Aummnunn
`us cw:-imam
`lnmlmnlouore
`
`Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices
`
`Toxicological profile
`
`NTIS order No.
`
`1. Di—N—OCTYLPHTHALATE
`2. ETHYLENE GLYCOLI .... ..
`PROPYLENE GLYCOL .
`. HEXACHLOROETHANE ............. ..
`. HMX .......................................... ..
`. HYDRAULIC FLUIDS
`. HYDRAZINES ..'.................. ..
`1,1—D|METHYLHYDRAZ|NE
`1,2-DIMETHYLHYDRAZINE
`DlMETHYLHYDRAZlNE ........ ..
`. MINERAL-BASED CRANKCASE OIL .
`. TITANIUM TETRACHLORIDE
`. WHITE PHOSPHORUS ............ ..
`
`PB98—101033
`PB98—101108
`
`PB98—101041
`PB98—-101058
`PB98—101066
`PB98—101025
`
`PB98—101066
`PB98—101074
`PB98—10’l 082
`
`67377
`
`CAS No.
`
`000117—84—0
`0O0107—21—1
`000O57—55—6
`O0O067~72—1
`O02691~41—0
`VANOUS
`000302—O1—2
`0O0057—14—7
`O0O540—73—8
`030260—66—3
`008002—05—9
`007550—45—O
`007723—14—0
`
`Dated: December 17, 1997.
`Georgi Jones,
`Director, Office ofPolicy and External Affairs,
`Agency for Toxic Substances and Disease
`Registry.
`[FR Doc. 97-33508 Filed 12 —23—97; 8:45 am]
`BILLING CODE 4163—7(1—P
`
`DEPARTMENT OF HEALTH AND
`HUMAN SERVICES
`
`Centers for Disease Control and
`Prevention
`
`National Vaccine Advisory Committee
`(NVAC), Subcommittee on Future
`Vaccines, Subcommittee on
`Immunization Coverage, and
`Subcommittee on Vaccine Safety:
`Meetings
`In accordance with section lO(a)(2) of
`the Federal Advisory Committee Act
`(Pub. L. 92-463), the Centers for Disease
`Control and Prevention (CDC)
`announces the following Federal
`advisory committee meetings.
`7 Name: National Vaccine’ACl‘\'/isory
`Committee (NVAC).
`Times and Dates: 9 a.m.—2 p.m., January
`12, 1998. 8:30 a.m.—l:l5 p.m.,]anuary 13.
`1998.
`Place: Hubert H. Humphrey Building,
`Room 800, 200 Independence Avenue, SW,
`Washington, DC 20201.
`Status: Open to the public, limited only by
`the space available.
`Notice: In the interest of security, the
`Department has instituted stringent
`procedures for entrance to the Hubert H.
`Humphrey Building by non-government
`employees. Thus, persons without a
`government identification card should plan
`to arrive at the building each day either
`between 8 and 8:30 a.m. or 12:30 and l p.m.
`so they can be escorted to the meeting.
`Entrance to the meeting at other times during
`the day cannot be assured.
`Purpose: This committee advises and
`makes recommendations to the Director of
`the National Vaccine Program on matters
`related to the Program responsibilities.
`Matters To Be Discussed: Agenda items
`will include updates on the National Vaccine
`Program Office (NVPO) activities; the
`
`National Vaccine Plan and NVAC’s role in
`defining priorities for action; unmet needs
`funding—past, present and future; adult
`immunization: report of the workgroup; use
`of non-traditional sites for adult
`immunization; influenza: a growing need for
`pandemic preparedness; and a discussion on
`vaccines for international travel.
`In addition, there will be updates on
`welfare reform and effects on immunization;
`moving towards a Department of Health and
`Human Services’ vaccine safety action plan;
`work group on philosophical exemptions—
`~
`I
`.>
`.
`.. _
`I
`..I
`I‘
`final report; the presidential initiative on
`J.LJlAllL.|||Al.ul1\.I1A mgr
`.
`-
`critically needed vac 1
`at gies to
`consider. There will be reports from the
`Subcommittee on Immunization Coverage,
`Subcommittee on Future Vaccines, and
`Subcommittee on Vaccine Safety.
`Name: Subcommittee on Immunization
`Coverage.
`Time and Date: 2 p.m.~5 p.m., january 12,
`1998.
`Place: Hubert I-I. Humphrey Building,
`Room 423A, 200 Independence Avenue, SW,
`Washington, DC 20201.
`Status.‘ Open to the public, limited only by
`the space available.
`Purpose: This subcommittee will identify
`cmd propose solutions that provide a
`W
`multifaceted and holistic approach to
`reducing barriers that result in low
`immunization coverage for children.
`Matters To Be Discussed: This
`subcommittee will hold a discussion on the
`review of recommendations from the
`document, “Strategies to Sustain
`Immunization Coverage,” and the
`finalization of those recommendations.
`Name: Subcommittee on Future Vaccines.
`Time and Date: 2 p.m.—5 p.m., January 12,
`1998.
`Place.‘ Hubert H. Humphrey Building,
`Room 405A, 200 Independence Avenue, SW,
`Washington, DC 20201.
`Status: Open to the public, limited only by
`the space available.
`Purpose: The Subcommittee on Future
`Vaccines will develop policy options and
`guide national activities which will lead to
`accelerated development, licensure, and best
`use of new vaccines in the simplest possible
`immunization schedules.
`Matters To Be Discussed: This
`subcommittee will hold discussions
`regarding the continued evaluation of
`methods to remove barriers to development,
`
`licensure and use of safe and effective new
`vaccines: combination vaccines, strategic
`options; and defining future vaccines policy
`issues for travelers’ vaccines.
`Name: Subcommittee on Vaccine Safety.
`Time and Date: 2 p.m.—5 p.m., January 12,
`l998.
`Place: Hubert H. Humphrey Building,
`Room 800, 200 Independence Avenue, SW,
`Washington, DC 20201.
`Status: Open to the public, limited only by
`the space available.
`Purpose: This subcommittee will review
`issues relevant to vaccine safety and adverse
`reactions to vaccines.
`Matters To Be Discussed: This
`subcommittee will hold discussions
`regarding its goals; a report from the Task
`Force on Safer Childhood Vaccines; a project
`report on bencfitrisk communication
`curriculum development; and agenda items
`for the next meeting.
`Agenda items are subject to change as
`priorities dictate.
`Contact Person for More Informa rion:
`Felecia D. Pearson, Committee Managenient
`Specialist, NVPO, CDC, 1600 Clifton Road,
`NE, M/S D50, Atlanta, Georgia 30333,
`telephone 404/639-4450.
`r Dated: December 19, 1997.
`Carolyn]. Russell,
`Director, Management Analysis and Services
`Office, Centers for Disease Control and
`Prevention (CDC).
`[FR Doc. 97-33666 Filed 12—23—97; 8:45 am]
`BILLING cope 4163-1B—P
`
`DEPARTMENT OF HEALTH AND
`HUMAN SERVICES
`
`Food and Drug Administration
`[Docket No. 97D-D148]
`
`International Conference on
`Harmonisation; Guidance on
`Impurities: Residual Solvents
`
`AGENCY: Food and Drug Administration,
`HHS.
`ACTION: Notice.
`
`SUMMARY: The Food and Drug
`Administration (FDA) is publishing a
`guidance entitled “Q3C Impurities:
`
`AVENTIS EXHIBIT 2057
`Mylan v. Aventis, IPR2016-00712
`
`

`
`67378
`Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices
`
`Residual Solvents." The guidance was
`prepared under the auspices of the
`International Conference on
`Harmonisation of Technical
`Requirements for Registration of
`Pharmaceuticals for Human Use (ICH).
`The guidance recommends acceptable
`amounts of residual solvents in
`
`pharmaceuticals for the safety of the
`patient, and recommends the use of less
`toxic solvents in the manufacture of
`drug substances and dosage forms.
`DATES: Effective December 24, 1997.
`Submit written comments at any time.
`ADDRESSES: Submit written comments
`on the guidance to the Dockets
`Management Branch (HFA—305), Food
`and Drug Administration, 12420
`Parklawn Dr., rm. 1-23, Rockville, MD
`20857. Copies of the guidance are
`available from the Drug Information
`Branch (HFD—210), Center for Drug
`Evaluation and Research, Food and
`Drug Administration, 5600 Fishers
`Lane, Rockville, MD 20857, 301-827-
`4573.
`FOR FURTHER INFORMATION CONTACT:
`Regarding the guidance: John J. Gibbs,
`Center for Drug Evaluation and
`Research (HFD—820), Food and
`Drug Administration, 5600 Fishers
`Lane, Rockville, MD 20857, 301-
`827-6430.
`Regarding ICH: Janet J. Showalter,
`Office of Health Affairs (HFY—20),
`Food and Drug Administration,
`5600 Fishers Lane, Rockville, MD
`20857, 301-827-0864.
`SUPPLEMENTARY INFORMATION: In recent
`years, many important initiatives have
`been undertaken by regulatory
`authorities and industry associations to
`promote international harmonization of
`regulatory requirements. FDA has
`participated in many meetings designed
`to enhance harmonization and is
`committed to seeking scientifically
`based harmonized technical procedures
`for pharmaceutical development. One of
`the goals of harmonization is to identify
`and then reduce differences in technical
`requirements for drug development
`among regulatory agencies.
`ICH was organized to provide an
`opportunity for tripartite harmonization
`initiatives to be developed with input
`from both regulatory and industry
`representatives. FDA also seeks input
`from consumer representatives and
`others. ICH is concerned with
`harmonization of technical
`requirements for the registration of
`pharmaceutical products among three
`regions: The European Union, Japan,
`and the United States. The six ICH
`sponsors are the European Commission,
`the European Federation of
`Pharmaceutical Industries Associations,
`
`,
`
`the Japanese Ministry of Health and
`Welfare, the Japanese Pharmaceutical
`Manufacturers Association, the Centers
`for Drug Evaluation and Research
`(CDER) and Biologics Evaluation and
`Research (CBER), FDA, and the
`Pharmaceutical Research and
`Manufacturers of America. The ICH
`Secretariat, which coordinates the
`preparation of documentation, is
`provided by the International
`Federation of Pharmaceutical
`Manufacturers Associations (IFPMA).
`The ICH Steering Committee includes
`representatives from each of the ICH
`sponsors and the IFPMA, as well as
`observers from the World Health
`Organization, the Canadian Health
`Protection Branch, and the European
`Free Trade Area.
`In the Federal Register of May 2, 1997
`(62 FR 24302), FDA published a draft
`tripartite guideline entitled “Impurities:
`Residual Solvents" (Q3C). The notice
`gave interested persons an opportunity
`to submit comments by June 16, 1997.
`After consideration of the comments
`received and revisions to the guidance,
`a final draft of the guidance was
`submitted to the ICH Steering
`Committee and endorsed by the three
`participating regulatory agencies on July
`17, 1997.
`In accordance with FDA’s Good
`Guidance Practices (62 FR 8961,
`February 27, 1997), this document has
`been designated a guidance, rather than
`a guideline.
`Residual solvents in pharmaceuticals
`are organic volatile chemicals that are
`used or produced in the synthesis of
`drug substances or excipients, or in the
`preparation of drug products. They are
`not completely removed by practical
`manufacturing techniques. The
`guidance recommends acceptable
`amounts of residual solvents in
`pharmaceuticals for the safety of the
`patient. The guidance recommends the
`use of less toxic solvents and describes
`levels considered to be toxicologically
`acceptable for some residual solvents.
`The guidance applies to residual
`solvents in drug substances, excipients,
`and drug products, and to all dosage
`forms and routes of administration. The
`guidance does not apply to potential
`new drug substances, excipients, or
`drug products used during the clinical
`research stages of development, nor
`does it apply to existing marketed drug
`products.
`This guidance represents the agency’s
`current thinking on acceptable amounts
`of residual solvents in pharmaceuticals.
`It does not create or confer any rights for
`or on any person and does not operate
`to bind FDA or the public. An
`alternative approach may be used if
`
`such approach satisfies the
`requirements of the applicable statute,
`regulations, or both.
`As with all of FDA’s guidances, the
`public is encouraged to submit written
`comments with new data or other new
`
`information pertinent to this guidance.
`The comments in the docket will be
`periodically reviewed, and, where
`appropriate, the guidance will be
`amended. The public will be notified of
`any such amendments through a notice
`in the Federal Register.
`Interested persons may, at any time,
`submit written comments on the
`guidance to the Dockets Management
`Branch (address above). Two copies of
`any comments are to be submitted,
`except that individuals may submit one
`copy. Comments are to be identified
`with the docket number found in
`
`brackets in the heading of this
`document. The guidance and received
`comments may be seen in the office
`above between 9 a.m. and 4 p.m.,
`Monday through Friday. An electronic
`version of this guidance is available on
`the Internet (http://www.fda.gov/cder/
`guidance.htm).
`The text of the guidance follows:
`Q3C Impurities: Residual Solvents 1
`1. Introduction
`
`The objective of this guidance is to
`recommend acceptable amounts for residual
`solvents in pharmaceuticals for the safety of
`the patient. The guidance recommends use of
`less toxic solvents and describes levels
`considered to be toxicologically acceptable
`for some residual solvents.
`_
`Residual solvents in pharmaceuticals are
`defined here as organic volatile chemicals
`that are used or produced in the manufacture
`of drug substances or excipients, or in the
`preparation of drug products. The solvents
`are not completely removed by practical
`manufacturing techniques. Appropriate
`selection of the solvent for the synthesis of
`drug substance may enhance the yield, or
`determine characteristics such as crystal
`form, purity, and solubility. Therefore, the
`solvent may sometimes be a critical
`parameter in the synthetic process. This
`guidance does not address solvents
`deliberately used as excipients nor does it
`address solvates. However, the content of
`solvents in such products should be
`evaluated and justified.
`Since there is no therapeutic benefit from
`residual solvents, all residual solvents should
`be removed to the extent possible to meet
`product specifications, good manufacturing
`practices, or other quality—based
`requirements. Drug products should contain
`
`1 This guidance represents the agency's current
`thinking on acceptable amounts of residual solvents
`in pharmaceuticals. It does not create or confer any
`rights for or on any person and does not operate to
`bind FDA or the public. An alternative approach
`may be used if such approach satisfies the
`requirements of the applicable statute, regulations,
`or both.
`
`

`
`67379
`Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices
` j_
`
`‘no higher levels of residual solvents than can
`be supported by safety data. Some solvents
`that are known to cause unacceptable
`toxicities (Class 1, Table 1) should be
`avoided in the production of drug
`substances, excipients, or drug products
`unless their use can be stronglyjustified in
`a risk—benefit assessment. Some solvents
`associated with less severe toxicity (Class 2,
`Table 2) should be limited in order to protect
`patients from potential adverse effects.
`Ideally, less toxic solvents (Class 3, Table 3)
`should be used where practical. The
`complete list of solvents included in this
`guidance is given in Appendix 1.
`The lists are not exhaustive and other
`solvents can be used and later added to the
`lists. Recommended limits of Class 1 and 2
`solvents or classification of solvents may
`change as new safety data becomes available.
`Supporting safety data in a marketing
`application for a new drug product
`containing a new solvent may be based on
`concepts in this guidance or the concept of
`qualification of impurities as expressed in
`the guidance‘ for drug substance (QSA,
`Impurities in New Drug Substances) or drug
`product (Q3B, Impurities in New Drug
`Products), or all three guidances.
`
`2. Scope of the Guidance
`Residual solvents in drug substances,
`excipients, and drug products are within the
`scope of this guidance. Therefore, testing
`should be performed for residual solvents
`when production or purification processes
`are known to result in the presence of such
`solvents. It is only considered necessary to
`test for solvents that are used or produced in
`the manufacture or purification of drug
`substances, excipients, or drug products.
`Although manufacturers may choose to test
`the drug product, a cumulative method may
`be used to calculate the residual solvent
`levels in the drug product from the levels in
`the ingredients used to produce the drug
`product. If the calculation results in a level
`equal to or below that recommended in this
`guidance, no testing of the drug protlucrfm
`residual solvents need he considered. If,
`however, the calculated level is above the
`recommended level, the drug product should
`be tested to ascertain whether the
`formulation process has reduced the relevant
`solvent level to within the acceptable
`amount. Drug product should also be tested
`if a solvent is used during its manufacture.
`This guidance does not apply to potential
`new drug substances, excipients, or drug
`products used during the clinical research
`stages of development, nor does it apply to
`existing marketed drug products.
`
`The guidance applies to all dosage forms
`and routes of administration. Higher levels of
`residual solvents may be acceptable in
`certain cases such as short»term (30 days or
`less) or topical application. Justification for
`these levels should be made on a case—by—
`case basis.
`See Appendix 2 of this document for
`additional background information related to
`residual solvents.
`
`Option 1.’ The concentration limits in
`parts per million (ppm) stated in Table
`2 can be used. They were calculated
`using equation (1) below by assuming a
`product mass of 10 grams (g)
`administered daily.
`
`(1) Concentration (ppm) =
`
`1000 >< PDE
`
`dose
`
`3. General Principles
`3.1 Classification of Residual Solvents by
`Risk Assessment
`
`The term "tolerable daily intake" (TDI) is
`used by the International Program on
`Chemical Safety (IPCS) to describe exposure
`limits of toxic chemicals and the‘ term
`“acceptable daily intake" (ADI) is used by
`the World Health Organization (WHO) and
`other national and international health
`authorities and institutes. The new term
`“permitted daily exposure” (PDE) is defined
`in the present guidance as a
`pharmaceutically acceptable intake of
`residual solvents to avoid confusion of
`differing values for ADl’s of the same
`substance.
`Residual solvents assessed in this guidance
`are listed in Appendix 1 by common names
`and structures. They were evaluated for their
`.L‘..I.......
`,..1,........\
`.... L‘n11n...n.
`possible risk to human health and placed
`iutu uin, vn L|1A\.\, LAlAuuvu um .....V.....
`Class 1 solvents: Solvents to be avoided-
`Known human carcinogens, strongly
`suspected human carcinogens, and
`environmental hazards.
`Class 2 solvents: Solvents to be li1nited—
`Nongenotoxic animal carcinogens or
`possible causative agents of other irreversible
`toxicity such as neurotoxicity or
`teratogenicity.
`Solvents suspected of other significant but
`reversible toxicities.
`Class 3 solvents: Solvents with low toxic
`potentialw
`Solvents with low toxic potential to man;
`no health-based exposure limit is needed.
`Class 3 solvents have PDE's of 50 milligrams
`(mg) or more per day.
`''
`3.2 Methods for Establishing Exposure Limits
`The method used to establish permitted
`daily exposures for residual solvents is
`presented in Appendix 3. Summaries of the
`toxicity data that were used to establish
`limits are published in Pharmeuropa, Vol. 9,
`No. 1, Supplement, April 1997.
`
`3.3 Options for Describing Limits of Class 2
`Solvents
`
`Two options are available when setting
`limits for Class 2 solvents.
`
`l-Iere, PDE is given in terms of mg/day and
`close is given in g/day.
`These limits are considered acceptable for
`all substances, excipients, or products.
`Therefore, this option may be applied if the
`daily dose is not known or fixed. If all
`excipients and drug substances in a
`formulation meet the limits given in Option
`1, then these components may be used in any
`proportion. No further calculation is
`necessary provided the daily dose does not
`exceed 10 g. Products that are administered
`in doses greater than l() g per day should be
`considered under Option 2.
`Option 2: It is not considered necessary for
`each component of the drug product to
`comply with the limits given in Option 1.
`The PDE in terms of mg/day as stated in
`Table 2 can be used with the known
`maximum daily dose and equation (1), as
`si1uwnn1Qptiun 1 in the previous pamgmplr,
`to determine the concentration of residual
`solvent allowed in drug product. Such limits
`are considered acceptable provided that it
`has been demonstrated that the residual
`solvent has been reduced to the practical
`minimum. The limits should be realistic in
`relation to analytical precision,
`manufacturing capability, and reasonable
`variation in the manufacturing process and
`the limits should reflect contemporary
`manufacturing standards.
`Option 2 may be applied by adding the
`amounts of a residual solvent present in each
`of the components of the drug product. The
`sum of the amounts ufsulvent per day should
`be less than that given by the PDE.
`Consider an example of the use of Option
`1 and Option 2 applied to acetonitrile in a
`drug product. The permitted daily exposure
`to acetonitrile is 4.1 mg per day; thus, the
`Option 1 limit is 410 ppm. The maximum
`administered daily mass of a drug product is
`5.0 g, and the drug product contains two
`excipients. The composition of the drug
`product and the calculated maximum content
`of residual acetonitrile are given in the
`following table.
`
`Component
`
`Amount in formulation
`
`Acetonitrile content
`
`Daily exposure
`
`Drug substance
`Excipient 1
`Excipient 2
`Drug product
`
`0.3 g
`0.9 g
`3.8 9
`5.0 g
`
`800 ppm
`400 ppm
`800 ppm
`728 ppm
`
`0.24 mg
`0.36 mg
`3.04 mg
`3.64 mg
`
`Excipient 1 meets the Option 1 limit, but
`the drug substance, excipient 2, and drug
`
`product do not meet the Option 1 limit.
`Nevertheless, the product meets the Option
`
`2 limit of 4.1 mg per day and thus conforms
`to the recommendations in this guidance.
`
`

`
`67380
`Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices
`
`Consider another example using
`acetonitrile as residual solvent. The
`maximum administered daily mass of a drug
`
`product is 5.0 g, and the drug product
`contains two excipients. The composition of
`the drug product and the calculated
`
`maximum content of residual acetonitrile are
`given in the following table.
`
`Component
`
`Amount in formulation
`
`Acetonitrile content
`
`Daily exposure
`
`Drug substance
`Excipient 1
`Excipient 2
`Drug product
`
`0.3 g
`0.9 g
`3.8 g
`5.0 g
`
`800 ppm
`2,000 ppm
`800 ppm
`1,016 ppm
`
`0.24 mg
`1.80 mg
`3.04 mg
`5.08 mg
`
`In this example, the product meets neither
`the Option 1 nor the Option 2 limit according
`to this summation. The manufacturer could
`test the drug product to determine if the
`formulation process reduced the level of
`acetonitrile. lf the level of acetonitrile was
`not reduced during formulation to the
`allowed limit, then the manufacturer of the
`drug product should take other steps to
`reduce the amount of acetonitrile in the drug
`product. If all of these steps fail to reduce the
`level of residual solvent, in exceptional cases
`the manufacturer could provide a summary
`of efforts made to reduce the solvent level to
`meet the guidance value, and provide a risk-
`benefit analysis to support allowing the
`product to be utilized with residual solvent
`at a higher level.
`
`3.4 Analytical Procedures
`Residual solvents are typically determined
`using chromatographic techniques such as
`gas chromatography. Any harmonized
`procedures for determining levels of residual
`solvents as described in the pharmacopoeias
`should be used, if feasible. Otherwise,
`manufacturers would be free to select the
`most appropriate validated analytical
`procedure for a particular application. If only
`Class 3 solvents are present, a nonspecific
`method such as loss on drying may be used.
`
`Validation of methods for residual solvents
`should conform to ICH guidances “QZA Text
`on Validation of Analytical Procedures" and
`"Q2B Validation of Analytical Procedures:
`Methodology."
`
`3.5 Reporting Levels of Residual Solvents
`Manufacturers of pharmaceutical products
`need certain information about the content of
`residual solvents in excipients or drug
`substances in order to meet the criteria of this
`guidance. The following statements are given
`as acceptable examples of the information
`that could be provided from a supplier of
`excipients or drug substances to a
`pharmaceutical manufacturer. The supplier
`might choose one of the following as
`appropriate:
`0 Only Class 3 solvents are likely to be
`present. Loss on drying is less than 0.5
`percent.
`* are
`*
`0 Only Class 2 solvents X, Y, *
`likely to be present. All are below the Option
`1 limit. (Here the supplier would name the
`Class 2 solvents represented by X, Y, *
`*
`*
`.)
`* * and
`- Only Class 2 solvents X, Y, *
`Class 3 solvents are likely to be present.
`Residual Class 2 solvents are below the
`Option 1 limit and residual Class 3 solvents
`are below 0.5 percent.
`
`If Class 1 solvents are likely to be present,
`they should be identified and quantified.
`“Likely to be present" refers to the solvent
`used in the final manufacturing step and to
`solvents that are used in earlier
`manufacturing steps and not removed
`consistently by a validated process.
`If solvents of Class 2 or Class 3 are present
`at greater than their Option 1 limits or 0.5
`percent, respectively, they should be
`identified and quantified.
`4. Limits of Residual Solvents
`
`4.1 Solvents to Be Avoided
`Solvents in Class 1 should not be
`employed in the manufacture of drug
`substances, excipients, and drug products
`because of their unacceptable toxicity or their
`deleterious environmental effect. However, if
`their use is unavoidable in order to produce
`a drug product with a significant therapeutic
`advance, then their levels should be
`restricted as shown in Table 1, unless
`otherwise justified. The solvent 1,1,1»
`Trichloroethane is included in Table 1
`because it is an environmental hazard. The
`stated limit of 1,500 ppm is based on a
`review of the safety data.
`
`TABLE 1.—CLASS 1 SOLVENTS IN PHARMACEUTICAL PRODUCTS
`
`(SOLVENTS THAT SHOULD BE AVOIDED)
`
`Solvent
`
`C°”°eEgLar,:1'§’" "mu
`
`Concern
`
`Benzene
`Carbon tetrachloride
`1,2-Dichloroethane
`1,1-Dichloroethene
`1,1,1-Trichloroethane
`
`2
`4
`5
`' 8
`1,500
`
`Carcinogen
`Toxic and environmental hazard
`Toxic
`Toxic
`Environmental hazard
`
`4.2 Solvents to Be Limited
`Solvents in Table 2 should be limited
`in pharmaceutical products because of
`their inherent toxicity. PDE’s are given
`
`to the nearest 0.1 mg/day, and
`concentrations are given to the nearest
`10 ppm. The stated values do not reflect
`the necessary analytical precision of
`
`determination. Precision should be
`determined as part of the validation of
`the method.
`
`TABLE 2.—CLASS 2 SOLVENTS IN PHARMACEUTICAL PRODUCTS
`
`Solvent
`
`Acetonitrile
`Chlorobenzene
`Chloroform
`Cyclohexane
`1,2-Dichloroethene
`
`PDE (mg/day)
`
`Concentration
`limit (ppm)
`
`4.1
`3.6
`0.6
`38.8
`18.7
`
`410
`360
`60
`3,880
`1,870
`
`

`
`
`
`Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices 67381a.
`
`TABLE 2.——CLASS 2 SOLVENTS IN PHARMACEUTICAL PRODUCTS—C0n'[Il'lUed
`
`Solvent
`
`PDE (mg/day)
`
`T
`
`Concentration
`limit (ppm)
`
`Dichloromethane
`1,2—Dimethoxyethane
`N,N-Dimethylacetamide
`N,N-Dimethylformamide
`1,4-Dioxane
`2-Ethoxyethanol
`Ethyleneglycol
`Formamide
`Hexane
`Methanol
`2-Methoxyethanol
`Methylbutyl ketone
`Methylcyclohexane
`N-Methylpyrrolidone
`Nitromethane
`Pyridine
`Sulfolane
`,Tetra|in
`Toluene
`1 ,1,2-Trichloroethene
`Xylene‘
`1 Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.
`
`6.0
`1.0
`10.9
`8.8
`3.8
`1.6
`6.2
`2.2
`2.9
`30.0
`0.5
`0.5
`11.8
`48.4
`0.5
`2.0
`1.6
`1.0
`8.9
`0.8
`21.7
`
`600
`100
`1,090
`880
`380
`160
`620
`220
`290
`3,000
`50
`50
`1,180
`4,840
`50
`200
`160
`100
`890
`80
`2,170
`
`4.3 Solvents with LOW Toxic Potential
`Solvents in Class 3 (shown in Table
`3) may be regarded as less toxic and of
`lower risk to human health. Class 3
`includes no solvent known as a human
`health hazard at levels normally
`accepted in pharmaceuticals. However,
`
`there are no long—term toxicity or
`carcinogenicity studies for many of the
`solvents in mass .5. /-wauaoie data
`indicate that they are less toxic in acute
`or short—term studies and negative in
`genotoxicity studies. It is considered
`that amounts of these residual solvents
`
`of 50 mg per day or less (corresponding
`to 5,000 ppm or 0.5 percent under
`Option 1) wuuld be acceptable vvitltuut
`justification. Higher amounts may also
`be acceptable provided they are realistic
`in relation to manufacturing capability
`and good manufacturing practice (GMP).
`
`TABLE 3.—CLASS 3 SOLVENTS WHICH SHOULD BE LIMITED BY GMP OR OTHER QUALITY-BASED REQUIREMENTS
`
`Acetic acid
`Acetone
`Anisole
`1-Butanol
`2—Butanol
`Butyl acetate
`tert—Butylmethyl ether
`Cumene
`Dimethyl sulfoxide
`Ethanol
`Ethyl acetate
`Ethyl ether
`Ethyl formate
`Formic acid
`
`Heptane
`lsobutyl acetate
`lsopropyl acetate
`Methyl acetate
`3—Methy|—1—butanol
`Methylethyl ketone
`Methylisobutyl ketone
`2-Methy|—1—propano|
`Pentane
`1—Pentano|
`1—Propanol
`2—Propano|
`Propyl acetate
`Tetrahydrofuran
`
`4.4 Solvents for Which No Adequate
`T0X1'C010g1'Ca1 Data Were Found
`The following solvents (Table 4) may also
`be of interest to manufacturers of excipients,
`
`drug substances, or drug products. However,
`no adequate toxicological data on which to
`base 3 PDE Were f0UT1d« Manufacturers
`
`should supply justification for residual levels
`of these solvents in pharmaceutical products.
`
`TABLE 4.—SOLVENTS FOR WHICH NO ADEQUATE TOXICOLOGICAL DATA WERE FOUND
`
`1,1-Dlethoxypropane
`1,1—Dimethoxymethane
`2,2-Dimethoxypropane
`lsooctane
`lsopropyl ether
`
`Methylisopropyl ketone
`Methyltetrahydrofuran
`Petroleum ether
`Trichloroacetic acid
`Trlfluoroacetic acid
`
`

`
`67382
`Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices7
`
`Glossary
`Genotoxic carcinogens: Carcinogens that
`produce cancer by affecting genes or
`chromosomes.
`LOEL: Abbreviation for lowest-observed
`effect level.
`Lowest-observed effect level: The lowest
`dose of substance in a study or group of
`studies that produces biologically significant
`increases in frequency or severity of any
`effects in the exposed humans or animals.
`Mod1‘fy1‘ng factor: A factor determined by
`professional judgment of a toxicologist and
`applied to bioassay data to relate that data
`safely to humans.
`
`Neurotox1’c1‘ty:The ability of a substance to
`cause adverse effects on the nervous system.
`NOEL: Abbreviation for no-observed—effect
`level.
`
`Reversible tox1'c1‘t_y.'The occurrence of
`harmful effects that are caused by a substance
`and which disappear after exposure to the
`substance ends.
`
`No—observed—effect level: The highest dose
`of substance at which there are no
`biologically significant increases in
`frequency or severity of any effects in the
`exposed humans or animals.
`PDE: Abbreviation for permitted daily
`exposure.
`Permitted daily exposure: The maximum
`acceptable intake per day of residual solvent
`in pharmaceutical products.
`
`Strongly suspected human carcinogen: A
`substance for which there is no
`epidemiological evidence of carcinogenesis
`but there are positive genotoxicity data and
`clear evidence of carcinogenesis in rodents.
`Teratogen1'c1'ty: The occurrence of
`structural malformations in a developing
`fetus when a substance is administered
`during pregnancy.
`BILLING CODE 4160—01~F
`
`

`
`67383
`
`Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices
`
`Appendix 1. List of Solvents Included in the Guidance
`
`Solvent
`
`Qther Names
`
`Structure
`
`CH3COOH
`
`CH3COCI-13
`
`Acetic acid
`
`Ethanoic acid
`
`Acetone
`
`Acetonitrile
`
`2—Propanone
`Propan—2—one
`
`Anisole
`
`Methoxybenzene
`
`Benzene
`
`Benzol
`
`l—Butanol
`
`2—Butanol
`
`n-Butyl alcohol
`Butan—1—ol
`
`CH3 (CH2) 30H
`
`§eg—Butyl alcohol
`Butan—2~ol
`
`CH3CH2CI-I (OH) CH3
`
`Class
`
`Class
`
`Class
`
`Class
`
`Class
`
`Class
`
`Class
`
`Butyl acetate
`
`Acetic acid butyl
`ester
`
`CH3COO (CH2) 3CH3
`
`Class
`
`te t—Butylmethyl
`ether
`
`2—Methoxy—2—methyl~
`propane
`
`(CH3)3COCH3
`
`Carbon
`tetrachloride
`
`Chlorobenzene
`
`Tetraohloromethane
`
`Cclq
`
`chloroform
`
`Trichloromethane
`
`Cumene
`
`Isopropylbenzene
`(1-Methyl)ethylbenzene
`
`Cyclohexane
`
`Hexamethylene
`
`1,2-
`Dichloroethane
`
`sym—Dichloroethane
`Ethylene dichloride
`Ethylene Chloride
`
`CH2ClCH2Cl
`
`Class
`
`Class
`
`Class
`
`Class
`
`Class
`
`Class
`
`Class
`
`

`
`67384
`Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices
`
`
`1,1-
`Dichloroethene
`
`l,1—Dichloroethylene
`Vinylidene chloride
`
`H2C=CCl2
`
`Class
`
`1
`
`1,2-
`Dichloroethene
`
`1,2—Dichloroethylene
`Acetylene dichloride
`
`ClHC=CHCl
`
`Class
`
`Dichloromethane
`
`Methylene chloride
`
`CH2Cl2
`
`1,2-
`Dimethoxyethane
`
`Ethyleneglycol
`dimethyl ether
`Monoglyme
`Dimethyl Cellosolve
`
`H3COCH2CH2OCH3
`
`Class
`
`Class
`
`N,N-
`Dimethylacetamide
`
`N,N—
`Dimethylformamide
`
`DMA
`
`DMF
`
`CH3CON(CH3)2
`
`Class
`
`HCON(CH3)2
`
`Class
`
`Class
`
`Class
`
`Class
`
`Class
`
`Class
`
`Dimethyl
`sulfoxide
`
`Methylsulfinylmethane
`Methyl sulfoxide
`DMSO
`
`(CH3)2SO
`
`l,4—Dioxane
`
`p—Dioxane
`[1,4]Dioxane
`
`rfi
`D
`\._l
`
`O
`
`Ethanol
`
`Ethyl alcohol
`
`CH3CH2OH
`
`2~Ethoxyethanol
`
`Cellosolve
`
`CH3CH2OCH2CH2OH
`
`Ethyl acetate
`
`Acetic acid ethyl
`ester
`
`CH3COOCH2CH3
`
`Ethyleneglycol
`
`1,2—Dihydroxyethane
`1,2-Ethanediol
`
`HOCHZCHZOH
`
`Class
`
`Ethyl ether
`
`Diethyl ether
`Ethoxyethane
`1,l’—Oxybisethane
`
`CH3CH2OCH2CH3
`
`Class
`
`Ethyl formate
`
`Formic acid ethyl
`ester
`
`HCOOCHZCH3
`
`Formamide
`
`Methanamide
`
`Formic acid
`
`HCONH2
`
`HCOOH
`
`Class
`
`Class
`
`Class
`
`

`
`
`Federal Register / Vol. 62, No. 247 / Wednesday, December 24, 1997 / Notices
`
`Heptane
`
`Hexane
`
`n-Heptane
`
`n-Hexane
`
`CH3 (CH2) 5CH3
`
`CH2 (CH2) 4CH3
`
`Isobutyl acetate Acetic acid isobutyl
`ester
`
`CI-13COOCH2CH