`P228
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`EL
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`m,
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`Technical Report No.
`Pmms [u Liunsuier rim
`Cleaning Validation
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`7L)
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`FDA Junmal of
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`Pharmaceutical
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`Science and
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`Technology
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`PDA
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`W
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`1998
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`Supplement
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`Volume 52
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`Number6
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`MYLAN INST. EXHIBIT 1075 PAGE 1
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`Points to Consider for
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`Cleaning Validation
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`Technical Report No. 29
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`PDA
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`August 1998
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`MYLAN INST. EXHIBIT 1075 PAGE 2
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`MYLAN INST. EXHIBIT 1075 PAGE 2
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`imes E. Akcrs. PILD.
`
`
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`mnie Allen/ell
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`layce L. Dchung. PILI).
`
`
`
`
`Stephanie R. Gray
`
`
`
`Frederick A, Gustat'son
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`
`llartin W. Ilenley
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`
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`(Henry K. Kwan. PhD.
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`Nikki V. Mehringer
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`Robert F. Morrissey. PhD.
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`lerry E. Manson
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`loshiaki Nishihata. PILD.
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`Glenn E. Wright
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`President: Edmund M. Fry
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`PDA Journal of
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`Pharmaceutical Science and Technology
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`Supplement. November-December 1998
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`EDITOR:
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`Joseph B. Schwartz.
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`Volume 52
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`ti OFFICERS AND DIRECTORS
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`Floyd Benjamin
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`CopyrightiPDA. Inc. 1998
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`MYLAN INST. EXHIBIT 1075 PAGE 3
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`MYLAN INST. EXHIBIT 1075 PAGE 3
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`1. Introduction
`
`I. I Background
`
`In recent years. cleaning has achieved a position of
`increasing importance in the phamtaceutical industry. The
`current good manufacturing practices (COMP) regulations
`recognize that cleaning is a critical issue to ensure product
`quality. Virtually every aspect of manufacturing involves
`cleaning. from the initial stages of hulk production to the
`final dosage form.
`The CGMPs in the United States. Europe and other parts
`of the world have provided the pharmaceutical industry with
`general guidance for cleaning requirements. For example. in
`the U.S.. section 21l.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. qttality. or pttrity of the
`drug product beyond the ofiicial or other established require—
`ments." Section 2| l.l82 of pan 2] of the CFR identities 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 pharmaceutical industry. Cleaning is also addressed in
`the PIC recommendations on cleaning validation and in the
`SFSTP Commission report "Validation des procédés de
`nettoyagc."
`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 elTectiveness through validation or verification.
`
`I .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 (‘GMPs but
`provides guidance for establishing a cleaning validation
`program. It identities the many factors to be considered for
`all segments of the pharmaceutical industry. It also identifies
`specilic points to be considered by dosage fonn manufactur-
`ers. manufacturers of clinical
`trial materials (CTMsl and
`manufacturers of bulk pharmaceutical chemicals and bio—
`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.
`
`I .3 5(7),)?
`
`This paper applies to hiopharmaceutical. bulk pharmaceu—
`tical and finished dosage form operations: liquid. dry. solid
`and semi-solid dosage forms are covered in both sterile and
`non-sterile presentations. Both clinical and marketed prod-
`uct cleaning validation programs are identified.
`
`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 specili-
`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 part of the cleaning validation program. However
`this document is not intended to be a comprehensive treatise
`on microbiological control. or endotosin limitation. Other
`documents have addressed microbiological programs and
`methods for the environmental monitoring 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 specilic
`industry segments such as hiopharmaceuticals. 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 phannaceuticals
`represent solid fomiulations. semi-solid fonnulations. liquid
`and aerosol l‘onnulations with various routes of administra-
`
`tion. Over-the-counter and prescription phannaceuticals 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 form.
`Pharmaceutical manufacturers often make a large nutrtber
`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 ot'cleaning methods. assays and types of equipment
`to be tested are often staggering. This is complicated by the
`issues surrounding the use of non-dedicated equipment.
`Thus.
`the establishment of a cleaning validation policy
`which is applicable to all products is often very difficult.
`Biopharmaceutieals: 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
`bioprocessing are constantly being developed. The most
`common method is through large scale fennentation (such as
`bacterial cell culture or mammalian cell culture) followed by
`
`highly specific purification steps. Other methods include the
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`1m
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`MYLAN INST. EXHIBIT 1075 PAGE 4
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`development of an antibody in host animals tsuch as
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`ascitest. cloning of cells or tissues. or transgenic generation
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`of cellular components. namely. proteins. Many in the
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`hiopharmaceutical industry consider the stages of fermenta-
`tion to be similar to other pharmaceutical industry processes.
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`For example. the initial stages of the large scale fermentation
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`have a striking similarity to bulk pharmaceutical chemical
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`production Later. harvest and purification steps find more in
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`common with pharmaceutical processes. It
`is important to
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`remember however. that other bioprocessing methods used
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`in the biophannaccutical industry differ greatly from tradi-
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`tional pharmaceutical processes.
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`Cleaning for biopharmaceuticals presents special con-
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`cerns due to the large number of impurities such as cellular
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`debris. waste products ofccllular metabolism. media constitu-
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`ents and buffer salts generated or added during manufacture
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`which must be eliminated from the equipment. In the case of
`mammalian cell cultures. due to the nature of the source
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`material. microbial contamination is of great concern. Iden-
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`tification of the residues is often quite difficult because they
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`may vary from batch to batch. The large variety of protein-
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`aceous materials present in the residue make differentiation
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`of the contaminants from one another a challenge.
`Due to the nature of the hiopharmaceutical production.
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`multi-product
`facilities represent an area of regulatory
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`concern. In order to control the production within a multi-
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`facility.
`is necessary to ensure that special
`product
`it
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`precautions are taken which preclude product to product
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`carryover. Cleaning is an integral part of the strategies
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`designed to ensure that there is no cross-contamination in
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`these facilities. The terms cleaning and cleaning validation
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`in mold-product facilities often include the facility itself.
`and therefore emphasis is placed on changeover validation.
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`Cleaning for biotechnology products has been described
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`in “Cleaning and Cleaning Validation: A Biotechnology
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`Perspective." FDA. Bethesda. MD. l996.
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`Bulk Pharmaceutical Chemicals: Bulk pharmaceutical
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`chemical processes are typically biochemical or chemical
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`syntheses carried out on a relatively large scale. The bulk
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`pharmaceutical chemicals may be provided to pharmaceuti-
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`cal manufacturers as active or
`inactive ingredients for
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`eventual inclusion in a finished dosage fomt pharmaceutical.
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`The bulk phannaceutical chemical manufacturing process
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`for active ingredients is typically enclosed in large tanks
`with direct transfer of materials from tank to tank after a
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`particular chemical reaction has occurred. The initial stages
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`of the bulk pharmaceutical chemical drug development are
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`reminiscent of the chemical industry. At some point during
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`the process.
`the manufacturer must.
`in accordance with
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`CGMPs have identified a process step after which the
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`process will strictly comply with the CGMPs.
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`Bulk pharmaceutical chemical production. due in large
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`part to the scale of manufacture and its use of strong reagents
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`and chemicals. is often performed in closed systems which
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`may use automated or semi-automated Clean-ln-Place tech-
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`nologies. The difficulties in the validation of cleaning
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`processes often stem from the inaccessibility of many areas
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`to direct sampling. The contaminants to be removed include
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`precursor molecules. intermediates. byproducts. impurities
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`forms such as isomers or polymorphs.
`or other physical
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`which exist from early stages in the process.
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`Clinical Products:
`In this document. clinical products
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`identify those products which are currently registered as an
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`investigationaI status due to their involvement
`in clinical
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`trials. The Clinical Products category identifies the special
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`care that must be taken with these prodUcts which may not
`he as
`fully characterized as marketed materials. Both
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`pharmaceutical and biopharmaceutical drug products and
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`drug substances are included in this category.
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`Cleaning in a clinical manufacturing setting is often
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`complicated by the use of small scale manually cleaned
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`equipment. Clinical manufacturing may represent a period
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`during which process improvements are made. and therefore
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`the same equipment may not be used each time the product
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`is made. Also. since clinical products are often manufactured
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`in development facilities. the subsequent products may not
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`he known. The next materials manufactured may be research
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`products. development products. placebo products or other
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`intent
`clinical products. Our
`is
`to address cleaning of
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`equipment in Phase III and later. but it may be appropriate to
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`consider the same approaches in earlier phases as well.
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`Typically. assays for
`low level detection of the active
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`ingredient and its excipients will need to be developed and
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`validated. Verification of cleaning effectiveness. as opposed
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`to traditional validation. is prevalent since information on
`the material is not readily available.
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`2. The Cleaning Continuum
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`The subject of cleaning validation is one which the
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`pharmaceutical and biotechnology industries have struggled
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`with. Progress to a consensus in approach in the industry has
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`been slowed by the number and complexity of
`issues
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`surrounding the cleaning process and the variety of facili-
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`ties. products and equipment in use. The development of a
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`universal approach to cleaning validation is unlikely given
`these variations.
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`2.! Use rrffflt‘ Chanting ('nrttinumn
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`The intent of this section is to describe the limits of the
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`cleaning continuum (see Table l ). These limits represent the
`extremes in the range of operating differences found within
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`the industry which preclude a uniform approach. At each end
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`of the continuum.
`the cleaning validation requisites are
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`either simple or complex. Recognition that there are many of
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`these coupled limits. and that each cleaning process has a
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`unique place within each level of the continuum. explains
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`why specific industry-wide approaches have been so diffi
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`cult to develop.
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`The cleaning continuum provides some of the primary
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`points to consider in any cleaning validation program. The
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`continuum helps firms to establish the parameters which are
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`critical
`factors for individual products.
`thereby enabling
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`them to set priorities. develop grouping philosophies and
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`establish the “scientific rationale" which will govern the
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`cleaning program. The continuum will assist in determining
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`which processes. equipment and products represent
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`greatest concerns and may help to establish the criticality of
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`cleaning limits and methods. The continuum should be used
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`PDA Journal oi Pharmaceutical Science a Technology
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`———_MYFKNTNBT_EXHI_—.BIT 1075 PAGE 5 _ —
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`MYLAN INST. EXHIBIT 1075 PAGE 5
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`during the initial phases of defining a cleaning validation
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`program or during new product development.
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`The cleaning continuum includes: cleaning program crite~
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`ria, equipment characteristics, quality attributes of equip
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`ment design, formulation/product attributes. analytical meth—
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`odology and manufacturing/process attributes. All of the
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`factors in the continuum directly affect the ability to clean:
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`however. their relative importance and criticality may be
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`different from one company to another.
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`2.2 Cleaning Program Critcrici
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`it
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`When establishing a cleaning validation program.
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`important to first characterize the types of cleaning that are
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`used in the facility. The cleaning methods that are used in a
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`facility can reveal important factors with regard to process
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`control. process reproducibility.
`the best ways in which to
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`challenge the process.
`the best ways in which to collect
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`samples and the best ways in which to monitor cleaning
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`effectiveness during routine cleaning.
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`Automated Cleaning—Manual Cleaning: Automated
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`cleaning will usually provide reproducible results. Process
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`control is inherent in automated systems and process moni-
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`toring is frequently integral with the control system. Auto-
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`mated systems may not adjust
`to present conditions. The
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`validation of an automated system requires that the cycle is
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`proven to he rugged and will provide reproducible results
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`under a given range ofopcrating conditions. Control system
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`validation is a large part of the validation of an automated
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`cleaning system.
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`Manual cleaning is a universal practice within the phanna-
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`ceutical industry. There are many pieces of equipment and
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`portions thereof for which construction and/or configuration
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`make manual cleaning a necessity. The control of manual
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`cleaning is accomplished by operator training. well defined
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`cleaning procedures. visual examination of equipment after
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`use and Prior to the next use. and well-defined change
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`control programs. It may be desirable to identify worst case
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`cleaning situations (in terms of operator experience and/or
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`cleaning methodology) for validation purposes. With manual
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`cleaning. concern must also be given to thc ruggedness of
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`the method Successful reproducibility is a function of strict
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`adherence to written procedures.
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`Clean~ln~Place iCIPl—Clean-Out-of-Plaee (COP): The
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`cleaning of large pieces of equipment may he performed in
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`TABLE I
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`The Cleaning Continuum
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`Manual ....................................................... Automated Cleaning
`Clean-outiofPlace (COP) ......................... Clean-in-Place (CIP)
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`Dedicated Equipment
`...................... Non-Dedicated Equipment
`Product Contact Surfaces ........... Non-Product Contact Surfaces
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`Non-Critical Site ...................................................... Critical Site
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`Minor Equipment
`........................................... Major Equipment
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`Low Risk Drugs
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`High Risk Drugs
`Highly Characterized
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`. Poorly Characterized
`Sterile ........................
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`Solid Formulations ............................
`.. Liquid Formulations
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`Soluble ......................................................................... insoluble
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`Single Product Facility
`Multiple Product Facility
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`Campaigned Production
`Non-Campaigned Production
`Simple Equipment Train .................. Complex Equipment Train
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`the equipment's permanent location. generally in a configu-
`ration very similar
`to that
`in which it
`is utilized for
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`production. This proeedure is widely known as Clean-in-
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`Place (CIP). Smaller equipment items are frequently trans‘
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`ported to a designated cleaning or wash area where the
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`cleaning procedure is performed. This practice is known as
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`CIean-Out-of—Place (COP). but the term is not as prevalent
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`as its counterpart.
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`The additional activities involved with transport of equip-
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`ment to and from the wash room. component identification.
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`the elimination of cross-contamination potential during
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`transfer. and cleaning and storage prior to use make the
`validation of COP procedures somewhat more difficult than
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`the comparable CIP activity. The need for manual manipula-
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`tion is an integral part of many COP procedures and requires
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`detailed procedures and training. The manual manipulation
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`makes COP concerns similar to those of manual cleaning in
`place.
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`The use of automated washing machines to COP smaller
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`items is an important part of many COP systems. The use of
`these systems reduces the differences between CIP and COP
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`significantly. These systems are considered to be highly
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`reproducible in their cleaning performance and are gaining
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`wide acceptance.
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`2.3 Equipment Chrn‘or‘terattan/Materials of Construction
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`Equipment usage during production is another important
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`to consider in establishing a cleaning validation
`aspect
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`program. It is important to understand not only the range of
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`products that are likely to come into contact with the various
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`equipment surfaces. but also the role that
`the equipment
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`plays in the production train. This will help to establish the
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`contamination and cross-contamination potentials of the
`equipment.
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`Equipment design characteristics. as established during
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`product development. are often driven by equipment func-
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`tionality and the requirements of the process. With the
`current emphasis on cleaning validation. it makes sense that
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`“cleattability” be a key criterion in the design of equipment.
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`Dedicated—Non-Dedicated Manufacturing Equip-
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`ment: Dedicated equipment is used solely for the production
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`of a single product or product line. Concerns over cross-
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`contamination with other products are markedly reduced.
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`Dedicated equipment must be clearly identified with the
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`restrictions of use in order to prevent potential errors during
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`cleaning and preparation.
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`Where the same piece of equipment is utilized for a range
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`of product formulations. (i.e.. nondedicated equipment). the
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`prevention of cross-contamination between products be:
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`comes the main objective in the cleaning validation effort.
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`Clearly. cleaning non-dedicated equipment
`represents a
`more significant obstacle to overcome.
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`Dedicated—Non-Dedicated Cleaning Equipment: The
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`issues of dedicated and non-dedicated equipment can also
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`arise when considering the equipment used for cleaning. CIP
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`systems. for example. are frequently used for many different
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`tanks in a single facility.
`inherently.
`the design of CIP
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`systems should preclude cross—contamination through appro-
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`priate valving and back—flow prevention. Care should be
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`taken with shared devices which apply cleaning agents. such
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`Vol. 52. No. 6 1 November—December 1998. Supplement
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`MYLAN INST. EXHIBIT 1075 PAGE 6
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`3
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`MYLAN INST. EXHIBIT 1075 PAGE 6
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`tnay
`themselves.
`as spray balls or spray nozzles which.
`require cleaning. Certainly any recirculation within the CIP
`system should be configured 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. itself is a concern. Sinks and washers frequently use
`recirculation systems to economically remove residuals
`from surfaces without undue waste. The cleanliness of the
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`recirculated materials should be evaluated during cleaning
`validation to ensure that contaminants are not being rcdepos—
`ited on the equipment to be cleaned.
`Non-Product Contact—Product Contact Surfaces: Tra-
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`ditionally. the validation of cleaning 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.
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`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
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`locations in which a contaminant is in danger of affecting a
`single dose with a high level of contamination. 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.
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`Minor Equipment—Major Equipment: The distinction
`between “major"and “minor" equipment is not a definitive
`one. The CGMPs make mention (2! 1.105) of "major“
`equipment. but are silent on the subject of “minor“ equip-
`tnent except with regard to items described as utensils
`(2| L67). 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-
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`tion of the equiptnent should be considered carefully when
`establishing a cleaning validation program. The attributes of
`the surface to be cleaned will define the residue to surface
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`to
`identify possible contaminants and point
`interactions.
`areas which may not be readily cleaned or accurately
`sampled. The CGMPs (2i i .65) state that.
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`"a) Equipment shall be constructed so that surfaces which
`contact components.
`in~pmcess materials. or dmg
`products shall not be reactive. additive or absorptive
`so as to alter the safety. identity. strength. quality or
`pttrity of the drug product beyond official or other
`established requirements.
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`"b) Any substances required for operation. such as lubri-
`cants or coolants. shall not come into contact with
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`components. drug product containers. closures in-
`process materials. or drug products so as to alter the
`safety. identity strength. quality or purity of the drug
`product beyond official or other established require-
`ments."
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`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 tillers). 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.
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`2.4 Product Allribulus
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`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.
`limits uti-
`Low Risk—High Risk Drugs: The residual
`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 fomiulations.
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`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.
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`Many firms have used dedicated facilities and/or equip-
`ment. or conducted cleaning verification in order to circumo
`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.
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`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. injectable 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 prc-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 formidabl