M7 Assessment and Control
`
`of DNA Reactive
`
`(Mutagenic) Impurities in
`Pharmaceuticals to Limit
`
`Potential Carcinogenic Risk
`
`Guidance for Industry
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CD
`Center for Biologics Evaluation and Research (C
`
`R)
`
`May 2015
`ICH
`
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`

`
`M7 Assessment and Control
`
`of DNA Reactive
`
`(Mutagenic) Impurities in
`Pharmaceuticals to Limit
`
`Potential Carcinogenic Risk
`
`Guidance for Industry
`
`Additional copies are availablefrom:
`
`Oflice of Communications, Division ofDrug Information
`Centerfor Drug Evaluation and Research
`Food and Drug Administration
`10001 New Hampshire Ave., Hillandale Bldg., 4"’ Floor
`Silver Spring, MD 20993-0002
`Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
`Email: dmginfo@fda.hhs.gov
`htgs//www.tda.gov/Drugs/GuidanceCom2lianceRegylato[2Intormation/Guidances/default.htm
`
`07'
`
`Oflice of Communication, Outreach and Development
`Centerfor Biologics Evaluation and Research
`Food and Drug Administration
`10903 New Hampshire Ave., Bldg. 71, Room 3128
`Silver Spring, MD 20993-0002
`Phone: 800-835-4709 or 240-402-7800
`
`ocod@fda.hhs.g0v
`http://wwwfda.gov/BiologicsliloodVaccines/GuidanceCompIianceReguIatorylnformation/Guidance/default.htm
`
`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)
`
`May 2015
`ICH
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`Contains Nonbinding Recommendations
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`IV.
`
`INTRODUCTION (1) ....................................................................................................... 1
`
`SCOPE OF GUIDANCE (2) ............................................................................................ 2
`
`GENERAL PRINCIPLES (3) .......................................................................................... 2
`
`CONSIDERATIONS FOR MARKETED PRODUCTS (4) ......................................... 4
`
`A.
`
`Post—Approval Changes to the Drug Substance Chemistry, Manufacturing, and
`
`Controls (4.1) ..................................................................................................................................4
`
`B.
`
`Post-Approval Changes to the Drug Product Chemistry, Manufacturing, and
`
`Controls (4.2) ..................................................................................................................................4
`
`C. Changes to the Clinical Use of Marketed Products (4.3) ............................................................ 5
`
`D. Other Considerations for Marketed Products (4.4) .................................................................... 5
`
`V.
`
`DRUG SUBSTANCE AND DRUG PRODUCT IMPURITY ASSESSMENT (5) ...... 5
`
`A.
`
`Synthetic Impurities (5.1) .............................................................................................................. 5
`
`B. Degradation Products (5.2) ........................................................................................................... 6
`
`C. Considerations for Clinical Development (5.3) ........................................................................... 7
`
`VI.
`
`HAZARD ASSESSMENT ELEMENTS (6) ................................................................... 7
`
`VII. RISK CHARACTERIZATION (7) ................................................................................. 8
`
`A. TTC-Based Acceptable Intakes (7.1) ............................................................................................ 8
`
`B. Acceptable Intakes Based on Compound-Specific Risk Assessments (7.2)...............................9
`
`1. Mutagenic Impurities With Positive Carcinogenicity Data (Class I in Table 1) (7.2.1) ............... .. 9
`2. Mutagenic Impurities With Evidencefor a Practical Threshold (7.2.2) ........................................ .. 9
`C. Acceptable Intakes in Relation to Less-Than-Lifetime (LTL) Exposure (7.3) ......................... 9
`
`I. Clinical Development (7.3.1) ....................................................................................................... ..11
`2. Marketed Products (7.3.2) ........................................................................................................... .. 11
`D. Acceptable Intakes for Multiple Mutagenic Impurities (7.4) ................................................. .. 11
`
`E. Exceptions and Flexibility in Approaches (7.5) ....................................................................... .. 12
`
`VIII. CONTROL ...................................................................................................................... 12
`
`A. Control of Process Related Impurities (8.1) ............................................................................ .. 13
`
`B. Considerations for Control Approaches (8.2) ......................................................................... .. 14
`
`C. Considerations for Periodic Testing (8.3) ................................................................................ .. 15
`
`D. Control of Degradation Products (8.4) ..................................................................................... .. 15
`
`E.
`
`Lifecycle Management (8.5) ...................................................................................................... .. 16
`
`F. Considerations for Clinical Development (8.6) ....................................................................... .. 17
`
`IX.
`
`DOCUMENTATION ...................................................................................................... 17
`
`A. Clinical Trial Applications (9.1) ............................................................................................... .. 17
`
`B. Common Technical Document (Marketing Application) (9.2) .............................................. .. 17
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`Contains Nonbinding Recommendations
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`NOTES ......................................................................................................................................... 19
`
`GLOSSARY................................................................................................................................. 24
`
`REFERENCES ............................................................................................................................ 26
`
`APPENDICES ............................................................................................................................. 28
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`Contains Nonbinding Recommendations
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`M7 Assessment and Control of DNA Reactive (Mutagenic)
`Impurities in Pharmaceuticals to Limit Potential
`Carcinogenic Risk
`Guidance for Industryl
`
`This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency)
`on this topic. It does not create any rights for any person and is not binding on FDA or the public.
`You can use an alternative approach if it satisfies the requirements of the applicable statutes and
`regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as
`
`listed on the title page.
`
`1.
`
`INTRODUCTION (1)2
`
`The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents,
`catalysts, and other processing aids. As a result of chemical synthesis or subsequent
`degradation, impurities reside in all drug substances and associated drug products. While
`ICH Q3A Impurities in New Drug Substances (Revision 2) (Q3A) and Q3B(R2) Impurities in
`New Drug Products (Q3B) (Refs. 1 and 2)3 provide guidance for qualification and control for
`the majority of the impurities, limited guidance is provided for those impurities that are DNA
`reactive. The purpose of this guidance is to provide a practical framework that is applicable
`to the identification, categorization, qualification, and control of these mutagenic impurities
`to limit potential carcinogenic risk. This guidance is intended to complement ICH Q3A, Q3B
`(Note 1), and M3 (R2) Nonclinical Safety Studies for the Conduct ofHuman Clinical Trials
`and Marketing Authorization for Pharmaceuticals (Ref. 3).
`
`This guidance emphasizes considerations of both safety and quality risk management in
`establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic
`risk. It outlines recommendations for assessment and control of mutagenic impurities that
`reside or are reasonably expected to reside in final drug substance or product, taking into
`consideration the intended conditions of human use.
`
`1This guidance was developed within the Expert Working Group (Multidisciplinary) 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 has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, June 2014. 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.
`
`2 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering
`Committee at Step 4 of the ICH process, June 2014.
`
`3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the
`FDA Drugs guidance Web page at
`http://wvvw.fda.gov/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/default.ht1n or the Vaccines,
`Blood & Biologics Web page at
`http://www.fda.gov/BiologicsB1oodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.ht
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`In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
`Instead, guidances describe the Agency’s current thinking on a topic and should be viewed
`only as recommendations, unless specific regulatory or statutory requirements are cited. The
`use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`11.
`
`SCOPE OF GUIDANCE (2)
`
`This document is intended to provide guidance for new drug substances and new drug
`products during their clinical development and subsequent applications for marketing. It also
`applies to post-approval submissions of marketed products, and to new marketing
`applications for products with a drug substance that is present in a previously approved
`product — in both cases, only where:
`
`0 Changes to the drug substance synthesis result in new impurities or increased
`acceptance criteria for existing impurities;
`
`0 Changes in the formulation, composition or manufacturing process result in new
`degradation products or increased acceptance criteria for existing degradation
`products;
`
`0 Changes in indication or dosing regimen are made which significantly affect the
`acceptable cancer risk level.
`
`Assessment of the mutagenic potential of impurities as described in this guidance is not
`intended for the following types of drug substances and drug products:
`biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation,
`herbal, and crude products of animal or plant origin.
`
`This guidance does not apply to drug substances and drug products intended for advanced
`cancer indications as defined in the scope of ICH S9 (Ref. 4). Additionally, there may be
`some cases where a drug substance intended for other indications is itself genotoxic at
`therapeutic concentrations and may be expected to be associated with an increased cancer
`risk. Exposure to a mutagenic impurity in these cases would not significantly add to the
`cancer risk of the drug substance. Therefore, impurities could be controlled at acceptable
`levels for non-mutagenic impurities.
`
`Assessment of the mutagenic potential of impurities as described in this guidance is not
`intended for excipients used in existing marketed products, flavoring agents, colorants, and
`perfumes. Application of this guidance to leachables associated with drug product packaging
`is not intended, but the safety risk assessment principles outlined in this guidance for limiting
`potential carcinogenic risk can be used if warranted. The safety risk assessment principles of
`this guidance can be used if warranted for impurities in excipients that are used for the first
`time in a drug product and are chemically synthesized.
`
`III.
`
`GENERAL PRINCIPLES (3)
`
`The focus of this guidance is on DNA reactive substances that have a potential to directly
`cause DNA damage when present at low levels leading to mutations and therefore, potentially
`causing cancer. This type of mutagenic carcinogen is usually detected in a bacterial reverse
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`mutation (mutagenicity) assay. Other types of genotoxicants that are non-mutagenic typically
`have threshold mechanisms and usually do not pose carcinogenic risk in humans at the level
`ordinarily present as impurities. Therefore, to limit a possible human cancer risk associated
`with the exposure to potentially mutagenic impurities, the bacterial mutagenicity assay is
`used to assess the mutagenic potential and the need for controls. Structure-based assessments
`are usefiil for predicting bacterial mutagenicity outcomes based upon the established
`knowledge. There are a variety of approaches to conduct this evaluation, including a review
`of the available literature and/or computational toxicology assessment.
`
`A Threshold of Toxicological Concern (TTC) concept was developed to define an acceptable
`intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic
`effects. The methods upon which the TTC is based are generally considered to be very
`conservative since they involve a simple linear extrapolation fiom the dose giving a 50%
`tumor incidence (TD5o) to a 1 in 106 incidence, using TD50 data for the most sensitive species
`and most sensitive site of tumor induction. For application of a TTC in the assessment of
`acceptable limits of mutagenic impurities in drug substances and drug products, a value of 1.5
`micrograms (ug)/day corresponding to a theoretical 10'5 excess lifetime risk of cancer can be
`justified. Some structural groups were identified to be of such high potency that intakes even
`below the TTC would theoretically be associated with a potential for a significant
`carcinogenic risk. This group of high potency mutagenic carcinogens, referred to as the
`cohort ofconcern, comprises aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds.
`
`During clinical development, it is expected that control strategies and approaches will be less
`developed in earlier phases where overall development experience is limited. This guidance
`bases acceptable intakes for mutagenic impurities on established risk assessment strategies.
`Acceptable risk during the early development phase is set at a theoretically calculated level of
`approximately one additional cancer per million. For later stages in development and for
`marketed products, acceptable increased cancer risk is set at a theoretically calculated level of
`approximately 1 in 100,000. These risk levels represent a small theoretical increase in risk
`when compared to human overall lifetime incidence of developing any type of cancer, which
`is greater than 1 in 3. It is noted that established cancer risk assessments are based on
`lifetime exposures. Less-Than-Lifetime (LTL) exposures both during development and
`marketing can have higher acceptable intakes of impurities and still maintain comparable risk
`levels. The use of a numerical cancer risk value (1 in 100,000) and its translation into risk-
`based doses (TTC) is a highly hypothetical concept that should not be regarded as a realistic
`indication of the actual risk. Nevertheless, the TTC concept provides an estimate of safe
`exposures for any mutagenic compound. However, exceeding the TTC is not necessarily
`associated with an increased cancer risk given the conservative assumptions employed in the
`derivation of the TTC value. The most likely increase in cancer incidence is actually much
`less than 1 in 100,000. In addition, in cases where a mutagenic compound is a non-
`carcinogen in a rodent bioassay, there would be no predicted increase in cancer risk. Based
`on all the above considerations, any exposure to an impurity that is later identified as a
`mutagen is not necessarily associated with an increased cancer risk for patients already
`exposed to the impurity. A risk assessment would determine whether any further actions
`would be taken.
`
`Where a potential risk has been identified for an impurity, an appropriate control strategy
`leveraging process understanding and/or analytical controls should be developed to ensure
`that the mutagenic impurity is at or below the acceptable cancer risk level.
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`There may be cases when an impurity is also a metabolite of the drug substance. In such
`cases, the risk assessment that addresses mutagenicity of the metabolite can qualify the
`impurity.
`
`IV.
`
`CONSIDERATIONS FOR MARKETED PRODUCTS (4)
`
`This guidance is not intended to be applied retrospectively (i.e., to products marketed prior to
`adoption of this guidance). However, some types of post-approval changes warrant a
`reassessment of safety relative to mutagenic impurities. This section applies to these post-
`approval changes for products marketed prior to, or after, the adoption of this guidance.
`Section VIII.E (8.5) (Lifecycle Management) contains additional recommendations for
`products marketed after adoption of this guidance.
`
`A.
`
`Post-Approval Changes to the Drug Substance Chemistry,
`Manufacturing, and Controls (4.1)
`
`Post-approval submissions involving the drug substance chemistry, manufacturing, and
`controls should include an evaluation of the potential risk impact associated with mutagenic
`impurities from changes to the route of synthesis, reagents, solvents, or process conditions
`after the starting material. Specifically, changes should be evaluated to determine whether
`the changes result in any new mutagenic impurities or higher acceptance criteria for existing
`mutagenic impurities. Reevaluation of impurities not impacted by changes is not
`recommended. For example, when only a portion of the manufacturing process is changed,
`the assessment of risk from mutagenic impurities should be limited to whether any new
`mutagenic impurities result from the change, whether any mutagenic impurities formed
`during the affected step are increased, and whether any known mutagenic impurities from up-
`stream steps are increased. Regulatory submissions associated with such changes should
`describe the assessment as outlined in Section lX.B (9.2). Changing the site of manufacture
`of drug substance, intermediates, or starting materials or changing raw materials supplier will
`not require a reassessment of mutagenic impurity risk.
`
`When a new drug substance supplier is proposed, evidence that the drug substance produced
`by this supplier using the same route of synthesis as an existing drug product marketed in the
`assessor’s region is considered to be sufficient evidence of acceptable risk/benefit regarding
`mutagenic impurities and an assessment per this guidance is not required. If this is not the
`case, then an assessment per this guidance is strongly recommended.
`
`B.
`
`Post-Approval Changes to the Drug Product Chemistry, Manufacturing,
`and Controls (4.2)
`
`Post-approval submissions involving the drug product (e.g., change in composition,
`manufacturing process, dosage form) should include an evaluation of the potential risk
`associated with any new mutagenic degradation products or higher acceptance criteria for
`existing mutagenic degradation products. If appropriate, the regulatory submission should
`include an updated control strategy. Reevaluation of the drug substance associated with drug
`products is not recommended or expected provided there are no changes to the drug
`substance. Changing the site of manufacture of drug product will not require a reassessment
`of mutagenic impurity risk.
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`C.
`
`Changes to the Clinical Use of Marketed Products (4.3)
`
`Changes to the clinical use of marketed products that can warrant a reevaluation of the
`mutagenic impurity limits include a significant increase in clinical dose, an increase in
`duration of use (in particular when a mutagenic impurity was controlled above the lifetime
`acceptable intake for a previous indication that may no longer be appropriate for the longer
`treatment duration associated with the new indication), or a change in indication from a
`serious or life-threatening condition where higher acceptable intakes were justified (Section
`VII.E (7.5)) to an indication for a less serious condition where the existing impurity
`acceptable intakes may no longer be appropriate. Changes to the clinical use of marketed
`products associated with new routes of administration or expansion into patient populations
`that include pregnant women and/or pediatrics will not warrant a reevaluation, assuming no
`increases in daily dose or duration of treatment.
`
`D.
`
`Other Considerations for Marketed Products (4.4)
`
`Application of this guidance to marketed products may be warranted if there is specific cause
`for concern. The existence of impurity structural alerts alone is considered insufficient to
`trigger follow-up measures, unless it is a structure in the cohort of concern (Section III (3)).
`However a specific cause for concern would be new relevant impurity hazard data (classified
`as Class 1 or 2, Section 6) generated after the overall control strategy and specifications for
`market authorization were established. This new relevant impurity hazard data should be
`derived from high-quality scientific studies consistent with relevant regulatory testing
`guidelines, with data records or reports readily available. Similarly, a newly discovered
`impurity that is a known Class 1 or Class 2 mutagen that is present in a marketed product
`could also be a cause for concern.
`Ir1 both of these cases when the applicant becomes aware
`of this new information, an evaluation per this guidance should be conducted.
`
`V.
`
`DRUG SUBSTANCE AND DRUG PRODUCT IMPURITY ASSESSMENT (5)
`
`Actual and potential impurities that are likely to arise during the synthesis and storage of a
`new drug substance, and during manufacturing and storage of a new drug product, should be
`assessed.
`
`The impurity assessment is a two-stage process:
`
`0 Actual impurities that have been identified should be considered for their mutagenic
`potential.
`
`0 An assessment of potential impurities likely to be present in the final drug substance
`is carried out to determine whether further evaluation of their mutagenic potential is
`warranted.
`
`The steps as applied to synthetic impurities and degradation products are described in
`Sections V.A (5.1) and V.B (5.2), respectively.
`
`A.
`
`Synthetic Impurities (5.1)
`
`Actual impurities include those observed in the drug substance above the ICH Q3A reporting
`thresholds. Identification of actual impurities is expected when the levels exceed the
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`identification thresholds outlined by ICH Q3A. It is acknowledged that some impurities
`below the identification threshold may also have been identified.
`
`Potential impurities in the drug substance can include starting materials, reagents, and
`intermediates in the route of synthesis from the starting material to the drug substance.
`
`The risk of carryover into the drug substance should be assessed for identified impurities that
`are present in starting materials and intermediates, and impurities that are reasonably
`expected by-products in the route of synthesis from the starting material to the drug
`substance. As the risk of carryover may be negligible for some impurities (e.g., those
`impurities in early synthetic steps of long routes of synthesis), a risk-based justification could
`be provided for the point in the synthesis after which these types of impurities should be
`evaluated for mutagenic potential.
`
`For starting materials that are introduced late in the synthesis of the drug substance (and
`where the synthetic route of the starting material is known), the final steps of the starting
`material synthesis should be evaluated for potential mutagenic impurities.
`
`Actual impurities where the structures are known and potential impurities as defined above
`should be evaluated for mutagenic potential as described in Section VI (6).
`
`B.
`
`Degradation Products (5.2)
`
`Actual drug substance degradation products include those observed above the ICH Q3A
`reporting threshold during storage of the drug substance in the proposed long-term storage
`conditions and primary and secondary packaging. Actual degradation products in the drug
`product include those observed above the ICH Q3B reporting threshold during storage of the
`drug product in the proposed long-term storage conditions and primary and secondary
`packaging, and also include those impurities that arise during the manufacture of the drug
`product. Identification of actual degradation products is expected when the levels exceed the
`identification thresholds outlined by ICH Q3A/Q3B. It is acknowledged that some
`degradation products below the identification threshold may also have been identified.
`
`Potential degradation products in the drug substance and drug product are those that may be
`reasonably expected to form during long-term storage conditions. Potential degradation
`products include those that form above the ICH Q3A/Q3B identification threshold during
`accelerated stability studies (e.g., 40°C/75% relative humidity for 6 months) and confirmatory
`photostability studies as described in ICH Q1B (Ref. 5), but are yet to be confirmed in the
`drug substance or drug product under long-term storage conditions in the primary packaging.
`
`Knowledge of relevant degradation pathways can be used to help guide decisions on the
`selection of potential degradation products to be evaluated for mutagenicity, e. g., from
`degradation chemistry principles, relevant stress testing studies, and development stability
`studies.
`
`Actual and potential degradation products likely to be present in the final drug substance or
`drug product and where the structure is known should be evaluated for mutagenic potential as
`described in Section VI (6).
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`C.
`
`Considerations for Clinical Development (5.3)
`
`It is expected that the impurity assessment described in Sections V.A (5.1) and V.B (5.2)
`applies to products in clinical development. However, it is acknowledged that the available
`information is limited. For example, information from long-terrn stability studies and
`photostability studies may not be available during clinical development and thus information
`on potential degradation products may be limited. Additionally, the thresholds outlined in
`ICH Q3A/Q3B do not apply to products in clinical development and, consequently, fewer
`impurities will be identified.
`
`VI.
`
`HAZARD ASSESSMENT ELEMENTS (6)
`
`Hazard assessment involves an initial analysis of actual and potential impurities by
`conducting database and literature searches for carcinogenicity and bacterial mutagenicity
`data in order to classify them as Class 1, 2, or 5 according to Table 1. If data for such a
`classification are not available, an assessment of Structure-Activity Relationships (SAR) that
`focuses on bacterial mutagenicity predictions should be performed. This could lead to a
`classification into Class 3, 4, or 5.
`
`Table 1: Impurities Classification With Respect to Mutagenic and Carcinogenic
`Potential and Resulting Control Actions
`
`Class Definition
`
`No structural alerts, or alerting structure
`with sufficient data to demonstrate lack of
`
`Treat as non-mutagenic impurity
`
`mutagenicity or carcinogenicity
`
`*Or other relevant positive mutagenicity data indicative of DNA-reactivity-related induction
`of gene mutations (e.g., positive findings in in vivo gene mutation studies)
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`Proposed action for control
`(details in Section VII (7) and VIII
`8
`
`Control at or below compound-
`specific acceptable limit
`
`Control at or below acceptable limits
`(appropriate TTC)
`
`Control at or below acceptable limits
`(appropriate TTC) or conduct
`bacterial mutagenicity assay;
`If non-mutagenic = Class 5
`If mutagenic = Class 2
`
`Treat as non-mutagenic impurity
`
`Known mutagenic carcinogens
`
`Known mutagens with
`unknown carcinogenic potential
`(bacterial mutagenicity positive,* no rodent
`'
`enicit data
`
`Alerting structure, unrelated to the
`structure of the drug substance;
`no mutagenicity data
`
`Alerting structure, same alert in drug
`substance or compounds related to the drug
`substance (e.g., process intermediates)
`which have been tested and are non-
`
`mutagenic
`
`1
`
`2
`
`3
`
`4
`
`5
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`A computational toxicology assessment should be performed using Quantitative Structure-
`Activity Relationship ((Q)SAR) methodologies that predict the outcome of a bacterial
`mutagenicity assay (Ref. 6). Two (Q)SAR prediction methodologies that complement each
`other should be applied. One methodology should be expert rule-based, and the second
`methodology should be statistical-based. (Q)SAR models utilizing these prediction
`methodologies should follow the general validation principles set forth by the Organisation
`for Economic Co-operation and Development (OECD).
`
`The absence of structural alerts from two complementary (Q)SAR methodologies (expert
`rule-based and statistical) is sufficient to conclude that the impurity is of no mutagenic
`concern, and no further testing is recommended (Class 5 in Table 1).
`
`If warranted, the outcome of any computer system-based analysis can be reviewed with the
`use of expert knowledge in order to provide additional supportive evidence on relevance of
`any positive, negative, conflicting, or inconclusive prediction and to provide a rationale to
`support the final conclusion.
`
`To follow up on a relevant structural alert (Class 3 in Table 1), either adequate control
`measures could be applied or a bacterial mutagenicity assay with the impurity alone can be
`conducted. An appropriately conducted negative bacterial mutagenicity assay (Note 2) would
`overrule any structure-based concern, and no further genotoxicity assessments would be
`recommended (Note 1). These impurities should be considered non-mutagenic (Class 5 in
`Table 1). A positive bacterial mutagenicity result would warrant further hazard assessment
`and/or control measures (Class 2 in Table 1). For instance, when levels of the impurity
`carmot be controlled at an appropriate acceptable limit, it is recommended that the impurity
`be tested in an in vivo gene mutation assay in order to understand the relevance of the
`bacterial mutagenicity assay result under in vivo conditions. The selection of other in vivo
`genotoxicity assays should be scientifically justified based on knowledge of th