Guidance for Industry
`
`Q3C Impurities: Residual Solvents
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`December 1997
`ICH
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`Guidance for Industry
`
`Q3C Impurities: Residual Solvents
`
`Additional copies are available from:
`Center for Drug Evaluation and Research (CDER),
`Division of Drug Information (HFD-240),
`5600 Fishers Lane, Rockville, MD 20857
`(Tel) 301-827-4573
`http://www.fda.gov/cder/guidance/index.htm
`or
`Office of Communication, Training, and
`Manufacturers Assistance (HFM-40),
`Center for Biologics Evaluation and Research (CBER)
`1401 Rockville Pike, Rockville, MD 20852-1448,
`http://www.fda.gov/cber/guidelines.htm;
`(Fax) 888-CBERFAX or 301-827-3844
`(Voice Information) 800-835-4709 or 301-827-1800
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`December 1997
`ICH
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`TABLE OF CONTENTS
`
`INTRODUCTION (1)............................................................................................................. 1
`I.
`II. SCOPE OF THE GUIDANCE (2)......................................................................................... 2
`III. GENERAL PRINCIPLES (3) ................................................................................................ 2
`A. Classification of Residual Solvents by Risk Assessment (3.1).................................................3
`
`B. Methods for Establishing Exposure Limits (3.2) ....................................................................3
`
`C. Options for Describing Limits of Class 2 Solvents (3.3) .........................................................3
`
`D. Analytical Procedures (3.4)....................................................................................................5
`
`E. Reporting Levels of Residual Solvents (3.5)...........................................................................5
`IV. LIMITS OF RESIDUAL SOLVENTS (4)............................................................................. 6
`A.
`Solvents to Be Avoided (4.1) .................................................................................................6
`
`B.
`
`C.
`
`Solvents to Be Limited (4.2) ..................................................................................................6
`
`Solvents with Low Toxic Potential (4.3).................................................................................6
`
`D.
`Solvents for Which No Adequate Toxicological Data Were Found (4.4) ................................7
`GLOSSARY .................................................................................................................................... 8
`APPENDIX 1: ADDITIONAL BACKGROUND.......................................................................... 9
`APPENDIX 2: METHODS FOR ESTABLISHING EXPOSURE LIMITS ............................. 10
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`Guidance for Industry1
`
`Q3C Impurities: Residual Solvents
`
`This guidance represents the Food and Drug Administration's (FDA's) current thinking on this
`topic. 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 statutes and regulations.
`
`I.
`
`INTRODUCTION (1)
`
`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. A
`complete list of the solvents included in this guidance is provided in a companion document
`entitled Q3C — Tables and List.2 The list is not exhaustive, and other solvents may be used and
`later added to the list.
`
`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.
`
`
`1 This guidance was developed within the Expert Working Group (Quality) of the International Conference on
`Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to
`consultation by the regulatory parties, in accordance with the ICH process. This document was endorsed by the ICH Steering
`Committee at Step 4 of the ICH process in July 1997. At Step 4 of the process, the final draft is recommended for adoption to
`the regulatory bodies of the European Union, Japan, and the United States.
`
`Arabic numbers in subsections reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at
`Step 4 of the ICH process.
`
`
`2 This guidance was published originally in the Federal Register on December 24, 1997 (62 FR67377). At that time
`the list was included as Appendix 1. In this reformatted version, the list has been removed and made into a companion document,
`and the remaining appendices have been renumbered.
`
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`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 no higher levels of residual
`solvents than can be supported by safety data. Some solvents that are known to cause unacceptable
`toxicities (Class 1, see Table 1 in the companion document Q3C — Tables and List) should be
`avoided in the production of drug substances, excipients, or drug products unless their use can be
`strongly justified in a risk-benefit assessment. Some solvents associated with less severe toxicity
`(Class 2, see Table 2 in the campanion document ) should be limited in order to protect patients
`from potential adverse effects. Ideally, less toxic solvents (Class 3, see Table 3 in the companion
`document) should be used where practical.
`
`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, Q3A Impurities in New
`Drug Substances (January 1996) or drug product, Q3B Impurities in New Drug Products
`(November 1997), or all three guidances.
`
`II.
`
`SCOPE OF THE GUIDANCE (2)
`
`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 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 product for residual
`solvents need be 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 1 for additional background information related to residual solvents.
`
`III. GENERAL PRINCIPLES (3)
`
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`A.
`
`Classification of Residual Solvents by Risk Assessment (3.1)
`
`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 ADI’s of the same substance.
`
`Residual solvents assessed in this guidance are listed in a companion document entitled Q3C —
`Tables and List. Common names and structures are used. They were evaluated for their possible
`risk to human health and placed into one of three classes as follows:
`
`Class 1 solvents: Solvents to be avoided—
`
`Known human carcinogens, strongly suspected human carcinogens, and environmental
`hazards.
`
`Class 2 solvents: Solvents to be limited—
`
`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 potential—
`
`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.
`
`B. Methods for Establishing Exposure Limits (3.2)
`
`The method used to establish permitted daily exposures for residual solvents is presented in
`Appendix 2. Summaries of the toxicity data that were used to establish limits are published in
`Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997.
`
`C.
`
`Options for Describing Limits of Class 2 Solvents (3.3)
`
`Two options are available when setting limits for Class 2 solvents.
`
`Option 1: The concentration limits in parts per million (ppm) stated in Table 2 (see companion
`document) can be used. They were calculated using equation (1) below by assuming a product
`mass of 10 mass of 10 grams (g) mass of 10 grams administered daily.
`
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`(1)
`
`Concentration (ppm) = 1000 x PDE
` dose
`
`Here, PDE is given in terms of mg/day and dose 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 10 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 (see companion
`document) can be used with the known maximum daily dose and equation (1) above 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 of solvent 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
`
`Drug substance
`Excipient 1
`Excipient 2
`Drug product
`
`Amount in
`Formulation
`
`Acetonitrile
`Content
`
`Daily Exposure
`
`0.3 g
`0.9 g
`3.8 g
`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.
`
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`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
`
`Drug substance
`Excipient 1
`Excipient 2
`Drug Product
`
`Amount in
`Formulation
`0.3 g
`0.9 g
`3.8 g
`5.0 g
`
`Acetonitrile
`Content
` 800 ppm
`2,000 ppm
` 800 ppm
`1,016 ppm
`
`Daily Exposure
`
`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. If 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.
`
`D.
`
`Analytical Procedures (3.4)
`
`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, Q2A Text on
`Validation of Analytical Procedures (March 1995) and Q2B Validation of Analytical
`Procedures: Methodology (November 1996).
`
`E.
`
`Reporting Levels of Residual Solvents (3.5)
`
`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:
`
`•
`
`Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5 percent.
`
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`•
`
`•
`
`Only Class 2 solvents X, Y, . . . are likely to be present. All are below the Option 1 limit.
` (Here the supplier would name the Class 2 solvents represented by X, Y, . . . .)
`
`Only Class 2 solvents X, Y, . . . and 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.
`
`IV.
`
`A.
`
`LIMITS OF RESIDUAL SOLVENTS (4)
`
`Solvents to Be Avoided (4.1)
`
`Solvents in Class 1 (Table 1; see companion document) 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 (see
`companion document) because it is an environmental hazard. The stated limit of 1,500 ppm is
`based on a review of the safety data.
`
`B.
`
` Solvents to Be Limited (4.2)
`
`Solvents in Class 2 (Table 2; see companion document) should be limited in pharmaceutical
`products because of their inherent toxicity. PDEs 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.
`
`C.
`
`Solvents with Low Toxic Potential (4.3)
`
`Solvents in Class 3 (Table 3; see companion document) 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 Class 3. Available 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) would be acceptable without justification. Higher amounts may also be
`
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`acceptable provided they are realistic in relation to manufacturing capability and good
`manufacturing practice (GMP).
`
`D.
`
`Solvents for Which No Adequate Toxicological Data Were Found (4.4)
`
`The solvents listed in Table 4 (see companion document) may also be of interest to manufacturers
`of excipients, drug substances, or drug products. However, no adequate toxicological data on which
`to base a PDE were found. Manufacturers should supply justification for residual levels of these
`solvents in pharmaceutical products.
`
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`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.
`
`Modifying factor: A factor determined by professional judgment of a toxicologist and applied to
`bioassay data to relate that data safely to humans.
`
`Neurotoxicity: The ability of a substance to cause adverse effects on the nervous system.
`
`NOEL: Abbreviation for no-observed-effect level.
`
`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.
`
`Reversible toxicity: The occurrence of harmful effects that are caused by a substance and which
`disappear after exposure to the substance ends.
`
`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.
`
`Teratogenicity: The occurrence of structural malformations in a developing fetus when a
`substance is administered during pregnancy.
`
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`APPENDIX 1: ADDITIONAL BACKGROUND
`
`Environmental Regulation of Organic Volatile Solvents (A2.1)
`
`Several of the residual solvents frequently used in the production of pharmaceuticals are listed as
`toxic chemicals in Environmental Health Criteria (EHC) monographs and the Integrated Risk
`Information System (IRIS). The objectives of such groups as the International Programme on
`Chemical Safety (IPCS), the U.S. Environmental Protection Agency (EPA), and the U.S. Food and
`Drug Administration (FDA) include the determination of acceptable exposure levels. The goal is
`protection of human health and maintenance of environmental integrity against the possible
`deleterious effects of chemicals resulting from long-term environmental exposure. The methods
`involved in the estimation of maximum safe exposure limits are usually based on long-term studies.
`When long-term study data are unavailable, shorter term study data can be used with modification
`of the approach such as use of larger safety factors. The approach described therein relates
`primarily to long-term or lifetime exposure of the general population in the ambient environment
`(i.e., ambient air, food, drinking water, and other media).
`
`Residual Solvents in Pharmaceuticals (A2.2)
`
`Exposure limits in this guidance are established by referring to methodologies and toxicity data
`described in EHC and IRIS monographs. However, some specific assumptions about residual
`solvents to be used in the synthesis and formulation of pharmaceutical products should be taken
`into account in establishing exposure limits. They are as follows:
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Patients (not the general population) use pharmaceuticals to treat their diseases or for
`prophylaxis to prevent infection or disease.
`
`The assumption of lifetime patient exposure is not necessary for most pharmaceutical
`products but may be appropriate as a working hypothesis to reduce risk to human health.
`
`Residual solvents are unavoidable components in pharmaceutical production and will often
`be a part of drug products.
`
`Residual solvents should not exceed recommended levels except in exceptional
`circumstances.
`
`Data from toxicological studies that are used to determine acceptable levels for residual
`solvents should have been generated using appropriate protocols such as those described,
`for example, by the Organization for Economic Cooperation and Development, EPA, and
`the FDA Red Book.
`
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`APPENDIX 2: METHODS FOR ESTABLISHING EXPOSURE LIMITS
`
`The Gaylor-Kodell method of risk assessment (Gaylor, D. W., and R. L. Kodell, "Linear
`Interpolation Algorithm for Low Dose Assessment of Toxic Substance," Journal of
`Environmental Pathology and Toxicology, 4:305, 1980) is appropriate for Class 1 carcinogenic
`solvents. Only in cases where reliable carcinogenicity data are available should extrapolation by
`the use of mathematical models be applied to setting exposure limits. Exposure limits for Class 1
`solvents could be determined with the use of a large safety factor (i.e., 10,000 to 100,000) with
`respect to the NOEL. Detection and quantitation of these solvents should be by state-of-the-art
`analytical techniques.
`
`Acceptable exposure levels in this guidance for Class 2 solvents were established by calculation
`of PDE values according to the procedures for setting exposure limits in pharmaceuticals
`(Pharmacopeial Forum, Nov-Dec 1989), and the method adopted by IPCS for Assessing Human
`Health Risk of Chemicals (EHC 170, WHO, 1994). These methods are similar to those used by
`the U.S. EPA (IRIS) and the U.S. FDA (Red Book) and others. The method is outlined here to give
`a better understanding of the origin of the PDE values. It is not necessary to perform these
`calculations in order to use the PDE values tabulated in Section 4 of this document.
`
`PDE is derived from the NOEL or the LOEL in the most relevant animal study as follows:
`
` NOEL x Weight Adjustment
`PDE = F1 x F2 x F3 x F4 x F5
`
`(1)
`
`The PDE is derived preferably from a NOEL. If no NOEL is obtained, the LOEL may be used.
`Modifying factors proposed here, for relating the data to humans, are the same kind of uncertainty
`factors used in EHC (EHC 170, WHO, Geneva, 1994), and modifying factors or safety factors in
`Pharmacopeial Forum. The assumption of 100 percent systemic exposure is used in all
`calculations regardless of route of administration.
`
`The modifying factors are as follows:
`
`F1 = A factor to account for extrapolation between species.
`F1 = 5 for extrapolation from rats to humans.
`F1 = 12 for extrapolation from mice to humans.
`F1 = 2 for extrapolation from dogs to humans.
`F1 = 2.5 for extrapolation from rabbits to humans.
`F1 = 3 for extrapolation from monkeys to humans.
`F1 = 10 for extrapolation from other animals to humans.
`
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`F1 takes into account the comparative surface area:body weight ratios for the species concerned
`and for man. Surface area (S) is calculated as:
`S = kM0.67
`
`(2)
`
`in which M = body mass, and the constant k has been taken to be 10. The body weights used in the
`equation are those shown below in Table A3.1.
`
`F2 = A factor of 10 to account for variability between individuals.
`
`A factor of 10 is generally given for all organic solvents, and 10 is used consistently in this
`guidance.
`
`F3 = A variable factor to account for toxicity studies of short-term exposure.
`
`F3 = 1 for studies that last at least one half-lifetime (1 year for rodents or rabbits; 7 years
`for cats, dogs and monkeys).
`
`F3 = 1 for reproductive studies in which the whole period of organogenesis is covered.
`
`F3 = 2 for a 6-month study in rodents, or a 3.5-year study in nonrodents.
`
`F3 = 5 for a 3-month study in rodents, or a 2-year study in nonrodents.
`
`F3 = 10 for studies of a shorter duration.
`
`In all cases, the higher factor has been used for study durations between the time points (e.g., a
`factor of 2 for a 9-month rodent study).
`
`F4 = A factor that may be applied in cases of severe toxicity (e.g., nongenotoxic carcinogenicity,
`neurotoxicity or teratogenicity). In studies of reproductive toxicity, the following factors are used:
`
`F4 = 1 for fetal toxicity associated with maternal toxicity.
`
`F4 = 5 for fetal toxicity without maternal toxicity.
`
`F4 = 5 for a teratogenic effect with maternal toxicity.
`
`F4 = 10 for a teratogenic effect without maternal toxicity.
`
`F5 = A variable factor that may be applied if the NOEL was not established.
`
`When only an LOEL is available, a factor of up to 10 could be used depending on the severity of
`the toxicity.
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`The weight adjustment assumes an arbitrary adult human body weight for either sex of 50
`kilograms (kg). This relatively low weight provides an additional safety factor against the standard
`weights of 60 kg or 70 kg that are often used in this type of calculation. It is recognized that some
`adult patients weigh less than 50 kg; these patients are considered to be accommodated by the
`built-in safety factors used to determine a PDE. If the solvent was present in a formulation
`specifically intended for pediatric use, an adjustment for a lower body weight would be
`appropriate.
`
`As an example of the application of this equation, consider a toxicity study of acetonitrile in mice
`that is summarized in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997, page S24. The NOEL
`is calculated to be 50.7 mg kg-1 day-1. The PDE for acetonitrile in this study is calculated as
`follows:
`
` 50.7 mg kg-1 day-1 x 50 kg
`PDE = 12 x 10 x 5 x 1 x 1 = 4.22 mg day-1
`
`In this example,
`
`F1 = 12 to account for the extrapolation from mice to humans.
`
`F2 = 10 to account for differences between individual humans.
`
`F3 = 5 because the duration of the study was only 13 weeks.
`
`F4 = 1 because no severe toxicity was encountered.
`
`F5 = 1 because the NOEL was determined.
`
`12
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`NOVARTIS EXHIBIT 2016
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 15 of 16
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`

`

`Table A3.1 – Values Used in the Calculations in This Document
`
`Rat body weight
`
`425 g
`
`Mouse respiratory volume
`
`Pregnant rat body weight
`Mouse body weight
`Pregnant mouse body weight
`Guinea pig body weight
`Rhesus monkey body weight
`Rabbit body weight
`(pregnant or not)
`Beagle dog body weight
`Rat respiratory volume
`
`330 g
`28 g
`30 g
`500 g
`2.5 kg
`4 kg
`
`Rabbit respiratory volume
`Guinea pig respiratory volume
`Human respiratory volume
`Dog respiratory volume
`Monkey respiratory volume
`Mouse water consumption
`
`11.5 kg
`290 L/day
`
`Rat water consumption
`Rat food consumption
`
`43 liter
`(L)/day
`1,440 L/day
`430 L/day
`28,800 L/day
`9,000 L/day
`1,150 L/day
`5 milliliter
`(mL)/day
`30 mL/day
`30 g/day
`
`The equation for an ideal gas, PV = nRT, is used to convert concentrations of gases used in
`inhalation studies from units of ppm to units of mg/L or mg/cubic meter (m3). Consider as an
`example the rat reproductive toxicity study by inhalation of carbon tetrachloride (molecular weight
`153.84) summarized in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997, page S9.
`n = P = 300 x 10-6 atm x 153840 mg mol-1 = 46.15 mg = 1.89 mg/L
`V RT 0.082 L atm K-1 mol-1 x 298 K 24.45 L
`
`The relationship 1000 L = 1 m3 is used to convert to mg/m3.
`
`13
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`NOVARTIS EXHIBIT 2016
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 16 of 16
`
`