CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER: 020717
`
`CHEMISTRY REVIEW! S)
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`‘ _..‘ -'.
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`._._\.-2 ~-.-._,...4~ ~ ~..- ',
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`DIVISION OF NEUROPHARMACOLOGI CAL DRUG PRODUCTS
`
`Review of Chemistry, Manufacturing, and Controls
`
`NDA#: 20-7 1 7
`
`CHEMISTRYREVIEW: # 1
`
`DATE REVIEWED: 21-APR-97
`
`Submission Type
`ORIGINAL
`
`Document Date
`27-DEG96
`
`CDER Date
`30-DEC~96
`
`Assigned Date
`07-JAN-97
`
`NAME AND ADDRESS OF APPLICANT: Cephalon, Inc.
`145 Brandywine Parkway
`West Chester, PA 19380-4245
`
`DRUG PRODUCT NAME:
`
`PROVIGIL
`Proprietary:
`Nonproprietary l Established/USAN: modafinil
`Code Name /#:
`CEP-1538
`
`Chem. Type/Ther. Class:
`
`1 S
`
`DESI / PATENT STATUS: Modafinil has Orphan Drug status
`
`PHARMACOLOGICALCATEGORY/INDICATION: Narcolepsy
`DOSAGE FORM:
`Tablets
`
`STRENGTH(S):
`ROUTE OF ADMINISTRATION:
`
`DISPENSED:
`
`100 mg, 200 mg
`Oral
`
`& Rx
`
`__ OTC
`
`CHEMICALNAME, STRUCTURALFORMULAANDMOLECULARFORMULA:
`2-[(Diphenylmethyl)sulfinyl]acetamide. CAS No. 68693-11-8
`C,5H,5Nozs
`Mol. Weight:
`273.34
`
`SUPPORTING DOCUMENTS:
`
`DMF
` .
`_ and DMF
` .
`
` .
`
`RELATED DOCUMENTS (if applicable): IND-
` .
`
`o
`
`‘
`
`" ‘
`
`O RJLS
`
`"H“
`
`0
`
`, DMF_
` .
`
`Environmental Assessment V- Consulted to HFD-357 by Project Manager, not complete
`CONSULTS:
`REMARKS/ COMMENTS:
`
` .
`
` .
`
`Cephalon will not be doing any of the
`actual manufacturing and release testing of the product. Drug substance will be manufactured in
`
`_ by a- subsidiary
`and Modafinil tablets will be manufactured in the-
` .
` .
` .
` .
`
`— DMF covering—as been
` .
` .
` .
`
`reviewed
`
` .
`Inspections and EA review and method validation are not done. Ther are some deficiencies in the
`NDA itself— these are relatively minor-
` .
`
`CONCLUSIONSAND RECOMMENDATIONS:
`
`Recommend Information Request letter to sponsor.
`
`cc: Orig. NDA 20-717
`HFD-lZO/Division File
`HFD-lZO/MHeimann/Z -
`HFD-120/SHardeman
`/S/
`HFD-lZO/SBlum/Im;
`
`/S/
`
`Martha R Heimann, Ph.D., Review Ch mist
`Filename: N20-717.001
`
`_ :42/é Z '
`
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`

`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS
`Review of Chemistry. Manufacturing, and Controls
`
`NDA#: 20-717
`
`CHEMISTRY REVIEW: #8
`
`Submisslon Type
`N(BC). revised Env. Ass.
`N(BC). responses to IR letter
`N(BC). responses to IR letter
`N(BZ)
`
`Document Date
`02-MAY-97
`28_—JUL-97
`02-SEP-97
`22-SEP-97
`
`CDER Date
`OS-MAY-97
`29-JUL-97
`03-SEP-97
`23-SEP-97
`
`-
`
`DATE REVIEWED: 02-DEC-97
`
`Assigned Date
`05-MAY-97
`29-JUL-97
`O3~SEP-97
`23-SEP-97
`
`'
`
`NAME AND ADDRESS OF APPLICANT: Cephalon. Inc.
`145 Brandywine Parkway
`West Chester, PA 19380-4245
`
`DRUG PRODUCT NAME:
`
`PROVIOIL
`Proprietary:
`Nonproprietaryl Established/USAN: mOdafinil [adopted 1994]
`Code Name/#:
`CEP-1538
`Chem. TypeITher. Class:
`1 S
`
`DESII PATENT STATUS: Modafinil drug substance, and the drug product formulation. are licensed to Cephalon
`by the French developer. Laboratoire Lafon.
`
`PHARMACOLOGICAL CATEGORYIINDICATION: Narcolepsy (Orphan Drug status)
`DOSAGE FORM:
`Tablets
`STRENGTH(S):
`100 mg. 200 mg
`ROUTE OF ADMINISTRATION:
`Oral
`DISPENSED:
`& Rx _ OTC
`
`CHEMICAL NAME, STRUCTURAL FORMULA AND MOLEcULAR FORMULA:
`2-[(Diphenylmethyl)sulfinyl]acetamide. CAS NO. 68693-11-8
`C15H15NO,S
`MOI. Weight'
`273.36
`SUPPORTING DocUMENTs: DMF
` .
` .
`RELATED Documems (If applicable): IND-
` .
`
`and DMF
`
` .
`
`o
`O i?
`\JKM-h
`
`DMF-
` .
`
`0
`
`CONsULTs: Environmental Assessment - Consulted to HFD—357. FONSI issued 25-JUN-97
`REMARKS/COMMENTS:
`
`The s ~onsor h -
`
` .
`
`
`
`CONCLUSIONS AND RECOMMENDATIONS:
`
`- Recommend Approvable for Chemistry pending resolution of forei n ins
`standard paragraph concerning completion of methods validation.h
` .
`
`
`cc: Orig. NDA 20-717
`HFD-120IDivision File
`HFD-120/MHeimann/02-DEC-97
`HFD-120/MMalandrucOO
`HFD—120/MGuzews
`
`/S/
`
`'
`
` .
`
`2,2 37
`
`, Ph.D.. Review Chemist
`a R eima
`Me
`file me: N20-117.002
`
`'on. Action letter should contain
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`(
`
`NDA#: 20-717
`
`DIVISION OF NEUROPHARMACOLOGICAL DRUG PRODUCTS
`Review of Chemistry. Manufacturing. and Controls
`
`CHEMISTRY REVIEW: #1 3
`
`DATE REVIEWED: 16-JUL-98
`
`Submission Type
`N(BZ) partial response to AE letter
`NC
`
`Document Date
`30-MAR.98
`06-MAY-98
`
`CDER Date
`31-MAR-98
`07-MAY-98
`
`Assigned Date
`31-MARo98
`07-MAY-98
`
`NAME AND ADDRESS OF APPLICANT: Cephalon, Inc.
`145 Brandywine Parkway
`West Chester. PA 19380-4245
`
`DRUG PRODUCT NAME:
`
`PROVICIL
`Proprietary:
`NonproprietaryIEstablished/USAN: modafinil [adopted 1994]
`Code Namel#:
`CEP-1538
`Chem. Type/Then Class:
`1 S
`
`DESI] PATENT STATUS: Modafinil drug substance. and the drug product formulation, are licensed to Cephalon
`by the French developer. Laboratoire Lafon.
`
`PHARMACOLOGICAL CATEGORY/INDICATION: Narcolepsy (Orphan Drug status)
`DOSAGE FORM:
`Tablets
`
`STRENGTH(S):
`ROUTE OF ADMINISTRATION:
`
`DISPENSED:
`
`100 mg. 200 mg
`Oral
`
`&_ Rx _ OTC
`
`_
`
`._
`( i
`
`I
`
`'
`
`'
`
`'
`
`SUPPORTING DOCUMENTS:
`
`CHEMICAL NAME, STRUCTURAL FORMULA AND MOLECULAR FORMULA:
`2-[(Diphenylmethyl)sulfinyl]acetamide. CAS No. 68693-11—8
`c.5H,sNo,s
`MOI. Weight
`273.36
`
`DMF_
` .
`andmm:—
` .
`RELATED DOCUMENTs (if applicable): IND—
` .
`
` .
`
` .
`
`O o
`
`o
`\JKM'h
`
`0
`
`CONSULTS: Environmental Assessment - Consulted to HFD-357. FONSI issued 25-JUN-97
`
`REMARKS! COMMENTS:
`
` .
`
`The Sponsor submitted two amendments in response to the 29-DEC-97 approvable letter. The first
`submission (30-MAR-98) contains adequate responses to the two remaining CMC related review issues; i.e.,
`the expiration dating period requested by the sponsor and the adoption of uniform dissolution specifications for
`both tablet strengths. The 30-MAR-98 amendment provides real time data to support the proposed 3
`year expiry. The 06-MAY-98 submission is a request for
`en
`concurrence with a stability matrix plan to
`be used to support post-approval chang
` .
`
`CONCLUSIONS AND RECOMMENDATIONS:
`
`Recommend Approval for Chemis
`of methods validation.
` .
`
`. Action letter should contain standard
`
`re re h concemin com letion
`
`- .
`
`“
`
`DC: Orig. NDA 20-717
`HFD-120/Division File
`HFD-120/MHeimann/164UL-98
`HFD—120IAHommonay
`
`HFD—120/MGuz
`"1.45
`
`/S/
`
`/S/
`
`/
`Ma
`a R. Heimann. Ph.D.. Review Chemist
`Fiienarne: N20.717.ooa
`
`.
`
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`ENVIRONMENTAL ASSESSMENT AND/OR FONSI\
`
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`

`

`ENVIRONMENTAL ASSESSMENT
`
`AND
`
`FINDING OF NO SIGNIFICANT IMPACT
`
`FOR
`
`Provigil®
`(Modifmil)
`Tablet
`
`NDA 20-717
`
`Cephalon® Inc.
`
`If g‘
`
`‘
`
`U. S. FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Division of Neuropharmacological Drug Products
`(HFD-IZO)
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`FINDING OF NO SIGNIFICANT IIVIPACI‘ .
`
`NDA 20~7l7
`
`Provigil®
`
`(Modafinil)
`
`Tablets
`
`The National Environmental Policy Act of 1969 (NEPA) requires all Federal agencies to assess
`the environmental impact of their actions. FDA is required under NEPA to consider the
`environmental impact of approving certain drug product applications as an integral part of its
`regulatory process.
`
`The Food and Drug Administration, Center for Drug Evaluation and Research, has carefully
`considered the potential environmental impact ofthis action and has concluded that it will not
`have a significant effect on the quality of the human environment and that an environmental
`impact statement therefore will not be prepared.
`
`In support of their new drug application for Provigil®, Cephalon® Inc., prepared an
`environmental assessment (attached) in accordance with 21 CFR 25.31a(b)(3), which evaluates
`the potential environmental impact ofthe manufacture, use and disposal of the product.
`
`Modifinil is a— drug which is administered as a tablet to increase
` .
`wakefulness in patients with excessive daytime sleepiness associated with narcolepsy. The drug
`product will be manufactured by Circa Phannaceuticals, Copiague, New York The finished drug
`product will be used by patients in hospitals, clinics and in their homes.
`
`Modafinil may enter the environment from excretion by patients, from disposal of pharmaceutical
`waste or fi'om emissions fiom manufacturing sites.
`
`Disposal ofthe drug may result from out of specification lots, discarding ofunused or expired
`product, and user disposal of empty or partly used product and packaging. Returned drug
`product will be disposed of at a licensed incineration or landfill facility. At US. hospitals and
`clinics, empty or partially empty packages will be disposed according to hospital/clinic
`regulations. From home use, empty or partially empty containers will typically be disposed ofby
`a community’s solid waste management system which may include landfills, incineration and
`recycling, while minimal quantities ofunused drug may be disposed of in the sewer system
`
`FONSI for NBA 20.717
`
`2
`
`A,r
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`/S/
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`PREPARED BY
`Carl J. Beminger, PhD.
`Environmental Scientist
`Environmental Assessment Team
`Center for Drug Evaluation and Research
`
`Date
`
`’
`
`/S/
`
` ‘ Nancy B. Sag r
`
`Team Leader
`
`Environmental Assessment Team
`Center for Drug Evaluation and Research
`
`Attachments: Environmental Assessment (F01 copy)
`Material Safety Data Sheet for drug substance
`
`APPEARS THIS WAY 0N ORIGINAL
`APPEARS THIS WAY ON ORIGINAL
`
`FONSI for NDA 20-717 ’
`
`3 '
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`("'
`
`ENVIRONMENTAL ASSESSMENT
`
`NON-CONFIDENTIAL
`NBA 20 .. 7/7
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`(
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`Environmental Assessment for
`Modafinil Tablets
`
`'
`
`ITEM 1. Date:
`
`April 30, 1997
`(Supercedes October 11, 1996)
`
`ITEM 2. Name of Applicant:
`
`Cephalon’, Inc.
`
`ITEM 3. Address:
`
`145 Brandywine Parkway
`Building 300
`West Chester, PA 193 80-4245
`
`(' 7.
`
`ITEM 4. Description of Proposed Action:
`
`A. Requested Approval:
`
`"
`
`FDA approval for the manufacture and commercial distribution ofmodafinil tablets in the
`United States. Approval is being sought for a NDA for a human drug intended for the
`treatment of patients with a rare disease (i.e., treatment to increase wakefulness in patients
`with‘excessive daytime sleepiness associated with narcolepsy). Modafinil was designated '
`as an orphan drug product for treatment ofthis indication on March 15, 1993. As a result,
`this environmental assessment has been prepared using the abbreviated format provided in
`21 CFR §25.31a(b)(3).
`
`- a
`
`B. Need for the Action (Proposed Use):
`
`Modafinil is indicated to increase wakefulness in patients with excessive daytime
`sleepiness associated with narcolepsy.
`
`C. Description of Drug Product
`
`Information on the composition and components ofmodafinil tablets is presented in
`confidential Appendix A The drug product will be available in tablet formulations
`
`
`
`
` .
`
` (“ containin either 100 01-200 f '
`
` .
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`D. Production Locations:
`
`1. Manufacturing of the key intermediate used in modafinil synthesis: ‘
`
`.F’.
`
`The key intermediate used in modafinil synthesis will be produced by a foreign
`contract manufacturer. The identity of this intermediate and the contractor are
`considered proprietary and are given in confidential Appendix B. The, contractor's
`manufacturing site is approximately_ in size, located in a temperate region
` .
`near a large metropolitan area The site is in an industrial area surrounded by a mix of
`industry and warehouses and located adjacent to large river. The nearest residential
`area is across the river fi'om the site. See confidential Appendix B for additional
`information.
`
`2. Manufacturing of the drug substance (modafmil):
`
`The drug substance will be produced by a foreign contract manufacturer. The identity
`ofthis contractor is considered pro rie
`and is given in confidential Appendix C.
`The contractor’s production site isfiin size, located near a large metropolitan
` .
`area in a temperate region. The plant is about 3 km west of a small village,
`surrounded by a mix of light industrial and commercial development. The facility is
`situated on flat land approximately 15 km from a river. See confidential Appendix C
`for additional information
`
`3. Manufacture and packaging of the drug product (modafmil tablets):
`
`roduct will be contract manufactured and packaged at-
`The dru
` .
`h A wfificwon orcompliance by Circa
` .
`‘ Pharmaceuticals is provided in Appendix D. The manufacturing site is located in a
`temperate region on flat land. The site is approximately_in size, surrounded
` .
`by a mix of industrial, commercial and residential development. There are no
`significant water bodies (rivers, lakes, or oceans) within 1.6 km ofthe facility. See
`confidential Appendix E for additional information
`
`-
`
`'
`
`'“
`
`E. Locations of Use:
`
`Modafinil tablets will be distributed by, or on behalfof, Cephalon‘, Inc. to hospitals and
`pharmacies throughout the US. for prescription use by patients with narcolepsy.
`
`~ll'. Disposal Sites
`
`Cephalon’, Inc. will request that all unsold or expired modafmil tablets be returned to a
`contract facility in the United States for disposal. Returned, expired, or rejected drug
`product will be disposed ofat a facility which is licensed by the EPA or an appropriate
`state authority to destroy hazardous materials. The identity of this contractor is
`considered proprietary and is given in confidential Appendix F.
`
`I
`
`..
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`04'?
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`-3-
`
`Identification of Chemical Substances that are the Subject
`ITEM 5.
`of the Proposed Action:
`
`.9.
`
`The active drug substance in modafinil tablets is modafinil. Table 1 summarizes infomation on
`the identity ofthis substance. The stmcmre ofmodafinil is depicted in Figure 1.
`
`L.“
`
`Identification of Drug Substance in Modafinil Tablets
`
`Table 1:
`
`1 Ii1 }
`
`—,
`
`m
`
`Expected degradation products
`
`Chenncal Names
`
`»
`
`2-(benzhydzylsulfinyl)acetamide
`
`2-[(diphenyhnethyl)sulfinyl]acetamide
`
`——
`
`modafinil acid 50.5%
`
`(2-[(diphenylmethyl)sulfinyl]acetic acid)
`
`modafinil sulfone s0.5%
`
`(2-[(diphenylmethyl)sulfonyl]aoetamide)
`
`modafinil ester 50.5%
`
`(methyl 24(diphenylmethyl)mlfiny1]a°etate)
`
`Unknowns s 0.1%
`
`Total s 1.5%
`
`modafinil acid
`
`(2-[(diphenylmethyl)sulfinyl]acetie acid)
`
`modafinil sulfone
`
`(2-[(diphenyhnethyl)sulfonyl]acetamide)
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`
`FIGURE 1. Structure of Modafinll
`
`' APPEARS THIS WAY ON ORIGINAL
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`-5-
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`Modafinil is a white to ofilwhite crystalline powder with a molecular weight of273.36. It is
`practically insoluble in water and cyclohexane. It is sparingly to slightly soluble in methanol and
`acetone (NDA #2o,717; Item 3; Chemistry, Manufacturing and Control Section). A material
`safety data sheet (MSDS) for modafinil drug substance is provided in Appendix G.
`
`ITEM 6.
`
`Introduction of Substances into the Environment:
`
`A. Contract Manufacturing Facility - Key Intermediate
`
`The key intermediate used in the synthesis ofmodafinil will be produced at a foreign contract
`facility. Because this is a foreign facility with appropriate certification (see below), no
`information is being provided regarding substances to be emitted or controls exercised. This
`facility is currently in compliance with all applicable environmental laws and emission
`requirements. A certified statement ofcompliance for this facility is contained in confidential
`Appendix B. Approval ofthe proposed action is expected to have no efi‘ect on compliance
`with current emission requirements at this facility.
`
`B. Contract Manufacturing Facility - Drug Substance (Modafinil)
`
`The drug substance modafinil will be manufactured at a foreign contract facility. Because this
`is a foreign facility with appropriate certification (see below), no information is being provided
`regarding substances to be emitted or controls exercised. This facility is currently in
`compliance with applicable environmental laws and emission requirements. A certified
`statement ofcompliance for this facility is contained in confidential Appendix C. Approval of
`the proposed action is expected to have no efl‘ect on compliance with current emission
`requirements at this facility.
`
`C. Manufacture and Packaging of Drug Product - Modafinil Tablets:
`
`_ a contract facility located in_ will formulate and
` .
` .
`package the drug product for Cephalon‘, Inc. This contract facility is an existing facility that
`currently manufactures solid dosage forms and gum products for itselfand other companies.
`ThefacifityopemesmderGoodManufaaudnngcficesmdisregistaedwimmeFDA
`The Drug Establishment Registration number for the facility is given in confidential Appendix
`E.
`'
`
`1. Substances Expected to be Emitted
`
`Appropriate controls are exercised to limit potential emissions to air and wastewater and
`to limit occupational exposures to the drug substance and excipients. Because of the in-
`place emission controls, neither modafinil nor any ofthe other drug product or packaging
`components, or process aids are expected to be released to air or water in suficient
`quantities to produce any significant environmental impact (see confidential Appendix E).
`
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`2. Controls Exercised
`
`fir Handling and Treatment:tAll manufacturing and packaging areas are connected to a
`non-recirculating dust collection system The system removes particles by vacuum action,
`controlling the amount of dustin manufacturing areas.
`
`WW: All manufacmring and packaging buildings are
`connected to the local municipal sewage collection system. All treatment of wastewater is
`performed at the local municipal wastewater treatment plant. A spill prevention plan is in
`place and responses are governed by a company Standard Operating Procedure (SOP).
`Depending on the type of spill (hazardous or non-hazardous), one oftwo waste disposal
`companies is asked to respond (see confidential Appendix E).
`
`Wm: All significant Production waste
`and non-usable product is collected for destruction by incineration by licensed disposal
`companies. This includes laboratory solvents, acids, and bases. Information on the
`companies used for disposal of hazardous and non-hazardous waste, including permit
`numbers, is presented in confidential Appendix E.
`
`Occupational Expom: Appropriate safety precautions are observed during all
`manufacturing operations to prevent occupational exposures. Employees are given
`instructions regarding safe product handling procedures and are provided with proper
`safety clothing and protective equipment (i.e., masks, gloves, uniforms, etc). Respirators
`are used during the manufacture ofmodafinil tablets. These respirators are OSHA
`recommended, with filters appropriate for handling various solvents and acid/base
`materials. Material Safety Data Sheets (MSDSs) are obtained and retained in the
`company files for each material handled at the facility. MSDSs are readily available and
`accessible to employees for their reference.
`
`.-
`
`( '
`
`‘
`
`Citation of, and Statement of Compliance with, Applicable Emission Requirements
`
`Circa Pharmaceuticals holds several “Permits to Operate” for air emissions from the
`appropriate state regulatory agency. A listing of these permits, including permit numbers,
`expiration dates, and authorized activities, is presented in confidential Appendix E.
`
`For wastewater handling and treatment. Circa Pharmaceuticals has a discharge
`certification, but not a specific discharge permit, fiom the local municipal sewer district.
`Sewer district authorities monitor the effluent that leaves each building and have
`determined that the facility discharges do not exceed the relevant limits for pH, color, total
`suspended solids (T88), and biochemical oxygen demand (BOD).
`
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`In addition to these permits and certifications, Circa Pharmaceuticals has US.
`Environmental Protection Agency “Acknowledgment ofNotification of Hmrdous Waste
`Activity” and necessary identification numbers (see confidential Appendix E).
`
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`.. .A._‘.>‘-l-—..-Al-:'»‘~ a
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`-7-
`
`c
`
`Circa Pharmaceuticals operates in compliance with all emission requirements, including
`occupational, set forthin applicable federal, state and local environmental laws
`regulations, and permits. A certified statement ofcompliance for this facilityisincludedin
`Appendix D.
`
`4. Effect of Approval on Compliance with Applicable Emission Requirements
`
`Circa Pharmaceuticals currently manufactures formulated drug products for itself and
`other companies. Approval of the proposed action and subsequent manufacture of
`production quantities of modafinil tablets will not significantly increase facility production
`and, therefore, is not expected to afi‘ect facility compliance with current discharge or
`emission requirements.
`
`D. Estimate of Maximum Yearly Market Volume:
`
`An estimate of the maximum yearly market volume for modafinil tablets is contained in
`confidential Appendix H
`
`ITEMS 7-11. Fate of Emitted Substances in the Environment; Environmental Effects of
`Released Substances; Use of Resources and Energy; Mitigation Measures;
`and Alternatives to the Proposed Action:
`
`Approval is being sought for a NDA for a human drug intended for the treatment of patients with
`a rare disease. Modafinil was designated as an orphan drug product on March 15, 1993. As a
`result, this environmental assessment has been prepared using the abbreviated format provided in
`21 CFR §25.3 la(b)(3) which specifies that Items 7 through 11 are not included.
`
`ITEM 12.
`
`List of Preparers:
`
`Daniel M Woltering, Ph.D., Principal, ENVIRON International Corporation, Arlington,
`Virginia Twenty years ofexperience in wotoxicology and environmental risk assessment.
`
`Eric M. Silberhorn, Ph.D., Senior Associate, ENVIRON International Corporation, Arlington,
`Virginia. Fourteen years of experience in ecotoxicology, environmental science, and
`ecological risk assessment
`
`George P. Grandolfi, Ph.D., Associate Director, Formulation Development, Cephalon, Inc,
`West Chester, Pennsylvania. Eight years ofexperience in pharmaceutical formulation research
`and development.
`
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`Certification:
`
`The undersigned Cephalon®, Inc. oficial certifies that the information presented-is true,
`accurate, and complete to the best ofthe knowledge ofthe preparers ofthe environmental
`assessment.
`
`The undersigned oficial certifies that the environmental assessment summary document
`(page: 1-8) contains non-confidential information and acknowledges that this information will
`be made available to the public in accordance with 40 CFR §1506.6.
`
`
`
`Date
`
`ITEM 15.
`
`Appendices:
`
`Appendix A:
`
`Appendix B:
`
`Appendix C:
`
`Identification ofChemical Substances in Modafinil Tablets (CONFIDENTIAL)
`
`Contract Manufacturer - Key Intermediate: Facility Information and Compliance
`Statement (CONFIDENTIAL)
`
`Contract Manufacturer . Drug Substance: Facility Information and Compliance
`Statement (CONFIDENTIAL)
`
`Contract Manufacturing Facility - Drug Product: Certification ofCompliance
`(NON-CONFIDENTIAL)
`
`Contract Manufacturing Facility - Drug Product: Applicable Regulations and
`Environmental Permits (CONFIDENTIAL)
`
`Contract Disposal Facility - Drug Product: Facility Location and Applicable .
`Permits (CONFIDENTIAL)
`
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`: Material Safety Data Sheet for Modafinil Drug Substance
`(NObi-CONFIDENTIAL)
`
`: Maximum Yearly Market Volume Estimate for Modafinil Tablets
`-(CONFH)ENTIAL)
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`APPENDIX D:
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`Contract Manufacturing Facility - Drug Product:
`
`Certification of Compliance
`
`(NON- CONFIDENTIAL)
`
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`CIR“ PHARMACEUTICAIS. INC-
`
`)! M AVENIE HO. BOX 30 com NY "736-0030
`(SIG! “2-0383 FAX [SIG] “2‘630
`
`.
`
`.
`( "
`-
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`Cirm Pharmaceuticals, Inc. hereby certifies that
`'it is in compliance with, or on an enforceable
`schedule to be in compliance with, all emission
`requirements set forth inpermits, consent decrees
`and administrative orders applicable to the
`production of modafinil at our
`facilities
`in
`Copiague, New York as well
`as emission
`requirements set forth in applicable federal, state,
`and local statutes and regulations applicable to
`the production of modafinil at its facilities in
`Copiague, New York. Approval and subsequent
`manufacture of production quantities of this drug
`product
`are
`not
`expected to affect
`this
`compliance.
`
`Director, Quality Assurance
`
`3/7/96
`
`Date
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`APPENDIX G:
`
`Material Safety Data Sheet
`for Modafinil Drug Substance
`
`(NON-CONFIDENTIAL)
`
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` Emergency Phone Nu
`
`
`
`
`West Chester, PA 19380
`
`(800) 424-9300
`Phone Number for Information:
`(610) 344-0200
`'
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`
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`Prepared By: S. Field, J. Mallamo. I. Patterson, D. Stong
`Date Prepared: 12/96
`Substance: 2-[(diphenylmethyl ) sulfinyl] aoetamide, 2-(benzhyd1ylsulfinyl) acetamide
`Other Designation (cg, synonyms, trade names): modafinil, PROVIGIL®, CEP 1538
`
`
`
`
`
`Component-(i5: 2-[(diphenylmethyl)sulfinyl] lacetamide, 2-(benzhydry) acetamide
`
`CAS Numberm: 68693-11-8
`Percentage“): > 99%
`
`
` Potential Health Effects
`Primary Entry Routes:
`Inhalation, ingestion
`
`
`Target Organs:
`
`
`
`Inhalation
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`Short Term Effects: data not available
`Long Term Effects:
`data not available
`Skin Contact
`
`data not available
`data not available
`
`data not available
`data not available
`
`data not available
`
`Short Term Effects:
`Long Term Effects:
`Eye Contact
`Short Term Effects:
`. Long Term Effects:
`Ingestion
`Short Term Effects: Rodent oral LDso>lOOO mg/kg, Dog oral LD” >200 mg/kg
`Long Term Etl'ects: Non-toxic to rats at 20 mg/kg/day and dogs at 10 mg/kg/day
`Parenteral Contact
`data not available
`Short Term Effects:
`Long Term Effects: data not available
`Carcinogeu Status
`(answer yes, no or not applicable)
`OSHA ("vaunted carcinogen): no
`NTP (confirmed or suspect):
`no
`IARC(1, 2A or 23):
`no
`Medical Conditions Aggravated by Long-Term Exposure:
`Other: N/A
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`Inhalation: Remove fiom eimoSure area 0 fi'eshmair. Ifbreathing has stopped, perform artificial
`respiration Contact physician immediately.
`
`
`Skin Contact: Wash with copious amounts ofwater or soap and water. Contact physician
`immediately.
`
`
`Eye Contact: Flush eyes with copious amounts ofwater or normal saline. Contact physician
`immediately.
`
`
`Ingestion: Induce vomiting. (Keep head lower than hips to prevent aspiration). Contact
`physician immediately
`
`
`Note to Physician (i.e.. specific medical info. on treatment & diagnostic procedures): data not
`available
`
`A t’d
`° da
`
`
`
`
`Extinguishing Media: Dry chemical, carbon dioxide, water spray, foam
`Flash Point: N/A
`
`Lower Flammable Limit: NIA
`Upper Flammable Limit: N/A
`Autoignition Temperature: N/A
`~
`Flammability Class-:(OSHA) N/A
`
`Hazardous Combustion Products: data not available
`
`
`
`
`
`
`
` Fire and Explosion Hazard: N/A
`
`
`
`
`Indoor Spill
`
`
`
`
`
`usewet methods to preventan’oorneldusts Remove residuewith HEPA-
`
`
`equipped vacuum.
`
`Release into Soil: data not available
`
`
`ReleaselDischarge into Ambient Air: data not available
`
`
`
` Handling Precautions: The-efi‘ects ofoccupational cxposureltothis product are unknown
`
`
`Handle as potentially hazardous material using traditional industrial hygiene methods.
`Stora - e R-- uirements: Store at ambient t-m . .
`:
`-
`below 40 d--
`
`
`
` Exposure Limits: not defined
`Ventilation: Local exhaust, mechanical
`
`Eye Protection:
`safety glasses
`
`
`Clothing: Body covering clothing to prevent contact with skin
`Gloves: for handling dry powder, use uitrile or other suitable disposable glove. When handling
`
`
`solutions, select glove based on solvent.
`
`Respiratory Protection: MOSH-certified negative air-purifying respirator with HEPA
`
`
`cartridges. Ifairborne concentration is unlmown or suspected to exceed the respirator’s
`
`
`maximum use concentration, select a respirator with a higher protection actor.
`
`
`For Firefighting and Other Immediately Dangerous to Life or Health Conditions:
`Self-contained breathing apparatus in pressure-demand mode, and personal protective clothing
`
`suitable to revent dermal «u osure
`
`
` Description: White, crystalline powder. Odoriess.
`
`Molecular Weight: 273.35
`
`
`
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`Boiling Point: N/A
`Freezing Point: N/A
`
`
`Melting Point: melts with decomposition between 165°-l70°
`
`
`Vapor Pressure (mm Hg): N/A
`Density (H;O=1 at 4°C): N/A
`
`
`Saturated Vapor Density (air-1): 0.4
`
`
`Specific Gravity (H,O=l): N/A
`Water Solubility: 0.4 mg/mL
`
`
`Percent Volatiles by Volume: < 0.1%
`
`
`pH: N/A
`Odor Threshold: N/A
`
`
`Evaporation Rate (Butyl Acetate - 1): N/A
`Viscosity: N/A
`
`
`
`
`
`
`Incompatibilities: unknown
`
`
`Hazardous Decomposition: n
`
`'
`Pol merization' not ob
`
`
`Acute and Chronic Studies
`
`Inhalation: data not available
`
`Ingestion: Rodent oral LDso>1000 mg/kg, Dog oral LDso >200 mg/kg
`
`Non-toxic to rats at 20 mg/kg/day and dogs at 10 mg/kg/day
`
`
`Skin: data not available
`.
`Eye: data not available
`
`
`
`
`
`
`
`
`
`III
`DOT Packing Group:
`
`DOT Labeling Requirements: UN NA281 1
`
`
`DOT Packaging Authorizations: N/A
`
`DOT I uanti
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`(
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`TSCA Status: N/A
`CERCLA Section 103 (40 CFR 302.4):
`N/A
`SARA Section 302 (40 CFR 355.30):
`N/A
`SARA Section 304 (40 CFR 355.40):
`SARA Section 313 (40 CFR 372.65): N/A
`OSHA Process Safety (29 CFR 1910.119): N/A
`California Proposition 65: N/A
`Sara Hazard Categories, SARA Sections 311/312 (40 CFR 370.21)
`Acute Hazard:
`
`N/A
`
`, ,
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