(cid:9)(cid:4)(cid:1)(cid:10)(cid:7)(cid:16) (cid:3)(cid:13)(cid:16)(cid:6)(cid:5)(cid:2)(cid:12)(cid:11)(cid:14)(cid:16)
`
`(cid:5)(cid:6)(cid:7) (cid:8)(cid:16) (cid:15)(cid:16) (cid:1)(cid:2)(cid:3)(cid:4)(cid:7)
`
`(cid:31)
`
`(cid:8) (cid:32)
`
`(cid:5)(cid:6) (cid:30)(cid:34)(cid:38) (cid:7) (cid:1)(cid:35)(cid:15)(cid:36)(cid:22)(cid:19)(cid:38) (cid:1)(cid:2) (cid:18)(cid:21)(cid:38)
`(cid:13)(cid:16)(cid:27)(cid:17)(cid:37)(cid:38)(cid:28)(cid:11)(cid:9)(cid:20)(cid:38)(cid:24)(cid:23)(cid:25)(cid:2)(cid:38)(cid:3)(cid:33)(cid:4)(cid:12)(cid:38) (cid:26)(cid:14)(cid:10)(cid:29)(cid:38)
`
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`(cid:3)(cid:16)(cid:10)(cid:13)(cid:21)(cid:20)(cid:23)(cid:22)(cid:17)(cid:23)(cid:1)(cid:16)(cid:14)(cid:20)(cid:10)(cid:6)(cid:7)(cid:19)(cid:23)(cid:8)(cid:16)(cid:19)(cid:23)
`(cid:2)(cid:12)(cid:7)(cid:5)(cid:13)(cid:11)(cid:15)(cid:9)(cid:23)(cid:4)(cid:5)(cid:12)(cid:10)(cid:6)(cid:5)(cid:22)(cid:10)(cid:18)(cid:14)(cid:23)
`
`(cid:13)(cid:16)(cid:15)(cid:18)(cid:21)(cid:19)(cid:15)(cid:14)(cid:20)(cid:29)(cid:12)(cid:16)(cid:23)(cid:22)(cid:24)(cid:26)(cid:29)(cid:10)(cid:22)(cid:1)(cid:29)(cid:3)(cid:5)(cid:29)
`(cid:11)(cid:9)(cid:7)(cid:29)
`
`(cid:8)(cid:5)(cid:2)(cid:9)(cid:7)(cid:3)(cid:4)(cid:10)(cid:13)(cid:12)(cid:13)(cid:1)(cid:13)(cid:5)(cid:4)(cid:2)(cid:3)(cid:1)(cid:6)(cid:6)(cid:11)(cid:13)
`
`(cid:5)(cid:4)(cid:6)(cid:3)(cid:17)(cid:9)(cid:10)(cid:8)(cid:14)(cid:7)(cid:15)(cid:1)(cid:11)(cid:2)(cid:17)(cid:13)(cid:17)(cid:16)(cid:17) (cid:12)(cid:17)
`(cid:23)(cid:19)(cid:27)(cid:4)(cid:27)(cid:16)(cid:18)(cid:20)(cid:17)(cid:11)(cid:3) (cid:24)(cid:7) (cid:22)(cid:21)(cid:25)(cid:8)(cid:9) (cid:10)(cid:26)(cid:27) (cid:5)(cid:6)(cid:27) (cid:1)(cid:2)(cid:27) (cid:14)(cid:15)(cid:12)(cid:13)(cid:27)
`
`(cid:8)(cid:28)(cid:17)(cid:28)(cid:25)(cid:27)(cid:29)(cid:2)(cid:6)(cid:6)(cid:4)(cid:29)
`
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`

`

`PDA Journal of
`Pharmaceutical Science and Technology
`
`iupplement, November—December 1998
`EDITOR: Joseph B. Schwartz
`
`
`Volume 52
`
`‘8 OFFICERS AND DIRECTORS
`
`Joyce H. Aydletl
`mirman:
`hairmtm-Eleet: Robert B. Myers
`ecretary:
`Floyd Benjamin
`'masurer:
`R. Michael Enzinger. PhD.
`mmediate Past
`
`Chairman:
`
`Raymond Shaw. Jr.. PhD.
`
`antes E. Akers. Ph.D.
`ennie Allewell
`
`loyce L. DeYoung. l’h.|).
`itephanie R. Gray
`Frederick A. Gustat‘son
`llat‘tin W. Henley
`‘Henry K, Kwan. PhD.
`.‘likki V. Mehringer
`Robert F. Motrissey. PhD.
`Terry E. Manson
`Toshiaki Nishihalu. PhD.
`Glenn E. Wright
`
`President: Edmund M. Fry
`
`PDA Joumal of Pharmaceutical Science & Technology (ISSN
`|076—397X) is published bimonthly hy the FDA. Inc.. 7500 Old
`Georgetown Rd.. Suite 620. Bethesda. MD 20814.
`Subsi'riplinm'iMembership dues in the FDA. luc.. include an
`annual subscription to the Journal for each member and corporate
`representative. For an application form and information regarding
`membership. address the Association.
`lndustriaL university and
`public libraries and government agencies may subscribe at the rate
`of $|3500 per year. Back issues of the journal are available from
`the Association for $50.00 plus $l.50 postage and handling per in
`stock reprint: or $65.00 plus $3.00 postage and handling for
`photocopies of reprints not in stock.
`Claimr—lssues lost
`in transit will not be replaced if claim is
`received more than 90 days from date of issue or if loss was due to
`failure to give notice of change of address. The Association cannot
`accept responsibility for delivery outside the United States when
`shipment has been made by first‘elass mail.
`Periodicals postage paid at Bethesda. Maryland and additional
`mailing offices, Postmaster: send address changes to the PDA
`Journal of Pharmaceutical Science & Technology. 7500 Old
`Georgetown Rd.. Suite 620. Bethesda. MD 208M.
`Printed in the U.S.A,
`
`Formerly the
`“Journal of Parenteral Science and Technology"
`
`Copyright—FDA. Inc. 1998
`ISSN l076-397X
`
` 3
`3
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`1. Introduction
`
`/.I Background
`
`In recent years. cleaning has achieved a position of
`increasing importance in the pharmaceutical industry. The
`current good manufacturing practices (CGMI’) regulations
`recognize that cleaning is a critical issue to ensure product
`quality. Vinually every aspect of manufacturing involves
`cleaning. from the initial stages of bulk production to the
`final dosage form.
`The CGMPs in the United States. Europe and other parts
`ofthe world have provided the pharmaceutical industry with
`general guidance for cleaning requirements. For example. in
`the U.S.. section ll I.67 of part 2| of the Code of Federal
`Regulations (CFR) states that “Equipment and utensils shall
`be cleaned. maintained. and sanitized at appropriate inter-
`vals to prevent malfunctions or contamination that would
`alter the safety. identity. strength. quality. or purity of the
`drug product beyond the ofiicial or other established require—
`ments.“ Section 2| 1.182 of pan 2i of the CFR identifies that
`cleaning procedures must be documented appropriately. and
`that a cleaning and use log should be established. In addition
`to CGMPs. various inspectional guideline documents pub-
`lished by the FDA contain expectations regarding cleaning
`in the phamraceutical industry. Cleaning is also addressed in
`the PIC recommendations on cleaning validation and in the
`SFSTP Commission report "Validation des procédés de
`nettoyage."
`It has always been the responsibility of the regulated
`industry and the regulatory agencies to interpret the CGMPs
`and to create programs and policies which establish the
`general requirements as specific practices. Recognizing the
`importance of the relationship between cleaning and product
`quality. regulatory agencies are demanding greater evidence
`of cleaning effectiveness through validation or verification.
`
`1.2 Purpose
`
`The purpose of this publication is to identify and discuss
`the many factors involved in the design. validation. imple-
`mentation and control of cleaning programs for the pharma-
`ceutical industry.
`The document does not attempt to interpret CGMPs but
`provides guidance for establishing a cleaning validation
`program. It identifies the many factors to be considered for
`all segments of the pharmaceutical industry. It also identifies
`specific points to be considered by dOsagc l'onn manufactur-
`ers. manufacturers of clinical trial materials (CTMs) and
`manufacturers of bulk pharmaceutical chemicals and bid
`chemicals. The report covers the different approaches which
`may be appropriate for the different stages of product
`development from the early research stages to the commer—
`cially marketed product.
`
`1.3 Scope
`
`This paper applies to biopharmaceutical. bulk pharmaceu-
`tical and finished dosage form operations: liquid. dry. solid
`and semi-solid dosage fomis are covered in both sterile and
`non-sterile presentations. Both clinical and marketed prod—
`uct cleaning validation programs are identified.
`
`—
`Vol. 52. No. 6/ November—December 1998. Supplement
`
`The manufacture of modem pharmaceuticals is a complex
`process involving highly technical personnel. complex equip-
`ment. sophisticated facilities and complicated processes.
`Individuals responsible for all aspects of the production.
`approval and validation of products. such as quality control.
`quality assurance. engineering. validation. production. re-
`search and development. contractors and vendors and regu-
`latory affairs personnel may use this document as a resource
`for establishing or reviewing the cleaning programs within
`their facilities.
`
`The validation programs described herein assume that an
`overall validation program with appropriate controls is
`already in place for the facility. utilities. equipment and
`processes. The cleaning of the environment is not specifi-
`cally covered. however many of the same concerns that are
`considered for
`the cleaning of process equipment also
`impact the cleaning of the environment. The monitoring of
`microbiological and endotoxin contamination and steps for
`their elimination are mentioned in several sections and
`should be pan of the cleaning validation program. However
`this document is not intended to be a comprehensive treatise
`on microbiological control. or endotoxin limitation. Other
`documents have addressed microbiological programs and
`methods for the environmental
`tnonitoring which can be
`applied to cleaning.
`
`[.4 Report Organization
`
`Each of the major topics of this document starts with a
`general section which applies to all segments of the pharma—
`ceutical
`industry. Points to be considered for specific
`industry segments such as biopharmaceuticals. bulk pharma-
`ceutical chemicals. clinical products may vary. depending on
`the specilic product type. A glossary is provided at the end of
`the report.
`Finished Pharmaceuticals: Finished pharmaceuticals
`represent solid fomiulations. semi-solid fonnulations. liquid
`and aerosol fonnulations with various routes of administra-
`tion. Over-the-counter and prescription pharmaceuticals for
`both human and veterinary use are included in this category.
`The common characteristics shared by finished pharmaceu-
`ticals are their manufacture by combining raw materials and
`active ingredients to create the final dosage fon'n.
`Pharmaceutical manufacturers often make a large number
`of product
`types in one facility; often there are several
`different strengths prepared of the same product. The
`cleaning problems include the large number of processes
`and product types manufactured within one facility. The
`number of cleaning methods. assays and types of equipment
`to he tested are often staggering. This is complicated by the
`issues surrounding the use of nonadedicated equipment.
`Thus.
`the establishment of a cleaning validation policy
`which is applicable to all products is often very difficult.
`Biopharmaceuticals: Bioprocess manufacturing. starting
`with microbial. animal or insect cells. or DNA derived host
`cells or other cells modified to make a specialized product.
`can be performed in several ways. Indeed. new methods for
`bioproccssing are constantly being developed. The most
`common method is through large scale fermentation (such as
`bacterial cell culture or mammalian cell culture) followed by
`highly specific ptrrilication steps. Other methods include the
`
`1
`
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`development of an antibody in host animals (such as
`ascitcs). cloning ofcclls or tissues. or transgenic generation
`of cellular components. namely. proteins. Many in the
`biopharmaceutical industry consider the stages of fermenta-
`tion to be similar to other phamiaccutical industry processes.
`For example. the initial stages of the large scale fermentation
`have a striking similarity to bulk pharmaceutical chemical
`production. Later. harvest and purification steps lind more in
`common with pharmaceutical processes. It
`is important to
`remember however. that other bioprocessing methods used
`in the biophamiaceutical industry ditl‘er greatly from tradi-
`tional pharmaceutical processes.
`Cleaning for biopharmaccuticals presents special con-
`cerns due to the large number of impurities such as cellular
`debris. waste products of cellular metabolism. media constitu—
`ents and buffer salts generated or added during manufacture
`which tnust be eliminated from the equipment. In the case of
`mammalian cell cultures. due to the nature of the source
`
`material. microbial contamination is of great concern. Iden~
`tification of the residues is often quite difficult because they
`may vary from batch to batch. The large variety of protein—
`aeeous materials present in the residue make differentiation
`of the contaminants from one another a challenge.
`Due to the nature of the biopharmaceutical production.
`multi-product
`facilities represent an area of regulatory
`concern. In order to control the production within a multi—
`product
`facility,
`it
`is necessary to ensure that
`special
`precautions are taken which preclude product to product
`carryover. Cleaning is an integral part of the strategies
`designed to ensure that there is no cross-contamination in
`these facilities. The terms cleaning and cleaning validation
`in multi—product facilities often include the facility itself.
`and therefore emphasis is placed on changeover validation.
`Cleaning for biotechnology products has been described
`in “Cleaning and Cleaning Validation: A Biotechnology
`Perspective." FDA. Bethesda. MD. I996.
`Bulk Pharmaceutical Chemicals: Bulk pharmaceutical
`chemical processes are typically biochemical or chemical
`syntheses carried out on a relatively large scale. The bulk
`pharmaceutical chemicals may be provided to pharmaceuti-
`cal manufacturers as active or inactive ingredients for
`eventual inclusion in a finished dosage form pharmaceutical.
`The bulk pharmaceutical chemical manufacturing process
`for active ingredients is typically enclosed in large tanks
`with direct transfer of materials from tank to tank after a
`
`particular chemical reaction has occurred. The initial stages
`of the bulk pharmaceutical chemical drug development are
`reminiscent of the chemical industry. At some point during
`the process.
`the manufacturer must.
`in accordance with
`CGMPs have identified a process step after which the
`process will strictly comply with the CGMl’s.
`Bulk pharmaceutical chemical production. due in large
`part to the scale of manufacture and its use of strong reagents
`and chemicals. is often performed in closed systems which
`may use automated or semi—automated Ciean—ln—Place tech:
`nologies. The difficulties in the validation of cleaning
`processes often stem from the inaccessibility of many areas
`to direct sampling. The contaminants to be removed include
`precursor molecules. intermediates. byproducts. impurities
`
`or other physical forms such as isomers or polymorphs.
`which exist from early stages in the process.
`Clinical Products: In this document. clinical products
`identify those products which are currently registered as an
`investigational status due to their involvement in clinical
`trials. The Clinical Products category identifies the special
`care that must be taken with these products which may not
`he as fully characterized as marketed materials. Both
`pharmaceutical and biopharmaceutical drug products and
`drug substances are included in this category.
`Cleaning in a clinical manufacturing setting is often
`complicated by the use of small scale manually cleaned
`equipment. Clinical manufacturing may represent a period
`during which process improvements are made. and therefore
`the same equipment may not be used each time the product
`is made. Also. since clinical products are often manufactured
`in development facilities. the subsequent products may not
`be known. The next materials manufactured may be research
`products. development products. placebo products or other
`clinical products. Our
`intent
`is
`to address cleaning of
`equipment in Phase III and later. but it may be appropriate to
`consider the same approaches in earlier phases as well.
`Typically. assays for
`low level detection of the active
`ingredient and its excipients will need to be developed and
`validated. Verification of cleaning effectiveness. as opposed
`to traditional validation. is prevalent since infonnation on
`the material is not readily available.
`
`2. The Cleaning Continuum
`
`The subject of cleaning validation is one which the
`pharmaceutical and biotechnology industries have struggled
`with. Progress to a consensus in approach in the industry has
`been slowed by the number and complexity of issues
`surrounding the cleaning process and the variety of facili-
`ties. products and equipment in use. The development of a
`universal approach to cleaning validation is unlikely given
`these variations.
`
`2.! Use nfrhe C(curring Crmtimtmn
`
`The intent of this section is to describe the limits of the
`
`cleaning continuum (see Table I ). These limits represent the
`extremes in the range of operating differences found within
`the industry which preclude a uniform approach. At each end
`of the continuum.
`the cleaning validation requisites are
`either simple or complex. Recognition that there are many of
`these coupled limits. and that each cleaning process has a
`unique place within each level of the continuum. explains
`why specific industry-wide approaches have been so did":-
`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 which are
`critical
`factors for individual products.
`thereby enabling
`them to set priorities. develop grouping philosophies and
`establish the “scientific rationale“ which will govern the
`cleaning program. The continuum will assist in determining
`which processes. equipment and products represent
`the
`greatest concerns and may help to establish the criticality of
`cleaning limits and methods. The continuum should be used
`
`& Technology
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`during the initial phases of defining a cleaning validation
`program or during new product development.
`The cleaning continuum includes: cleaning program crite-
`ria. equipment characteristics, quality attributes of equip-
`ment design, fonrtulationfproduct attributes. analytical meth~
`odology and manufacturing/process attributes. All of the
`factors in the continuum directly affect the ability to clean:
`however. their relative importance and criticality may be
`different from one company to another.
`
`2.2 Cleaning Program Criteria
`
`is
`it
`When establishing a cleaning validation program.
`important to first characterize the types of cleaning that are
`used in the facility. The cleaning methods that are used in a
`facility can reveal important factors with regard to process
`control. process reproducibility. the best ways in which to
`challenge the process.
`the best ways in which to collect
`samples and the best ways in which to monitor cleaning
`effectiveness du ring routine cleaning.
`Automated Cleaning—Manual Cleaning: Automated
`cleaning will usually provide reproducible results. Process
`control is inherent in automated systems and process moni—
`toring is frequently integral with the control system. Auto—
`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—
`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
`cleaning 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 operator experience and/or
`cleaning methodology) for validation purposes. With manual
`cleaning. concern must also be given to the ruggedness of
`the method. Successful reproducibility is a function of strict
`adherence to written procedures.
`Clean-[n-Place (cmt—Clean-Out-of-Place (COP): The
`cleaning of large pieces of equipment may be performed in
`
`TABLE I
`The Cleaning Continuum
`
`
`Manual ....................................................... Automated Cleaning
`Clean—outeof-Place (COP) ......................... Clean~in—Placc (CIP)
`
`Dedicated Equipment
`.....
`NoneDedicated Equipment
`Product Contact Surfaces
`. Non—Product Contact Surfaces
`Non~Critical Site
`..................... Critical Site
`Minor Equipment
`Major Equipment
`
`Low Risk Drugs ..
`High Risk Drugs
`
`Highly Characterize
`Poorly Characterized
`
`
`Sterile ...........................
`................... Non-Sterile
`
`
`................. Liquid Formulations
`Solid Formulations
`...................... Insoluble
`Soluble
`
`Multiple Product Facility
`Single Product Facility
`Non-Campaigned Production
`Campaigned Production
`
`
`Simple Equipment Train
`Complex Equipment Train
`
`the equipment‘s permanent location. generally in a configu-
`ration very similar to that
`in which it
`is utilized for
`production. This procedure is widely known as Clean-1n-
`Place (CIP). Smaller equipment items are frequently trans-
`ported to a designated cleaning or wash area where the
`cleaning procedure is performed. This practice is known as
`Clean-Out-of-Plaee (COP). but the term is not as prevalent
`as its counterpart.
`The additional activities involved With transport of equip-
`ment to and from the wash room. component identification.
`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 CIP activity. The need for manual manipula-
`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 cleaning 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 CIP and COP
`significantly. These systems are considered to be highly
`reproducible in their cleaning performance and are gaining
`wide acceptance.
`
`2.3 Equipment Chm‘ncteHades/Materials quonstrttctinn.
`
`Equipment usage during production is another important
`aspect
`to consider in establishing a cleaning validation
`program. it 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 during
`product development, are often driven by equipment func-
`tionality and the requirements of the process. With the
`current emphasis on cleaning validation. it makes sense that
`"clcanability” be a key criterion in the design ofequipment.
`Dedicated—Non-Dedicated Manufacturing Equip-
`ment: Dedicated equipment is used solely for the production
`of a single product or product line. Concerns over cross—
`contamination with other products are markedly reduced.
`Dedicated 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-
`comes lhc main objective in the cleaning validation effort.
`Clearly. cleaning non—dedicated equipment represents a
`more significant obstacle to overcome.
`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 facility.
`inherently.
`the design of CIP
`systems should preclude cross-contamination through appro—
`priate valving and hack-flow prevention. Care should be
`taken with shared devices which apply cleaning agents. such
`
`Vol. 52. No. 6 / November—December 1998. Supplement
`
`3
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`themselves, may
`as spray balls or spray nozzles which.
`require cleaning. Certainly any recirculation within the ClP
`system should be conligurcd carefully during system design
`and monitored closely during routine operation.
`COP equipment. such as an ultrasonic sink. may also be
`used for multiple equipment loads. With cleaning apparatus
`such as the sink. the removal of potential contaminants from
`the sink. itselfis aconeern. Sinks and washers frequently use
`recirculation systems to economically remove residuals
`from surfaces without undue waste. The cleanliness of the
`
`recirculated materials should be evaluated during cleaning
`validation to ensure that contaminants are not being rcdepos—
`itcd on the equipment to be cleaned.
`Non-Product Contact—Product Contact Surfaces: Tra-
`
`ditionally. the validation ofcleaning has focused on product
`contact surfaces. Programs for the elimination of cross-
`contamination must address non-product contact surfaces if
`they are to be truly effective. In practice. cleaning validation
`requirements may change with nonproduct contact surfaces
`in accordance with the less critical nature of these areas.
`
`When establishing the requirements for non-product contact
`surfaces. it is important to review the possible interactions of
`that area with the process.
`Non-Critical Site—Critical Site: Critical sites are those
`locations in which a contaminant is in danger of affecting a
`single dose with a high level of contatnination. Critical sites
`often require special cleaning emphasis. It may be appropri-
`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 to provide for reproducible cleaning of critical
`sites.
`
`Minor Equipment—Major Equipment: The distinction
`between “major" and "minor" equipment is not a definitive
`one. The CGMPs make mention (2| HOS) of "major"
`equipment. but are silent on the subject of “minor“ equip-
`ment except with regard to items described as utensils
`(2| 1.67). Despite this failure within the CGMPs.
`it
`is
`necessary to identify those pieces of equipment (major)
`which are central to the production process and those pieces
`of equipment (minor) which perform a secondary role.
`Typically the cleaning of “major" equipment will be the
`subject of individual. highly specific SOPs. In contrast.
`“minor" equipment and "utensils" are often cleaned using
`broadly defined procedures which describe the methods to
`be used in general terms.
`Materials of Construction: The materials of construc-
`
`tion of the equipment should be considered carefully when
`establishing a cleaning validation program. The attributes of
`the surface to be cleaned will define the residue to surface
`
`to
`identify possible contaminants and point
`interactions.
`areas which may not be readily cleaned or accurately
`sampled. The CGM Ps (2| L65) state that.
`
`“at Equipment shall be constructed so that surfaces which
`contact components.
`in-pmccss materials. 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
`established requirements.
`
`“b) Any substances required for operation. such as lubri-
`cams or coolants. shall not come into contact with
`components. drug product containers. closures in-
`proeess materials. or drug products so as to alter the
`safety. identity strength. quality or purity of the drug
`product beyond ofiicial or other established require-
`ments.“
`
`Equipment should not be reactive. additive or adsorptive
`with the process materials which contact them. The use of
`porous surfaces for multiple products should be avoided
`(filters. filter bags. fluid bed drier bags. membrane filters.
`ultra filters). Any surfaces which have these properties will
`require review during cleaning validation evaluations to
`ensure adequate product removal and minimize the potential
`for cross-contamination. The interaction of cleaning agents
`with surfaces that are likely to display these properties (e.g..
`seals. gaskets. valves) should be assessed.
`
`2.4 Pmdm'!Attributes
`
`The cleaning of equipment is closely tied to the type of
`materials being removed from the surface. The product
`formulation is often the key in establishing appropriate
`cleaning acceptance criteria. challenge methods and sam-
`pling techniques.
`Low Risk—High Risk Drugs: The residual limits uti-
`lized for cleaning validation are often closely related to the
`allergenicity/toxicity/potency of the materials in question.
`The limits are eased when the materials being removed are
`generally of lower pharmacological activity. At
`the other
`extreme.
`there are numerous materials and fonnulations.
`
`where even minute quantities can have pharmacological
`activity. The equipment and the procedures utilized to clean
`the equipment might be identical. yet
`the production of
`materials with known adverse effects may require that
`tighter limits be achieved. Cleaning. sampling and analytical
`methods may need to be refined to a high degree of
`sensitivity to ensure that the equipment has been properly
`cleaned.
`
`Many firms have used dedicated facilities and/or equip-
`ment. or conducted cleaning verification in order to circum~
`vent some of the inherent difficulties in processing high risk
`drugs. The difficulties of reproducibly demonstrating success-
`ful cleaning may make it operationally easier to dedicate the
`equipment and/or facility to the production of a single
`product rather than attempt to clean to the necessary level of
`cleanliness.
`
`The route of administration of a product may affect the
`level at which the product is found to be allergenic. toxic or
`potent. Generally speaking. injectahle products. intra-ocular
`formulations. and some inhalants which provide direct
`access to the systemic circulation systems of patients are a
`much greater concern in terms of cross—contamination.
`Highly Characterized—Poorly Characterized: The in-
`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
`formulation. Regulatory agency expectations for cleaning
`validation are fortnidable within the confines of marketed
`
`product manufacturing (typically highly characterized prod-
`
`1
`
`& Technology
`—— —
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1075, p. 7 of 26
`PFIZER, INC. v. NOVO NORDISK AIS - IPR2020-01252, Ex. 1075, p. 7 of 26
`
`

`

`ucts) but placing the same requirements upon developmental
`drugs (typically poorly characterized) makes cleaning valida-
`tion even more difficult. During product development. the
`formulation, process and equipment to be utilized in produc-
`tion are evaluated in order to ensure a consistent process for
`commercial scale manufacture. Before the final equipment
`selections are made. however. a wide variety of equipment
`combinations may be tried. resulting in a vast array of
`cleaning combinations.
`In addition to the myriad of cleaning processes which
`must be evaluated. there are additional difficulties: appropri-
`ate limits for active agents must be selected: this limit might
`be based upon a not yet identified therapeutic dose. Altenta-
`tivcly. using the lowest dose. or considering using the worst
`case might save time on scale up. provided that
`the
`appropriate assays for these levels have been developed and
`validated. Other difficulties include the requirement
`that
`appropriate analytical methods must be developed for all
`formulations. Clearly. while the validation of cleaning is a
`difficult task in a production facility. the unknowns inherent
`in clinical product manufacturing. where the product
`is
`poorly characteriaed. make the task even more challenging.
`Other areas where products may be poorly characterized
`include bioprocesscs and syntheses 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-
`facturing process be identified. these materials may not be
`characterized well enough to have specific, low-level assays
`developed for each of them. The establishment of appropri—
`ate limits for each of these substances is equally complicated
`and may not be feasible.
`Non-Sterile—Sterile: The production of sterile formula»
`tions increases the extent of cleaning operations relative to
`non—sterile products. Sterile manufacturing facilities must
`control microbial. cndotoxin and particulate levels to a
`degree not common with non-sterile products. Not only are
`the number of concerns increased but the nature of these
`contaminants makes the successful removal of these items
`(and their validation) more difficult. Sampling methods for
`these contaminants are more subjective.
`the analytical
`methods more demanding. and the validation generally more
`diflicult to complete.
`Concerns relative