment.
`Equipment design characteristics, as established drning
`product development, are often driven by equipment func(cid:173)
`tionality rmd the requirements of the process. With the
`current emphasis on cleaning validation, it makes sense that
`.. cleanability" be a key criterion in the design of equipment.
`Dedicated-Non-Dedicated Manufacturing Equip•
`ment: Dedicated equipment is used solely for the production
`of a single product or product line. Concerns over cross(cid:173)
`contamination with other products are markedly reduced.
`DcJicatcd equipment must be clearly identified with the
`restrictions of use in order to prevent potential errors during
`cleaning and preparation.
`Where the same piece of equipment is utilized for a range
`of product formulations. (i.e .. nondedicated equipment), the
`prevention of cross-contamination between products be(cid:173)
`comes the main objective in the cleaning validation effort.
`Clearly, cleaning non-dedicated equipment represents a
`more significant obstacle to oven.:ome.
`Dedicated-Non-Dedicated Cleaning Equipment: The
`issues of dedicated and non-dedicated equipment can also
`arise when considering the equipment used for cleaning. CIP
`systems. for example, are frequently used for many different
`tanks in a single fadlity. Inherently, the design of C IP
`sy1,tcms should preclude cross-contamination through appro(cid:173)
`priate valving and back-How prevention. C::ire should be
`taken with shared device~ which apply cleaning agent!>, :-uch
`
`Vol. 52, No. 6 / November- December 1998, Supplement
`
`3
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`FRESENIUS EXHIBIT 1075
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`as !-pray balls or spray nozzles which, themselves, may
`require cleaning. Certain ly any recirculation within the CIP
`,ysLem should be configured carefully during system design
`and monitored closely during routine operation.
`COP equipment. such ;ts 411 ultra,onic ;,,ink, may also be
`used for multiple equipment loads. With cleaning appar.uus
`such a.~ the sink. the removal of potential contaminanls from
`the ~ink. itself is a concern . Sinks and washers frequently use
`recirculation systems to economically remove residuab
`from 11urfaces whhout undue w.aMc. Tile cleanliness of the
`recirculated mc1terials should be evaluated during cleaning
`validation to cmurc that contaminants arc not being redepos(cid:173)
`ited on the equipment 10 be cleaned.
`Non-Product Contact-Product Contact Surfaces: 1'rn(cid:173)
`d i tionally, the validation of cleaning has focused on product
`contact surfaces. Programs for the elimination of cros!>(cid:173)
`contamination must address non-product contact surfaces if
`1hey are 10 be tmly effective. In rractice. cleaning validation
`requ'irements may change with nonproduct contm:,t surfoccs
`in accordance with the less critical nature of these areas.
`When establishing the requirements for non-prt)duct contact
`surfaces. it is important 10 review the possible interactions of
`that area with the process.
`Non-Critical Site-Critical Site: Critical site. are those
`locations in which a contaminant is in danger of affecLing a
`single dose with a high level of contamination. Critical sites
`often rcqllire special cleaning emphasis. It may be appropri(cid:173)
`ate to establish more intensive sampling schedules for
`critical sites. set tighter acceptance criteria for critical sites
`and ensure that enough detail is included in cleaning
`procedures m provide fo r reproducible cleaning or critical
`sites.
`Minor Equipment-Major Equipment: Tbe distinction
`between "major .. and •'minor'' equipment is not a deliniti ve
`one. The CGMPs make mention (2 11. JOS) of "major·•
`equipment, but are silent or. the subject of " minor'' equip(cid:173)
`ment except with reganl tu items de.-.cribed as utensib
`(21 1.67). Despite this failure within the CGMPs. it is
`necei-sary to identify those pieces of equipment (major)
`which arc central to the production process and those pieces
`of equipment (minor) which perform a secondary role.
`Typically I.he cleaning of ··major•· equipment will be the
`subject of individual, highly spedfic SOPs. fn contrast.
`"mi nor" equipment and ''utensils" arc often cleaned using
`broadly defined procedures which describe the methods to
`be used in general tcnns.
`Materials of Construction: The materials of construc(cid:173)
`tion of the equipment shouW be considered carefully when
`establishing a cleaning validation program. The attributes of
`the surface to be cleaned will define the residue to surface
`internclions. identify possible contaminants and point to
`urc.ui; whid, muy nol b,;, Nmlily cJ.,,.me<l ur ucs:ur<ltdy
`ampled. The CGMPs (2 1 1.65) state that.
`
`"a) Equipment shall be constructed so that surfaces which
`contact components. in-process m:11eriah., or drug
`products shall not be reactive. additive or absorptive
`so as to alter the safety. identity. strength. quality or
`purity of the drug product beyond official or other
`e~tabfo:hed requirement.~.
`
`"b) Any substances required for operation, such as lubri(cid:173)
`eants or coolants. shall not come into contact with
`components, drug product container.s, closures in(cid:173)
`process mutcric1Js, or drug products so as to alter lhe
`safety, identity strength. quality or purity of the drug
`product heyond official or other established require(cid:173)
`ments.··
`
`Equipment should not be reactive, additive or adsorptive
`with the process materials which contact them. The use of
`porous surfaces fo r multiple products should be avoided
`(fi lters. fi lter bags, fluid bed drier bags, membrane filters,
`ultra filters). Any surfaces which have these properties will
`require review during cleaning validation evaluations Lo
`ensure adequate proc.tuct removal and :minimi:1,e the potential
`for cross-contamination. 1 he interaction of deaning agents
`with surfaces th.it are likely to display these properties (e.g ..
`~ab. gaskets, valves) should he assessed.
`
`2.4 Pmduct Auribwe:;
`
`The cleaning of equipment is closely tied to the 1ype of
`materials being removed from the ~urfaee. The pro<luct
`formulation is often the key in esrablishing appropriate
`cleaning acceptance criteria. challenge methods and sam(cid:173)
`pling, techniques.
`Low Risk-High Risk Drugs : The residual limits uli(cid:173)
`lizcd for cleaning validation are often closely related to the
`allergenicity/tox icity/potency of the materials in question.
`The limits are eased when the matcri.11!> being n:move<l are
`generally of lower pharmacological ac1ivi1y. At the other
`ex treme. there nrc numerous mu1crials and formulaiion:;,
`where even minute quantities can have pharmac.:nlngical
`activity. The equipment and the procedures utili1.ed to clean
`the equipment might he identical, yet the production of
`material with known adverse effects may require that
`tighter limits be achieved. C leaning, sampling an<l analytical
`methods may need to be relined to a high degree of
`sensitivity to ensure that the c;4uipment has been properly
`cleaned.
`Many firms have used dedicated faci lities and/or equip(cid:173)
`men1. or conducted cleaning veritic:ition in order 10 circum(cid:173)
`vent some of the inherent difficulties ~n proces~ing high risk
`drugs. The difficulties of reproducibly demonstrating success(cid:173)
`fu l cleaning may make it operationally easier to dedicate the
`equipment and/or fac ility lo the produciicm of a single
`product rather than attempt to clean to the necessary level of
`cleanliness.
`The route of ::idministnuion of a product may :.iffeel the
`level at which the produci is found to be allergenic, toxic or
`polent Generally speaking_ injectable products. intra-ocular
`formulations, and some inhalants which provide direct
`access to lhe systemic circulation systems of paiients are a
`much greaterconcem in terms of cross-contamination.
`Highly Characterized-Poorly Characterized: The in(cid:173)
`troduction of pre-approval inspection requirements for NDA
`and ANDA approval has resulted in greater scrutiny being
`placed on documentation describing the development of the
`fonnulatiou. Regulatory agency expectations for cleaning
`validation are formidable within I.he confines of marketed
`product manufacturing (typically highly characterized prod-
`
`4
`
`PDA Journal of Pharmaceutical Science & Technology
`
`FRESENIUS EXHIBIT 1075
`Page 7 of 26
`
`

`

`ucts) bul placing the same requirements upon developmenLal
`drugs (typically poorly characterized) makes cleaning valida(cid:173)
`tion even more djfficult. During producl development. the
`formulation, process and equipment to be utilized in pr<l<luc(cid:173)
`Lion are evaluated in order to ensure a consiste nt process for
`commercial scale manufacture. Be fore the final equipment
`selec tions are made. bowe ver, a wide variety of equipment
`combinations may be tried , resulting in a vast array o f
`cleaning combinations.
`In addition to the myriad of cleaning processes whic h
`must be c val uated, there are additional difliculties: appropri(cid:173)
`ate limits for active age nts musr be selected; this limil might
`be based upo n a not yet identitied therapeutic dose. Alterna(cid:173)
`tive ly, using the lo west dose. or considering using the worst
`ca5e mig ht save time o n scale up. provided that
`the
`appropriate a ~says for these leve ls have been developed and
`validated . Other difliculLies include the requirement Lhat
`nppro priate analyLical methods must be developed for all
`fom1ula1ion~. Clearl y. while the validatio n of cleaning is a
`difficult task in a production facility, the unknowns inhere nt
`in clinical prodm:t manufacturing. where the product is.
`poo rl y charac terized. make the task e ven more challenging.
`Other areas where products may be poorly c haracterized
`include bioprm:esscs and sy ntheses where vast numbers of
`related molecules may be formed, in addition to the primary
`product. While there are generally requirements that all of
`these potential "contaminants " developed during the manu(cid:173)
`fac turing process be identified, the!se materials may not be
`characterized well enough lo have specific. low-level assays
`developed for each o f them. The establishment of appropri(cid:173)
`ate limits for each of these substanct:s is equally complicated
`and may not be feasible.
`Non-Sterile-Sterile: The production of sterile formula(cid:173)
`tions increases the extent o f cleaning operations relative to
`non-ste rile produc ts. Ste rile manufacturing fac ilities must
`control microbial. e ndotoxin and particulate le vels to a
`degree not common with no n-ste rile products. Nol only are
`the number of concerns increased but the nature of these
`contaminants makes the succe ssful removal o f these item!(cid:173)
`(and their validation) more difficult. Sampling method s for
`these contaminants are mo re subjective. the analytical
`method s more de manding, ond the validatio n generally more
`difficult to complete.
`Concerns relative to microbi.il and partic ulate control are
`lessened in the production o f nonsterile product$ but are still
`impo,tanl. Practices whicb minimize the pote ntial for con(cid:173)
`taminatio n by .. objectionable o rg.inism~ ·· are common in the
`manufaclllrc o f non-sterile formul atio ns such as o ral liquids
`and topical products .
`
`2.5 Formulation Att