ta & Nat
`
`B e a t a
`Tae|
`
`MYLAN INST. EXHIBIT 1124 PAGE 1
`
`MYLAN INST. EXHIBIT 1124 PAGE 1
`
`

`

`T H E UNITED STATES P H A R M A C O P E I A
`
`T H E N A T I O N A L F O R M U L A R Y
`
`By authority o f the United States Pharmacopeial
`Convention,
`Inc., meeting at Washington, D.C.,
`March 9-12, 1995. Prepared by the Committee o f
`Revision and published by the Board o f Trustees
`
`Official f r o m January I, 2000
`
`U N I T E D S T A T E S P H A R M A C O P E I A L C O N V E N T I O N ,
`12601 T w i n b r o o k Parkway, Rockville, M D
`20852
`
`I N C .
`
`MYLAN INST. EXHIBIT 1124 PAGE 2
`
`MYLAN INST. EXHIBIT 1124 PAGE 2
`
`

`

`?Wo
`
`N O T I C EANDWARNING
`Conceming U.S. Patent or Trademark Rights
`
`The inclusion in the Pharmacopeia o r in the National Formulary of a monograph on any drug in
`respect to which patent o r trademark rights may exist shall not be deemed, and is not
`intended
`as, a grant of, or authority to exercise, any right or privilege protected by such patent or
`trademark. All such rights and privileges are vested in the patent or trademark owner, and no
`other person may exercise the same without express permission, authority, or license secured
`from such patent or
`trademark owner.
`
`Concerning Use o f USP o r N F Text
`Attention is called to the fact that USP and NF text is fully copyrighted. Authors and others
`wishing to use portions of the text should request permission to do so from the Secretary of the
`USPC Board of Trustees.
`
`The United States Pharmacopeial Convention, Inc.
`1999
`©
`12601 Twinbrook Parkway, Rockville, MD 20852.
`All rights reserved
`ISSN 0195-7996
`ISBN 1-889788-03-1
`
`Printed by National Publishing, Philadelphia, PA?
`
`a
`
`2
`
`,
`
`MYLAN INST. EXHIBIT 1124 PAGE 3
`
`MYLAN INST. EXHIBIT 1124 PAGE 3
`
`

`

`USP 24
`
`General Information / (1074) Excipient Biological
`
`2037
`
`CALIBRATION
`For purposes of calibratio
`terials may be used. asrequt n, one o f
`the following reference ma-
`
`¢
`
`If the geometry
`geometry, may be used.
`of sample presentation precludes the use of such plaques, pressed
`barium sulfate, white reflectance standardgrade, mayb eused.?
`After calibration with the above-mentioned materials, it is desir-
`able whenever possible to Measure a reference material as close to
`the color of the sample as possible.
`If a sample of
`the material
`being tested is not Suitable for use as a long-term standard, color
`chips are available* which span the entire visually uniform color
`increments. The use of such a reference standard is
`space in small
`encouraged as a means of Monitoring instrument performance even
`for absolute color determinations.
`
`S P E C T R O P H O T O M E T R I C METHOD
`Determine the reflectance or
`transmittance from 380 to 770 nm
`at intervals of 10 nm. Express the result as a percentage, the max-
`imum being 100.0. Calculate the tristimulus values X, Y, and Z as
`follows.
`Reflecting Materials?For reflecting materials the quantities X,
`Y, and Z are
`
`X = Dito pXPANY?,
`¥ = Lito p,7,P,ANVY?, and
`z = Lazo PZPANY?,
`the
`reflectance of
`in which ¥? = X p ¥,P,AA, p,
`is the spectral
`material, x,P,, y , P , and z,P, are known values associated with each
`Standard Source,'2 and AA is expressed in nm.
`the quan-
`T r a n s m i t t i n g M a t e r i a l s ? F o r
`transmitting materials,
`tities X, Y, and Z are calculated as above, 7, (spectral transmittance)
`being substituted for p,.
`
`C O L O R I M E T R I C M E T H O D
`Operate a suitable colorimeter? to obtain values equivalent to the
`tristimulus values, X, Y, and Z. The accuracy with which the results
`obtained from the filter colorimeter match the tristimulus values
`may be indicated by determining the tristimulus values of plaques
`of strongly saturated colors and comparing these values with those
`computed from spectral measurements on a spectrophotometer.
`
`Interpretation
`COLOR COORDINATES
`The Color Coordinates, L*, a*, and b* are defined by
`? 16,
`L* = 116 ( Y Y ,
`a*
`500 [(X/X,)'° ? (Y/Y,)'*], and
`b* =
`200 [ ( Y / , )
`? (2Z,)'*],
`in which X,, Y,, and Z, are the tristimulus values of the nominaily
`
`w e e
`items are available from BYK-Gardner USA, 2431]
`2 Suitable
`Linden Lane,S i l v e r Spring, MD 20910, or from Hunter Associ-
`ates Laboratory, Inc., 11491 Sunset Hills Road, Reston, VA 22090.
`is available from Eastman Kodak Company,
`? Suitable material
`Rochester, NY 14650, as ??White Reflectance Standard.?
`?Centroid Color Charts may be obtained from suppliers of in-
`for measurement of color.
`Struments
`5A suitable tristimulus colorimeter isavailable from BYK-Gard-
`ner USA, 243] Linden Lane, Silver Spring, MD 20910, or from
`Hunter Associates Laboratory, Inc., 11491 Sunset Hills Road, Res-
`ton, VA
`22090.
`
`.
`
`white or colorless standard, and Y/Y, > 0.01. Usually they are equal
`to the tristimulus values of the standard illuminant, with Y, set equal
`In this case X, = 98.0 and Z, = 118.1.
`to 100.0.
`
`COLOR DIFFERENCE
`The total Color Difference AE* is
`
`AE* = [(AL*? + (Aa%)? + (b*y),
`in which AL*, Aa*, and Ab* are the differences in color coordinates
`of the specimens being compared.
`Instrumental variables can influence results. Although reliable
`comparisons can be made between similar colors measured con-
`comitantly,
`results obtained on different
`instruments or under dif-
`ferent operating conditions should be compared with caution.
`If
`it
`is necessary to compare data obtained from different instruments or
`is very helpful to have concomitant
`taken at different times, etc.,
`it
`data obtained on a standard reference material such as color chips
`for opaque materials. Comparison of the readings on the reference
`material helps to identify variations caused by instrument perfor-
`mance.
`
`(1074) EXCIPIENT B I O L O G I C A L
`SAFETY E V A L U A T I O N
`GUIDELINES
`
`I N T R O D U C T I O N
`This informational chapter presents a scientifically-based a p -
`proach for the safety assessment of new pharmaceutical excipients
`(ie.,
`those excipients that have not been previously used or per-
`mitted for use in a pharmaceutical preparation). The guidelines pre-
`sented herein provide a protocol
`for developing an adequate data-
`base upon which to establish conditions for the safe use of a new
`excipient intended for use in products administered by various dos-
`age routes.
`[ N o T E ? T h e final section of
`this chapter, Definition o f
`Terms,
`lists some terms referred to in this chapter.]
`An excipient may perform a variety of functionality roles in a
`pharmaceutical product; but, unlike pharmacologically active drug
`entities, the excipient displays either no pharmacological activity or
`very limited and directed activity. Because of these differences be-
`tween excipients and active drug substances in terms of risk and
`benefit
`the ap-
`relationships and expected biological activities,
`proaches for safety assessments of excipients and active drug sub-
`stances will differ. Therefore, it is important to note that the guide-
`lines presented in this informational chapter apply only to the safety
`assessment of excipients, not to the safety assessment of active drug
`substances.
`These testing guidelines are informational
`in nature and are in-
`tended to be used by professionals having a knowledge of toxicol-
`ogy and associated sciences. It is also intended that the applicable
`safety test method requirements of the receiving regulatory author-
`ity would be used in a proposal for market entry. For example, if
`a proposal
`is to be submitted to the U.S. Food and Drug Admin-
`istration, that agency?s safety test requirements would have to be
`met. These guidelines do not provide specific details regarding test
`methodology and data interpretation. Test procedures that are gen-
`erally recognized by experts and by the regulatory agencies should
`be used. Alternatives to the use of
`living animals areencouraged
`wherever these alternative procedures have been validated for the
`intended purpose and where it
`is known that the alternative proce-
`dure will provide sufficient data upon which to base a safety judg-
`ment. It is recommended that the Guiding Principles on the Use of
`Animals in Toxicology of the Society of Toxicology (1996) and, in
`the appropriate legal and professional codes, be
`other countries,
`adhered to in the conduct of all
`test procedures. All studies must
`meet the requirements of the appropriate national good laboratory
`practice guidelines in effect in the country where the studies are
`being conducted.
`In cases of extensive human experience based upon food use,
`there may be sufficient information to fulfill the requirements of the
`
`MYLAN INST. EXHIBIT 1124 PAGE 4
`
`MYLAN INST. EXHIBIT 1124 PAGE 4
`
`

`

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`USP 24
`
`U S P 24
`
`(1074)
`
`Information
`
`ining
`
`1
`
`s
`
`Excipient Biological / General
`2 0 3 8
`sets of base-
`:
`hanism for obtaining s
`.
`sals. The background in-
`ipi
`iti
`ideli
`idelines provide a mec:
`i
`guidelines for orally-ingested excipients only.
`In addition,
`These guidelines
`the
`there
`aoe p p o r t
`excipient materia s e
`P'
`i
`idate
`_line data for all candidate
`Fron
`imal-based data, which was developed
`for other purposes,
`©?
`formation andbaselinet o x i n ith er in a shorthalf-life product that
`that ae t o e d tofulfill
`the testing eaideines requirements. if
`use of the candidate exc
`uency that results in a residual excipient
`the data requirements have been met through prior human use e¢x-
`is not administered i n a eq a product used only once or twice in
`perience and pertinent human data have been collected in a scien-
`tifically sound manner, there is no need to provide animal data for ? build-up in body tissue oF in? pent. Additionai tests, listed under
`those endpoints evaluated by prior clinical experience.
`a lifetime, such as a diagno ont Guidelines, are necessary for can-
`Some dosage routes offer unique toxicological challenges, and
`Step 4 of the SafetyAssess
`ed in a manner that will
`i
`didate excipient ma
`ated exposure in humans?
`the guidelines include provisions for these routes (e.g., inhalation).
`t
`Also, further explanation is provided regarding numbers of species
`result in short- or intermediat
`hat will be administered for less
`and other basic information (e.g., two species, one rodent and one
`that is, a pharmaceutical produc?
`ive days, FesPectively. For a
`nonrodent).
`than 10 days or for 30 to 90 c o n s t
`ded for use in a pharma-
`The extent of information required to define a set of baseline
`candidate excipient material that is inten cent or chronic admin-
` ceytical product intended foreitherintermi ceatment for psoriasis
`data, which constitute a toxicological and chemical database, isde-
`pendent upon the intended use of, and duration of, dosing of the
`istration over a long timeperiod, such as a
`a a These tests are
`an insulin preparation, further tests are required.
`is critical that a thorough review of
`candidate excipient material. It
`TMS a
`listed under Step 7 of theguidelines and in the appropria secticon
`background information be conducted before embarking ona test-
`ing regimen. In addition to literature database reviews, information
`Is der Additional Requirements for Specific Exposure Routes.
`le
`should be obtained regarding the physical and chemical properties = "" vidi
`?dance for consumer safety, some of the required tests
`of
`its manufacturing process (or processes), and
`Prov! ing gu
`de information to address occupational safety
`the compound:
`limi
`iti
`are intended to provide
`i
`j
`i
`ifications
`product specifications including limits o f
`impurities, potential
`for
`(e.g. skin and eye irritation).
`in Table 1. Tests that are required
`armacological activity, exposure conditions (i.e., dose, duration,
`yam
`Pequency of use, dosage formulation, and route of administration),
`The guidelines are summarized from those that are recommended
`and potential user population. Also, base toxicity information cov-
`_(R) by theguidelines ath
`ditional
`tests are conducted is de-
`ering the topics is fundamental. Particular attention should be ad-
`conditionally (C). Whether con
`a
`a
`iti
`d available biological data.
`:
`.
`dressed to the absorption/distribution/metabolism/excretion/phar-
`pendent upon the conditionso f
`use an
`I
`7
`macokinetics
`(ADME/PK)
`studies because much o f
`the later
`Consideration must also be given to the requirements o f
`the regu
`decision process will be dependent upon these data.
`latory authorities when making the decision to test.
`
`ing
`
`amen
`
`it
`
`?sed
`
`o f E x c i p i e n t G u i d e l i n e s .
`Routes o f Exposure for H u m a n s . . .
`Dermal/Topical/
`Inhalation/
`Transdermal
`Intranasal
`
`Injectable*
`
`Ocular
`
`T a b l e 1.
`
`Summary
`
`Mucosal
`
`O r a l
`
`Tests
`Baseline Toxicity Data
`Acute Oral Toxicity
`Acute Dermal Toxicity
`Acute Inhalation Toxicity
`Eye Irritation
`Skin Irritation
`Skin Sensitization
`Acute Injectable Toxicity
`Application Site Evaluation
`Pulmonary Sensitization
`Phototoxicity/Photoallergy
`Genotoxicity Assays
`ADME/PK-Iniended Route
`28-Day Toxicity (2 Species)-Intended
`Route
`Additional Data: Short- or Intermediate-term Repeated Use
`90-Day Toxicity (Most Appropriate
`R
`Species)
`R
`E m b r y o - F e t a l T o x i c o l .
`c
`Additional Assays
`R
`Genotoxicity Assays
`R
`Immunosupression Assays
`Additional Data: Intermittent Long-term or Chronic Use
`c
`Chronic Toxicity (Rodent, Nonrodent)
`Reproductive Toxicity
`R
`Photocarcinogenicity
`c
`Carcinogenicit
`c
`
`i j
`
`_
`
`:
`S a y
`
`7
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`C = Conditional
`* Intravenous,
`intramuscular, subcutaneous,
`
`intrathecal, etc.
`
`SAFET
`
`Before proceey
`Checkpoints, the
`¢ Review litera
`* Define chemi
`¢ Define manu:
`* Define produ
`solvents (see
`+ Estimate expr
`¢ Define user p
`* Assess potent
`A t
`this point e
`approach to testin
`
`D a t a F
`Toxici
`STEP 1:
`T h e toxicity dat:
`tion:
`°E f f e c t s o f acu
`*
`Effects o f r e p
`¢ Effects in in v
`* A D M E / P K by
`doses
`Depen
`STEP 2:
`s i n g l e dose in hum
`STEP 3:
`Check
`e x p o s u r e condition:
`a l l o w use ina singl
`agent).
`Gather
`STEP 4:
`° Effects of. sub
`routes
`* Embryo-fetal
`exposure
`in v
`¢ Additional
`STEP 5:
`Depend
`g i v e n t o testing in h
`ingredient or as a st
`STEP 6:
`Checkp
`might a l l o w use in
`repeated intake (e.g.
`noninjectable excipit
`a product
`for 30 to ?
`STEP 7:
`Addition
`taken chronically, ¢i
`Period depending on
`* Results o f subch
`priate mammalia
`* Reproductive toy
`* O t h e r test result:
`i c i t y or carcinog
`
`«
`
`B:
`The following data
`Appropriate Acul
`Sensitization, approxi
`, Other Approprial
`limit
`test or approxi
`ADME/PK: single
`Genotoxicity: for ¢
`eration test, mammal
`28-Day Repeated |
`Priate Routes (One R
`a t i o n of injection sile
`?pending on route ©
`N o t e s ?
`In those cases 1
`1.
`Concentration) preclud
`
`MYLAN INST. EXHIBIT 1124 PAGE 5
`
`MYLAN INST. EXHIBIT 1124 PAGE 5
`
`

`

`General Information | (1074) Excipient Biological
`
`2039
`
`SAFETY ASSESSMENT GUIDELINES
`
`actor
`
`,
`
`roceen n tKeround I n f o r m a t i o n
`Ng to the steps und
`i
`Checkpoints, the| fone wings Points shouldb e revicgeairements and
`» Define chemical and physical proke bs Ppropriate databases
`. Define manufactari
`rocess
`Peres
`ne product specificat
`iti
`°
`i
`solvents Greeapplicable TCH g u i d e s mmpurites snd residual
`sure conditi
`.
`i
`* Estimate e xpopulation
`ons (dose, duration, frequency route)
`+ Assess potential for pharmacologic activit
`At
`this point evaluate
`;
`approach to testing.
`What
`is known, and develop the initial
`
`i
`
`D a t a R e q u i r e m e n t s a n d C h e c k p o i n t s
`STEP I T o x i c i t y Data (see Baseline Toxicity Data)
`a ?
`toxicity data should take into account the following informa-
`» Effects of acute ex
`i
`+ Effects ofrepeated exposures b e intended m a c e s
`+ Effectss i n in vitro> genotoxicity assays
`. ADM
`K by oral
`or appropriate ?routes; single or multiple
`
`s i l t dose Depending on results of above, evaluate effects of a
`step 3: Checkpoint: Evaluate results of above and
`pro
`exposure conditions and exposed population. The abovedata ent
`_~
`in a single product with a short half-life (e.g., a diagnostic
`step 4: Gather the following additional data:
`of subchronic exposure in appropriate species and
`.Effects
`« Embryo-fetal development studies via appropriate route of
`exposure
`* Additional
`in vitro and in vivo genotoxicity tests
`sTep 5:
`D e p e n d i n g on results o f above, consideration should be
`given to testing in humans as part of
`the clinical
`trials of an active
`ingredient or as a stand-alone procedure.
`,
`step 6: Checkpoint: Evaluate all of above information. Data
`might allow use in a variety of products intended for short-term,
`repeated intake (e.g., an antibiotic).
`i f
`the ADME/PK studies for a
`noninjectable excipient show no absorption, data may permit using
`a product for 30 to 90 consecutive days
`step 7: Additional data should be obtained for use in a product
`taken chronically, either daily or intermittently, over a long time
`period depending on
`o o ,
`* Results of subchronic studies and long-term toxicity 1n appro-
`priate mammalian nonrodents
`» Reproductive toxicity studies
`* Other test results and human exposuredata and long-term tox-
`icity or carcinogenicity in rodents
`
`Baseline Toxicity Data
`The following data should be taken into account:
`Appropriate Acute Toxicity by Intended Dose Routes: skin
`sensitization, approximate lethal dosemethod,
`limit
`test, etc.
`Other Appropriate Acute Toxicity Studies: oral toxicity by
`limit test or approximate lethal dose method, skin irritation, etc.
`ADME/PE: single or multiple doses.
`Genotoxicity:
`for example, Ames Test, in vitro chromosome ab-
`erration test, mammalian cell mutation assay.
`by A
`5
`Dosing Studies in Two
`28-
`Species
`Appro-
`p r i n )ay ReperneRodent, One Mammalian Nonrodent): eval-
`uation of injection site or similar considerations might be necessary
`depending on route of administration.
`N o T E s ?
`In those cases where intended route
`1.
`concentration) preclude an adequate asse
`
`restrictions (e.g., volume,
`ssment of
`the toxicity o f
`
`by
`
`the excipient, development of a toxicity profile by other relevant
`routes may be need
`2. The comparison of toxicity and ADME/PK data between oral
`and intended routes is critical at this point becauset h a tknowledge
`set the direction for future toxicity testing( e g . r e p r o d c t y
`may
`conducted by oral route rather than intended route).
`toxicity testing
`In addition, relevant studies using the intended route and anticipated
`duration of exposure may preclude performance of additional
`stu-
`dies.
`
`?
`
`:
`
`.
`
`Additional Requirements forSpecific
`Exposure Routes
`FOR ORAL EXPOSURE: No additional requirements beyond those
`presented for Baseline Toxicity Data.
`FOR MUCOSAL BXPOSURE: No additional requirements beyond
`those presented for Baseline Toxicity Data.
`FOR DERMAL, TOPICAL, OR TRANSDERMAL EXPOSURE:
`Baseline Toxicity D a t a ?
`* Effects of Acute Exposure byTransdermal Dose Route: dermal
`sensitization study for repeat applications
`Effects of Repeated Exposures by Transdermal Route
`1. Photoallergy/phototoxicity study
`ammalian non-
`2. Studies in two species (one rodent, one m:
`rodent) by transdermal route
`.
`Effects of Subchronic Exposure, Reproductive Toxicity E f -
`fects?Initial toxicity studies may be performed by the IV route
`to adequately profile the toxicity of
`the excipient. This will
`provide an assessment of potential target organs i f an adequate
`amount of the compound cannot be delivered via a transdermal
`dosage form. This is dependent upon the results from the
`ADME/PK studies.
`.
`:
`Reproductive studies may also be conducted via oral o r I V
`route w i t h demonstration o f absorption (oral) and pharmaco-
`kinetic comparisons o f
`the chosen route versustransdermal.
`Photocarcinogenicity studies may be required and should be
`considered i f data and the proposed use indicate when evalu-
`ating materials to be placed on the skin for prolonged periods
`of
`time and exposure to ultraviolet
`light is a factor (e.g., sun
`block). This also applies to oral, parenteral, and inhalation
`products where skin drug concentrations exceed plasma drug
`concentrations for a substantial period o f
`time, or where the
`to have the potential
`candidate material would appear
`for
`photo-activity or has demonstratedphoto-activity.
`FOR INJECTABLE DOSAGE FORMS:
`Background Information?
`1. Define compatibility of the dosage form with blood, i f appro-
`priate, based on route o f exposure.
`2. Define the pH and tonicity of
`injectable dose form,
`priate, based on the route o f exposure.
`Baseline Toxicity D a t a ?
`* Effects of Acute Exposure by Intended Injectable Dose Routes
`Include evaluation of injection site irritation in rabbit or dog
`1.
`Include evaluation of rate of administration
`2.
`FOR INHALATION OR INTRANASAL EXPOSURE:!
`Baseline Toxicity Data?
`for exam-
`test that would,
`* Acute Inhalation Toxicity?A limit
`ple, use the highest achievable concentration in a 4-hour ex-
`posure to vapor, aerosol, or solid particulate. Pulmonary
`sensitization may be performed along with other appropriate
`If exposure is to be to an aerosol or solid particulate,
`studies.
`particulates of appropriate mass median diameter should be
`generated.
`* Single and Repeated Dose ADME/PK by Inhalation or Intra-
`nasal and Oral Routes
`
`i f appro-
`
`' When designing studies to evaluate use in products intended for
`use by the inhalation or intranasal route, consideration should be
`given to the dosing regimen that will be used by humans. The
`appropriate study protocol
`for a product intended for inhalation
`therapy that will
`result
`in prolonged exposures (e.g., several
`hours per day) may differ from that used to evaluate a product
`that would result in exposure to several metered doses per day.
`
`MYLAN INST. EXHIBIT 1124 PAGE 6
`
`MYLAN INST. EXHIBIT 1124 PAGE 6
`
`

`

`2040
`
`(1078)
`
`GoodManufacturing Practices / General Information
`
`U S p 24
`
`erefore, relevant portions of
`.
`schemes is becomingnecessary. ved throughout this chapter
`manufacturing1 Guidance section provides an overview of
`the an
`T h eGeneral facturingpractices criteria applicable to eXcipien,
`propriatemanu d the point of application a ;CxcipientBood Many.
`facturing practices and quality sysems.
`?excivient an
`om.
`mends measures to limit contamination mm
`x ppient n PrOVides
`the relationship of excipients to finished
`inte
`m s list of
`to
`terms and their definitions used in this informa o n clapter,
`Appendix 1. The section Excipient Quality ystems Provides info.
`mation ont h e requirements necessary for comp clon w i t h Televan,
`good manufacturing practice principles and imp ementation of
`excipient quality system.
`Information for pro etion facility te.
`quirements are included under Process Control.
`© attempt
`been made to include details specific to particular excipients,
`information under Appendix 2, General Auditing Considerations
`sets forth key criteria to aid in the audit of an excipient Manufac.
`turing facility.
`
`GENERAL GUIDANCE
`ional regulations governing drugs require that compo.
`nente ot the drugs be manufactured, processed, packed, and heldi n
`accordance with good manufacturing practices. Unlike other phar.
`maceutical products and components, until now there was noguid.
`ance that specifically addressed the manufacture of bulk pharma.
`ceutical excipients.
`Excipients are substances, other than the active drug substance
`or finished dosage form, that have been appropriately evaluated for
`Safety and are included in drug delivery systems 1) to aid in the
`Processing of the drug delivery system during its manufacture; 2)
`to protect, support, or enhance stability, bioavailability, or patient
`acceptability; 3) to assist in product identification; or 4) to enhance
`any other attribute of the overall safety, effectiveness, ordelivery
`of the drug during storage or use.
`The application of goodmanufacturin
`relevant when it is determined that a c
`
`.
`
`toni
`
`Me-
`riate Mass
`data. w m
`
`pH and
`pi
`
`lari
`i
`osmolarity of topical
`
`° 28-Day[ e p e a t e d Dose Inhalation Studyi
`pecies Using
`Vapor o r Particulates of
`dian Diameter: Compare to similaro r a l
`FOR OPHTHALMICEXPOSURE:
`Background Information: define
`ocular doe f r r e
`Baseline Toxicity D a t a ?
`* Effects of Acute Exposure by OphthalmicRoutes:c y t o t o x i c i t y
`tests (¢.g., agar overlay)
`* Effectso f RepeatedExposures by Ophthalmic Routes
`1.a n e s
`i n two species (one rodent, one mammalian nonro-
`mt
`2 . E x a m i n a t i o n o f anterior and Posterior segments of
`3. Studies on allergenicity potential
`O t h e r D a t e ? C o m p a r i s o n o f pharmacokinetic parameters of the
`route chosen forreproductive Studies and the ophthalmic exposure
`a r e? s e n t i a l
`for extrapolation o f potential
`toxicity via the ophthal-
`mic route.
`
`the eye
`
`D E F I N I T I O N O F T E R M S
`Acute: exposure to a test agent withi
`In a single, 24-hourperiod.
`sts may be single, multiple or c
`period.
`Ontinuous during a 24-hour
`Subacute: repeated dosing of a test agent for up to 29 days. Daily
`doses| may be single, multiple or continuous during a 24-hour
`peri
`for 30 days to 10% of
`test agent
`S u b c h r o n i c : Tepeated dosing ofa
`the lifespan o f the test Species (90 di;
`ays in rodents). Daily doses
`é
`e
`may be single, multiple or continuous during a 24-hourperiod.
`
`(1078) GOOD MANUFACTURING
`PRACTICES FOR BULK
`PHARMACEUTICAL EXCIPIENTS
`
`B A C K G R O U N D
`the Principles in this general
`information chapter are
`M a n y o f
`derived from an international guidance on the extent and point of
`application of appropriate good manufacturing practiceprinciples.
`It
`is intended to assist excipient manufacturers in determining
`whether
`the methods used in, and the facilities and manufacturing
`controls used for, production adequately ensure that an excipient
`possesses the quality, purity, safety, and suitability for use that it
`purports to possess.
`.
`The principles and information in this chapter can be applied to
`the manufacture o f all bulk pharmaceutical excipients (referred to
`this document as ??excipient(s)??)
`intended for use in
`throughout
`human drugs, veterinary drugs, and biologics.
`It covers the quality
`systems and the extent of good manufacturing practices necessary
`throughout the chain of production up to and including delivery to
`customers. As an international guidance document,
`it does notp r o -
`vide information for all national
`legal
`requirements nor cover
`in
`detail
`the particular characteristics of every excipient. Theq u a l i t y
`system standard used as a framework for this chapter is ISO 9002,
`which is appropriate to manufacturing.
`Information specific to ex-
`cipients has been added. Because of
`the diversity of excipients,
`some principles in this information chapter may not beapplicable
`to certain products and processes,
`regula-
`This information chapter combines existing governmental
`tory good manufacturing Practices principles and internationalq u a l i t y
`management system requirements as developed by The Intemational
`Organization for Standardization (ISO).
`In view of
`the increasing
`globalization of
`the pharmaceutical
`industry and theharmonization
`of
`pharmaceutical
`registration requirements,
`deference
`to
`both
`
`ini
`
`:
`
`:
`
`>
`
`series
`
`;
`
`7
`
`and
`
`tion.
`
`Cturing practices should
`he remainder of thepro-
`which these manufacturing
`Practices should be implemente.
`> Z00d judgment and a thorough
`should wee ot
`the process are required. A detailed process flow
`identify the unit Operations, equipment used stages at which
`Ould
`various substances are added, ke
`in theprocess critical pat-
`itor
`?<mMperature, pressure etc.),
`ints.
`ISO 9000
`~'C-), and monitoring points.
`:
`cation thatcan be. ?$a quality system Standard of general appli-
`applied to covereve:
`i
`TY aspect of manufacturing
`It has taken
`to the benefit of both theManufacturer andc u s t o m e r
`Several years since its introduction j
`ies
`rane
`r e g u l a h e y
`to be utilizedw o r l d w i d e .T h e r e is n oc u e s
`€nt regulatory
`requirement
`:
`i n murope, papan, or the United States fort h i r d party cestfcation.
`However n y , aPPly the standard with or without certifica-
`However, certification has the benefit of Providing assurance
`1on.
`?0 sontomets that conformance tothis quality system has been it-
`vepen ently confirmed. Incorporation of GMP Tequirements into the
`SO 9000quality System enhances NOt only the qualit
`system, bul
`a company?sOperational Procedures asw e l l Final dosa e formu:
`latorsworldwide creasingly regard complia;
`sD 9002 as
`i
`an essential qualification for
`Pe O r e t h E
`i
`heir supphi
`ification
`t
`18 a business decision and is not d i s c u s G r a i n i n g certifi
`mation chapter.
`"Scussed in this general
`infor
`
`MYLAN INST. EXHIBIT 1124 PAGE 7
`
`MYLAN INST. EXHIBIT 1124 PAGE 7
`
`