What’s New with Impurities in
`Pharmaceuticals?
`
`Southern California Pharmaceutical Discussion Group
`
`January 15, 2015
`
`
`Bernard A. Olsen, Ph.D
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`Olsen Pharmaceutical Consulting, LLC
`bolsen@comcast.net
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`Pharmaceuticals?
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`Southern California Pharmaceutical Discussion Group
`
`January 15, 2015
`
`
`Bernard A. Olsen, Ph.D
`
`Olsen Pharmaceutical Consulting, LLC
`bolsen@comcast.net
`
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`B.A. Olsen
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`ICH Q3 Impurities
`
`Q3A Drug Substances– 1995 (step 4), R1 (2002), R2 (2006)
`
`Q3B Drug Products– 1996 (step 4), R1 (2003), R2 (2006)
`
`Q3C Residual Solvents– 1997, R1-5 (2002, 2005, 2009, 2011)
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`• Most ICH guidelines on impurities in drug substances and
`drug products are >15 years old
`
`• What else is there to say?
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`Filling the Gaps
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`• M7 – Genotoxic Impurities – Step 4 (June 2014)
`- changes from EMA and FDA guidance
`
`
`• Q3D Elemental Impurities – Step 4 (Dec. 2014)
`- USP <232>, <233>
`
`
`• Other gaps?
`
`• Revisions needed?
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`ICH M7 – Genotoxic Impurities
`
`Filling the ICH Q3 A/B gap for “impurities that are expected to
`be unusually potent, producing toxic or pharmacological effects
`at a level not more than (≤) the identification threshold.”
`
` -
`
` Identification of "unusually potent" impurities not described
`- No threshold of concern given
`
`
`
`EMA* guideline and FDA** draft guidance:
`
`Threshold of Toxicological Concern (TTC), 1.5 mg/day
`
`*http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002
`903.pdf
`
`**http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/uc
`m079235.pdf
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`Assessing Impurities – ICH M7
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`All impurities (actual and potential), where the structures
`are known, should be evaluated for mutagenic potential.
`
`
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`Classifying impurities – PhRMA paper
`
`recommendation*, adopted in M7
`
`All identified or predicted impurities should be classified into
`one of five classes:
`
`
`Class 1. Known to be genotoxic and carcinogenic
`Class 2. Known to be genotoxic but with unknown
`carcinogenic potential
`
`Class 3. With a unique alerting structure and of
`unknown genotoxic potential
`
`GTI
`
`?
`
`Class 4. With an alerting structure related to the
`parent API
`Class 5. With no structural alert
`
`Ordinary ICH
`impurity
`
`*Müller et al., Reg. Tox. Pharmacol. 44, 198-211 (2006);
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`Alerting Structures – examples
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`Müller et al.
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`Assessing Impurities – ICH M7, cont.
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`Is an impurity potentially genotoxic?
`
`Search databases and literature for carcinogenicity and
`bacterial mutagenicity data in order to classify impurity as
`Class 1, 2, or 5
`
`When data are not available:
`
`Use Structure-Activity Relationships (SAR) that focus on
`bacterial mutagenicity predictions. This could lead to a
`classification into Class 3, 4, or 5.
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`(Q)SAR/in silico assessments
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`Two (Q)SAR prediction methodologies that complement each
`other should be applied.
`
` - Expert rule-based
` - Statistical-based
` - follow Organisation for Economic Co-operation and
`Development (OECD) validation principles
` - review with expert knowledge
`
`
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`Absence of structural alerts from 2 Q(SAR) predictions = normal
`impurity
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`Toxicity Prediction Software
`
`Freely available software
`Caesar models
`Lazar
`OncoLogic
`PASS
`
`Commercially available software
`ACD/Tox Suite
`BioEpisteme
`HazardExpert
`MDL QSAR
`MultiCASE
`TOPKAT
`q-Tox
`
`EPI Suite
`OECD QSAR Application Toolbox
`Toxtree
`T.E.S.T
`
`ADMET Predictor
`DEREK
`Leadscope
`Molcode Toolbox
`OASIS TIMES
`ToxAlert
`
`CSGenoTox
`
`
`
`
`Review of Software Tools for Toxicity Prediction, M. F. Gatnik and A. Worth, European Commission
`Joint Research Centre, Institute for Health and Consumer Protection
`https://eurl-ecvam.jrc.ec.europa.eu/laboratories-research/predictive_toxicology/doc/EUR_24489_EN.pdf
`
`Industry Survey: Dobo et al., Reg. Tox. Pharmacol. 62 (2012) 449–455
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`Ames testing
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`• Negative result classifies compound as normal ICH
`impurity and overrides a positive in silico prediction for
`genotoxicity
`
`• Test on the isolated impurity preferred vs. impurity in
`drug substance; ≥250 μg/plate needed for compound
`of interest
`
`• GLP studies expected but test article characterization
`may not comply fully; exceptions also allowed for
`compounds difficult to prepare or isolate
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`ICH M7 - TTC-based acceptable limits
`
`Acceptable Daily Intakes* for an Individual Impurity, mg/day
`Clinical trials or marketed product
`
`Single
`Dose
`
`< 14
`days
`
`≤ 1
`mo.
`
`≤ 3
`mo.
`
`≤ 6
`mo.
`
`≤ 12
`mo.
`
`
`>1 – 10
`years
`
`
`>10 years
`to
`lifetime
`
`M7
`
`**
`
`**
`
`120
`
`20
`
`20
`
`20
`
`10
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`EMA
`
`120
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`60
`
`60
`
`30
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`10
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`5
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`1.5
`(marketed)
`
`1.5
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`1.5
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`*Compound-specific risk assessments to derive acceptable intakes should be applied
`instead of the TTC-based acceptable intakes where sufficient carcinogenicity data exist.
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`**Clinical trials of up to 14 days – class 3 impurities can be treated as normal impurities
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`Mitigating factors in application of TTC
`
`• Indication – life-saving therapy
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`• Exposure from other sources, e.g., foods or
`endogenous metabolism (e.g., formaldehyde)
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`• Reduced life expectancy
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`• Late onset but chronic disease
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`• Limited therapeutic alternatives
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`Strategies to Address GTIs
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`• Modify synthesis to remove compounds of concern
`or move them as early in the synthesis as possible
`
`• Purification – provide rationale and/or data to
`demonstrate that GTI has negligible risk of being in
`drug substance
`
`• Specification – commit to analytical testing and
`acceptance limit at intermediate (higher levels?) or
`drug substance (staged TTC levels)
`
`• Degradation product GTI – packaging and storage
`to prevent formation, implement specification
`through shelf-life
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`ICH M7 Control Options for Process
`Impurities
`
`Option 1
`Specification for impurity in drug substance with
`acceptable limit.
`
`Option 2
`Specification at precursor with drug substance
`acceptable limit.
`
`Option 3
`Specification at precursor with higher limit. Fate and
`purge data and associated process controls needed that
`assure the level in the drug substance is below the
`acceptable limit.
`
`Option 4
`No routine testing. Compelling fate and purge
`knowledge with sufficient confidence that the level of the
`impurity in the drug substance will be below the
`acceptable limit.
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`Probability of
`regulatory
`acceptance
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`Example – GSK, pazopanib HCl
`
`DMS=dimethylsulfate
`
`includes monohydrate isolation
`before salt formation?
`
`III and VII designated as API starting materials
`
`D.Q. Liu, T.K. Chen, M.A. McGuire, A.S. Kord, J. Pharm. Biomed. Anal. 50 (2009) 144-150
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`Strategy
`
`• Develop TTC-level LC-MS method for GTIs
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`• Analyze materials throughout process to show lack of
`carry-through (up to 79 batches of API)
`
`• Perform impurity rejection studies to show process
`capability
`
`• Establish tests for GTIs at levels higher than TTC using
`LC methods at starting materials or intermediates
`
`Note: Pazopanib HCl (Votrient) is a tyrosine kinase inhibitor approved for the
`treatment of renal cell carcinoma
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`Impurity rejection efficiency - DMS
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`DMS introduced 2 steps back from starting material III
`20 batches of III showed <1.7 ppm DMS
`79 batches of API showed <1.7 ppm DMS
`
`<1.7 ppm in V
`
`
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`50,000 ppm DMS spiked in III
`
`>29,000 fold rejection in step 1 followed by 4 subsequent steps
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`0.1% acceptance criterion set for DMS in starting material III
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`IS ROUTINE TESTING FOR DMS NEEDED?
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`Impurity rejection efficiency – compound II
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`79 batches of API showed <1.7 ppm II
`16 batches of III showed <24 ppm II
`
`50,000 ppm in III
`670 ppm in V
`23 ppm in VI
`
` 670 ppm in V
` 23 ppm in VI
`<1.7 ppm in IX
`
`75 fold rejection
`29 fold rejection
`>13 fold rejection
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`0.1% limit set for II in III
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`Higher Upstream limits for VI and VIII
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`limit of NMT 0.1% set for VIII in VII
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`limit of NMT 0.6% set for VI in IX
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`Genotoxic degradation products
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`• Identify potential degradation product GTIs during
`predictive stress testing
`
`• Does degradation product GTI form with time under
`normal storage conditions?
`
`• Can degradation product GTI formation be prevented
`through formulation design, packaging, or storage
`conditions?
`
`• Establish specification if necessary
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`Risk of Producing an Alerting Structure
`from Drug Degradation*
`
`• Analysis of over 1100 known degradation products from more than
`350 drugs suggests that degradation of drugs may lead to unique
`structure alerting functional groups in about 5-8% of the degradation
`products.
`
`• Roughly 50% or less of these alerting structures can be expected to
`be Ames positive
`
`• An average of 8-9 major deg products are observed in stress testing for a
`typical drug, so most drugs will have zero or one deg product for follow-up
`as a potential GTI
`
`
`
`*S.W. Baertschi et al., Stress Testing and Degradation-Derived Genotoxic Impurities:
`Scientific, Practical and Regulatory Considerations, Conference on Small Molecule
`Science, August 2, 2011, Chapel Hill, NC
`
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`ICH M7- Control for degradants
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`Is degradant relevant?
`
`• check accelerated stability study data (e.g.,
`40°C/75% relative humidity, 6 months)
`
`• kinetically equivalent shorter term stability
`studies at higher temperatures in the proposed
`commercial package may be used to determine
`the relevance of the degradation pathway prior
`to initiating longer term stability studies.
`
`S.W. Baertschi et al., “Stress testing as a predictive tool for the assessment of
`potential genotoxic degradants”, in Pharmaceutical Stress Testing, 2nd Ed., S.W.
`Baertschi, K.M. Alsante, R. A. Reed, 2011, Informa, London.
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`ICH M7 – Other Considerations
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`• Not applied to products for advanced cancer indications (see ICH S9)
`
`• Not applied to drug substances that are themselves genotoxic
`
`• Will be applied to changes in existing authorizations if new or greater levels
`of previous impurities are present
`
`• Assess potentially genotoxic impurities which may be present at levels below
`the Q3 A/B ID thresholds (same as current guidelines)
`
`
`• Previous data from similar compounds may be used with justification to
`discharge risk
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`Elemental Impurities
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`USP <232> Limits
`USP <233> Procedures
`replacing <231> Heavy Metals
`
`ICH Q3D
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`Disclaimer
`
`Information in this presentation related to USP Elemental
`Impurities is from publically-available sources.
`
`The speaker does not represent official USP positions or
`policy on Elemental Impurities or any other topic.
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`USP <231> Heavy Metals
`
`<231> has been in use for many years. What’s the problem?
`
`Lewen, N. et al., J. Pharm. & Biomed. Anal. 35 (2004) 739-752)
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`USP Results
`
`ICP-MS Results
`
`Pb As Se Sn Sb Cd Pd Pt Ag Bi Mo Ru
`
`In Hg
`
`Elements
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Average % Recoveries
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`USP key issue – elemental impurities
`
`<232> Elemental Impurities – Limits
`
`<233> Elemental Impurities – Procedures
`
`Revisions proposed in PF 40(2)
`
`http://www.usp.org/usp-nf/key-issues/elemental-impurities
`
`Implementation date when chapters apply to drug product
`monographs: December 1, 2015
`
`BUT, what about ICH Q3D?
`
`January 14, 2015: USP is announcing plans to establish January 1, 2018 as the
`new date of applicability of General Chapters <232> Elemental Impurities—Limits
`and <2232> Elemental Contaminants in Dietary Supplements.
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`Heavy metals limits – USP proposal
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`PDE = permitted daily exposure
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`Limits, cont.
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`Options for compliance
`
`Drug product analysis (Q3D option 3)
`
`Daily Dose PDE ≥ measured value (μg/g) × maximum daily dose (g/day)
`
`Summation option (add metals present in each component, Q3D option
`2b)
`
`Daily Dose PDE ≥ [ΣM
`1(CM × WM)] × DD
`
` M
`
` = each ingredient used to manufacture a dosage unit
`CM = element concentration in component (drug substance or excipient) (μg/g)
`WM = weight of component in a dosage unit (g/dosage unit)
`DD = number of units in the maximum daily dose (unit/day)
`
`Individual component option (Large volume parenterals only)
`
`API and excipients meet limits given in Table 1 for LVP components
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`Testing
`
`If, by validated processes and supply-chain control,
`manufacturers can demonstrate the absence of impurities,
`then further testing is not needed.
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`USP Updates – stay tuned
`
`October 2014 expert panel recommendation: Limits be revised
`to align with the ICH Q3D Step 4 document to the extent
`possible.
`
`
`
`Separately, USP is considering potential adjustments to the
`elemental impurities implementation timeline as specified in
`General Notices 5.60.30 (Dec.1, 2015) based on developments
`related to the anticipated ICH Q3D Step 4 document.
`
`http://www.usp.org/usp-nf/key-issues/elemental-impurities
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`ICH Q3D – Guideline for Elemental
`Impurities
`
`• Focus is on risk assessment for occurrence of
`and limits for elemental impurities
`
`• Step 4 guideline published December 16, 2014
`
`http://www.ich.org/fileadmin/Public_Web_Site/ICH_
`Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf
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`ICH Q3D: Risk-based assessment of need for
`
`control of metal impurities
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`ICH Q3D – Risk assessment
`
`Identify: Identify known and potential sources of elemental
`impurities that may find their way into the drug product.
`
`Evaluate: Evaluate the presence of a particular elemental impurity in
`the drug product by determining the observed or predicted level of
`the impurity and comparing with the established PDE.
`
`Control: Summarize and document the risk assessment. Identify if
`controls built into the process are sufficient or identify additional
`controls to be considered to limit elemental impurities in the drug
`product.
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`Sources of Elemental Impurities
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`ICH Q3D: Limits for Elemental Impurities
`
`5.0
`
`5.0
`15
`15
`
`120
`600
`
`100
`100
`
`100
`100
`100
`
`100
`
`180
`1300
`
`2.5
`5.0
`15
`1.5
`
`12
`60
`
`10
`10
`10
`
`10
`10
`
`10
`
`90
`130
`
`3.4
`
`5.0
`1.9
`
`1.2
`
`1.2
`6.0
`
`1.0
`
`1.5
`1.5
`1.5
`1.5
`
`1.5
`
`7.6
`13
`
`2.9
`
`Red = USP <232> PDEs
`
`Option 1: Assume 10 g/day
`dose. If all components meet
`PDE concentration, they may
`be used in any proportion
`
`Option 2a: Use the actual
`dose to calculate PDE
`concentration. If all
`components meet the PDE,
`they may be used in any
`proportion.
`
`Option 2b: Use the amounts
`of each component present
`and data on metals present
`to set limits for individual
`components.
`
`Option 3: Drug product
`analysis with limits based on
`daily dose.
`
` 38
`
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`SCPDG January 15, 2015
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`Q3D – Other Limit Considerations
`
`• When PDEs are necessary for other routes of administration,
`the concepts described in the guideline may be used to derive
`PDEs.
` - Consider local effects, bioavailability, quality considerations
`
`
`• Higher PDEs may be permitted for:
`
`- Intermittent dosing;
`- Short term dosing (i.e., 30 days or less);
`- Specific indications (e.g., life-threatening, unmet medical
`needs, rare diseases).
`
`
`
`B.A. Olsen
`SCPDG January 15, 2015
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` 39
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`ICH Q3D Implementation
`
`• Application of Q3D to existing products is not expected prior to 36
`months after publication of the guideline by ICH. December 2017?
`
`• Will USP implementation timing be revised to December 2017? –
`January 1, 2018
`
`
`
`• Q3D implementation plan 21 Oct 2014
`- Training materials
`- FAQ document
`
`
`
`http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_IWG_Final_Concept_Paper_
`October_21_2014.pdf
`
`http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_IWG_Final_Business_Plan_
`October_21_2014.pdf
`
`B.A. Olsen
`SCPDG January 15, 2015
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`USP <233> Method Proposal
`
`Procedure 1 can be used for elemental impurities
`generally amenable to detection by inductively
`coupled plasma–atomic (optical) emission
`spectroscopy (ICP–AES or ICP–OES).
`
`Procedure 2 can be used for elemental impurities
`generally amenable to detection by inductively
`coupled plasma–mass spectrometry (ICP–MS).
`
`B.A. Olsen
`SCPDG January 15, 2015
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` 41
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`Performance-based method
`
`Analysts are free to select a method/procedure that works for their
`samples
`
`The method selected may include plasma spectrochemistry, atomic
`absorption spectroscopy, OR ANY OTHER METHOD that displays
`adequate accuracy, sensitivity and specificity.
`
`
`
`B.A. Olsen
`SCPDG January 15, 2015
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` 42
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`Other ICH Impurity Questions
`
`• Other gaps?
`
`• Thresholds and limits
`
`• Impurity control in
`- multisource products
`- starting materials
`- reagents
`
`• Depth of impurity investigations
`
`
`B.A. Olsen
`SCPDG January 15, 2015
`
` 43
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`Products not covered by ICH
`
`Excluded product types:
`
`• biological/biotechnological (ICH Q6B)
`• peptide (PhEur general monograph 2034)
`• oligonucleotide
`• radiopharmaceutical
`• fermentation product and semi-synthetic products
`(EMA guideline for antibiotics)
`• herbal products
`• crude products of animal or plant origin
`
`
`B.A. Olsen
`SCPDG January 15, 2015
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` 44
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` P. 44
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` 45
`
`Extractable and Leachable Impurities
`
`Multitude of guidelines, but lack of harmonized expectations,
`focus has been on inhaled and nasal products
`
`• Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug
`Products; FDA Draft Guidance for Industry
`
`• Nasal Spray and Inhalation Solution, Suspension, and Spray Drug
`Products – Chemistry, Manufacturing, and Controls Documentation;
`FDA Guidance for Industry
`
`• CHMP Guideline on the Pharmaceutical Quality of Inhalation and
`Nasal Products
`
`• PQRI: Safety Thresholds and Best Practices for Extractables and
`Leachables in Orally Inhaled and Nasal Drug Products
`
`
`
`B.A. Olsen
`SCPDG January 15, 2015
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`
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`Threshold limit disconnects
`
`Drug substance process impurity:
`• 0.2% in a drug substance with 0.5 mg maximum daily dose requires
`identification and qualification
`
`• Patient exposure - Total daily intake (TDI) of impurity: 1 mg
`
`• TDI is less than 1.5 mg/day limit for a potentially genotoxic impurity
`
`Residual solvent:
`• A drug substance with benzene at 2 ppm meets Q3C(R5) limit, but for
`a dose of 2 g/day, TDI is 4 mg
`
`• A drug substance with benzene present at 5 ppm exceeds limit, but for
`a dose of 2 mg/day, TDI is 0.01 mg
`
`
`
`D.J. Snodin, S.D. McCrossen, “Guidelines and pharmacopoeial standards for pharmaceutical
`impurities: Overview and critical assessment”, Reg. Tox. Pharmacol. 63 (2012) 298–312
`
`B.A. Olsen
`SCPDG January 15, 2015
`
` 46
`
`
`
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` P. 46
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`
`Degradation impurities threshold concerns
`
`Degradation impurity in drug substance
`Dose:
`1 mg
`10 mg
`ID threshold (TDI)
` 1 mg
`10 mg
`Qual threshold (TDI) 1.5 mg
`15 mg
`
`100 mg
`100 mg
`150 mg
`
`
`
`Degradation impurity in drug product
`10 mg
`1 mg
`Dose:
`ID threshold (TDI)
` 5 mg
`20 mg
`Qual threshold (TDI)
`10 mg
`50 mg
`
`100 mg
`200 mg
`200 mg
`
`Should thresholds for degradation impurities in a drug substance be
`consistent with those for the drug product?
`
`B.A. Olsen
`SCPDG January 15, 2015
`
` 47
`
`
`
`
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` P. 47
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`
`Other Threshold Considerations
`
`Should more latitude in application of Q3 thresholds
`be allowed based on:
`
`-Chronic vs. limited-duration therapy
`-Indication
`-Population
`
`Should in silico, literature, or other structure-based
`rationale be acceptable for impurity qualification in lieu
`of additional animal studies?
`
`
` 48
`
`
`
`B.A. Olsen
`SCPDG January 15, 2015
`
`
`
`
`
` P. 48
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`UT Ex. 2040
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`
`
`Risk assessment for impurities in multi-sourced
`
`materials (starting materials, reagents)
`
`• What method(s) are used to prepare the material?
`
`• What impurities could be introduced with the material?
`
`• What is the likelihood QC methods will detect new
`impurities?
`
`• Does supplier’s change control for manufacturing
`changes evaluate the potential for new impurities?
`
`• Does buyer’s change control evaluate potential for new
`impurities from a different supplier?
`
`B.A. Olsen
`SCPDG January 15, 2015
`
` 49
`
`
`
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` P. 49
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`IPR2016-00006
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`
`
`Example: Impurity from reagent
`
`Repaglinide synthesis
`
`+
`
`+
`
`DCC
`
`hydrolysis
`
`Impurity derived from
`cyclohexylamine in DCC
`
`K.V.S.R. Krishna Reddy et al., J. Pharm. Biomed.Anal. 32 (2003) 461-467
`
`B.A. Olsen
`SCPDG January 15, 2015
`
` 50
`
`
`
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` P. 50
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`UT Ex. 2040
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`
`
`DCC Quality?
`
`74 suppliers (52 from China)
`
`Quality range: 98.0-99.5%
`Unknown control of cyclohexylamine impurity
`
`Switching suppliers without knowledge of the impact of
`cyclohexylamine as an impurity could generate a new impurity
`in the drug substance
`
`Do suppliers control cyclohexylamine levels?
`What levels are acceptable for regalinide process?
`Would the QC impurities test for repaglinide detect the
`cyclohexylamine-derived impurity?
`
`B.A. Olsen
`SCPDG January 15, 2015
`
` 51
`
`
`
`
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` P. 51
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`UT Ex. 2040
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`
`
`Ambiguity in Impurity Investigation
`How much is enough?
`
`Q3A(R2)
`
`…summarise the actual and potential impurities most likely to arise during
`the synthesis, purification, and storage of the new drug substance.
`
`This discussion can be limited to those impurities that might reasonably be
`expected based on knowledge of the chemical reactions and conditions
`involved.
`
`Potential Impurity: An impurity that theoretically can arise during manufacture
`or storage. It may or may not actually appear in the new drug substance.
`
`??????
`How are “most likely to arise” and “might reasonably be expected”
`interpreted?
`
`“Theoretical” impurities can encompass an unreasonably large number of
`compounds, especially if genotoxicity thresholds are considered.
`
` 52
`
`
`
`B.A. Olsen
`SCPDG January 15, 2015
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`
`
`
`
` P. 52
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`UT Ex. 2040
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`
`
`In Practice…
`
`Focus investigation on potential, not hypothetical/theoretical impurities
`
`• Theoretical/hypothetical: based on in cerebro or in silico predictions of synthetic by-
`products or degradation chemistry
`
`• Potential: used in process, found during process development ,or formed as major
`degradation products during stress testing
`
`• Actual or relevant: impurities present in drug or with a high likelihood of being present
`
`*S. Baertschi et al., Conference on Small Molecule Science UNC-Chapel Hill, NC, August 2, 2011
`
`B.A. Olsen
`SCPDG January 15, 2015
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` P. 53
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`SteadyMed v. United Therapeutics
`IPR2016-00006
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` 54
`
`Summary
`
`Despite ongoing questions, ICH impurity guidelines
`have provided harmonized expectations for drug
`development.
`
`Changes being effected:
`• Genotoxic impurities
`• Elemental impurities
`
`
`Opportunities for improvement:
`• guidance for other product types
`• greater flexibility when justified
`• reexamination of threshold rationale and
`inconsistency
`
`
`
`
`
`B.A. Olsen
`SCPDG January 15, 2015
`
`
`
`
`
` P. 54
`
`UT Ex. 2040
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`
`
`Thank You!
`
`B.A. Olsen
`SCPDG January 15, 2015
`
` 55
`
`
`
`
`
` P. 55
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`UT Ex. 2040
`SteadyMed v. United Therapeutics
`IPR2016-00006
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