Advanced Drug Delivery Reviews 59 (2007) 29 – 37
`
`www.elsevier.com/locate/addr
`
`The role of degradant profiling in active pharmaceutical ingredients
`and drug products ☆
`Karen M. Alsante a,⁎, Akemi Ando b, Roland Brown c, Janice Ensing a, Todd D. Hatajik a,
`Wei Kong d, Yoshiko Tsuda b
`
`a Pfizer Global Research and Development, Analytical Research and Development, Eastern Point Road, Groton, CT 06340, USA
`b Pfizer Global Research and Development, Analytical Research and Development, Nagoya, Japan
`c Pfizer Global Research and Development, Analytical Research and Development, Sandwich, Kent, CT13 9NJ, UK
`d Pfizer Global Research and Development, Analytical Research and Development, 700 Chesterfield Parkway West, Q1B, Chesterfield, MO 63017, USA
`
`Received 2 February 2006; accepted 25 October 2006
`Available online 15 November 2006
`
`Abstract
`
`Forced degradation studies are used to facilitate the development of analytical methodology, to gain a better understanding of active
`pharmaceutical ingredient (API) and drug product (DP) stability, and to provide information about degradation pathways and degradation
`products. In order to fulfill development and regulatory needs, this publication provides a roadmap for when and how to perform studies, helpful
`tools in designing rugged scientific studies, and guidance on how to record and communicate results.
`© 2006 Published by Elsevier B.V.
`
`Keywords: Forced degradation; Oxidation; Acid/base hydrolysis; Thermal; Humidity; Stability-indicating; CAMEO
`
`Contents
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`2.
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`1. Regulatory requirements .
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`1.1.
`Summary of requirements at the IND stage .
`1.2.
`Summary of requirements for marketing application .
`Forced degradation timing and strategy .
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`2.1. Degradation discussion .
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`3. Degradation prediction tools .
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`3.1.
`CAMEO .
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`Experimental approach tools .
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`4.1. API .
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`4.1.1. Acid .
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`4.1.2.
`Base .
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`4.1.3. Oxidation .
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`4.1.4.
`Thermal/humidity.
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`4.1.5.
`Photostability .
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`4.2. Drug product
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`4.
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`☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Pharmaceutical Impurities: Analytical, Toxicological and Regulatory Perspectives".
`⁎ Corresponding author. Tel.: +1 860 441 5408; fax: +1 860 715 7280.
`E-mail address: karen.m.alsante@pfizer.com (K.M. Alsante).
`
`0169-409X/$ - see front matter © 2006 Published by Elsevier B.V.
`doi:10.1016/j.addr.2006.10.006
`
`Opiant Exhibit 2302
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 1
`
`

`

`30
`
`K.M. Alsante et al. / Advanced Drug Delivery Reviews 59 (2007) 29–37
`
`5.
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`Stability-indicating method development
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`5.1. Mass balance .
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`5.2. Key degradation sample set
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`5.3.
`Stereochemical stability .
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`5.4.
`Physiochemical stability .
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`5.5.
`Identify degradants .
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`6. Degradation database .
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`Appendix A. General protocol of API and DP degradation experiments .
`Appendix B. Recommended API and DP degradation conditions .
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`Appendix C. Relative rate factors of degradation.
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`References .
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`33
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`34
`34
`34
`34
`34
`35
`35
`36
`37
`
`1. Regulatory requirements
`
`From a regulatory perspective, forced degradation studies
`provide data to support the following:
`
`• identification of possible degradants
`• degradation pathways and intrinsic stability of the drug
`molecule
`• validation of stability indicating analytical procedures.
`
`Issues addressed in regulatory guidances include:
`
`• Forced degradation studies are typically carried out using
`one batch of material.
`• Forced degradation conditions are more severe than accelerated
`stability testing such as N50 °C; ≥75% relative humidity; in
`excess of ICH light conditions; high and low pH, oxidation, etc.
`• Photostability should be an integral part of forced degrada-
`tion study design [1].
`• Degradation products that do not form in accelerated or long-
`term stability may not have to be isolated or have their
`structure determined.
`• Mass balance should be considered.
`
`Issues not specifically addressed in regulatory guidance:
`
`• Exact experimental conditions for forced degradation studies
`(temperatures, duration, extent of degradation, etc.) are not
`specified.
`• Experimental design is left to the applicant's discretion.
`
`There are guidances available from the FDA as well as from
`private industry on regulatory requirements for IND and NDA
`filings [2]. This paper gives a global perspective on regulatory
`requirements (e.g., USA, Europe and Japan) based on current
`regulations and guidances.
`
`1.1. Summary of requirements at the IND stage
`
`The reporting of forced degradation study conditions or
`results is not required in Phase 1 or 2 INDs. However,
`preliminary studies are encouraged to facilitate the development
`of stability indicating methodology. It is recommended that
`forced degradation testing outlined in the table in Appendix A
`
`be conducted as early in the development of API and DP as
`possible. Studies can be conducted on the API and develop-
`mental formulations to examine for degradation by thermolysis,
`hydrolysis, oxidation, and photolysis to evaluate the potential
`chemical behavior of the active. A draft guidance document
`suggests that results of one-time forced degradation studies
`should be included in Phase 3 INDs [3].
`
`1.2. Summary of requirements for marketing application
`
`Completed studies of the degradation of the API and DP are
`required at
`the NDA stage,
`including isolation and/or
`characterization of significant degradation products and a full
`written account of the degradation studies performed [4].
`Requirements at the time of registration include [1]:
`
`• Forced degradation products should be accurately charac-
`terized and the reaction kinetics established.
`• Structural elucidation of degradation products should be
`attempted, even if not successful, should be referenced in
`the NDA.
`• Mass balance should be determined or at least attempted.
`• Main band peak purity should be confirmed.
`• Any degradants present in ICH stability samples which are
`greater than the identification threshold should be isolated
`and identified.
`
`Information from these studies should be referenced in the
`filing and should provide:
`
`• degradation pathways of the API, alone and in DP
`• discussion of any possible polymorphic or enantiomeric
`substances, and
`• differentiation between drug related degradation and excip-
`ient interferences.
`
`The tables in Appendices A and B outline general pro-
`tocol of tests and conditions recommended for regulatory
`submissions.
`
`2. Forced degradation timing and strategy
`
`The requirements for forced degradation testing depend on
`project needs and the stage of development of the compound.
`
`Opiant Exhibit 2302
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 2
`
`

`

`K.M. Alsante et al. / Advanced Drug Delivery Reviews 59 (2007) 29–37
`
`31
`
`For example, pre-clinical through phase 2 project needs dictate
`intense method development, and the rate of compound
`attrition is high. Therefore, when developing a rational study
`design, forced degradation deliverables should be focused on
`method development activities, and not isolation and identifi-
`cation of degradants. As a compound progresses into later
`phase 2 through registration, method development activities
`center on optimization. The focus of stress testing should be
`directed to characterization and elucidation of degradants.
`Table 1 and Fig. 1 below outline the timing and strategy for
`carrying out forced degradation experiments.
`
`2.1. Degradation discussion
`
`Degradation background discussion is a critical first step in
`the process. In these initial discussions, degradation predic-
`tion, background knowledge and lessons learned can be
`shared. The purpose of the discussion is to review stability and
`degradation mechanisms for API and DP in a team-based
`environment to be used as a resource tool to aid analysts in
`performing forced degradation studies. Degradation discus-
`
`sions are held to facilitate meeting milestone deliverables,
`such as stability indicating methodology. Participants include
`analysts, process chemists, formulators and discovery repre-
`sentatives. Discussion should be reassessed for API process or
`salt changes, DP formulation changes as well as line extension
`efforts.
`
`3. Degradation prediction tools
`
`3.1. CAMEO
`
`CAMEO [5] is a computer program that predicts the pro-
`ducts of organic reactions given starting materials, reagents
`and conditions (see Fig. 1, Step 1: Predict degradants). The
`analyses cover the following key degradation conditions:
`basic/nucleophilic, acidic/electrophilic,
`radical, oxidative/
`reductive and photochemical as well as mechanistic inter-
`pretations of these reactions. In general, the CAMEO algo-
`rithms have been designed to give product mixtures that err on
`predicting more degradation products than actually observed.
`This is preferable to rules that are too restrictive and reject a
`
`Table 1
`Forced degradation timing
`
`Development timing
`
`Actions
`
`Recommendations/rational study design
`
`Pre-phase 1
`
`Pre-phase 1 + 6–12 weeks or after lab
`experiments are complete
`
`➢ Milestone: Initial IND
`
`Formulation development
`Phase I–Phase II
`
`➢Milestone:
`
`Phase III: ICH stability start
`
`Phase III: ICH stability start
`
`➢ Milestone: registration
`
`Step 1
`• Predict API degradants (Fig. 1, Sec. 1)
`• Design experimental protocol (Fig. 1, Sec. 2)
`• Perform experiments (Fig. 1, Sec. 3)
`
`• Focus on experiments resulting in at least 5–20% degradation
`• If degradation by a certain pathway is not predicted and/or
`experimental data prove it unlikely, minimal effort should be
`exerted on that condition
`
`Step 2
`• Assessment of API forced degradation data
`(Fig. 1, step 4)
`• Selection of key degradants for analytical
`method development (Fig. 1, step 6)
`• Challenge existing analytical methodology
`(Fig. 1, step 4)
`• Update degradation database (Fig. 1, step 8)
`➢ Provide analytical methodology with data to support stability indicating confidence
`➢ Methods supplied with expectation of future method development with change of process and/or salt form
`
`• Forced degradation data used for rugged method development
`• Mass balance not required
`• Track only significant degradants
`• Track and/or ID significant peaks by RRT and MW (LC/MS) only
`• Isolation and structure elucidation at this stage not required
`
`Step 3
`• Comprehensive forced degradation experiments
`for DP and API (Fig. 1, steps 2–3)
`• Review excipient compatibility data
`(Fig. 1, step 2)
`• Challenge existing analytical methodology
`(Fig. 1, step 4–5)
`• Update key degradation sample set for DP and
`API (Fig. 1, step 6)
`• Update degradation database (Fig. 1, step 8)
`➢ Rugged analytical method with high confidence in stability indicating ability, no further method development
`activities expected
`
`• Design experiments to highlight process, salt form and/or
`formulation changes
`• Mass balance and peak purity assessment as necessary for method
`development
`• ID significant peaks by RRT and MW (LC/MS) only unless more work
`is necessary for RRF determination or project needs
`
`Step 4
`• Attempt full characterization of significant
`degradants (Fig. 1, step 7)
`• Update degradation database (Fig. 1, step 8)
`
`• Isolation, mechanistic understanding and structure elucidation
`as required
`• Significant degradants that are fully characterized should include
`those seen on real time stability
`➢ Full characterization of significant degradation products completed
`
`Opiant Exhibit 2302
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 3
`
`

`

`32
`
`K.M. Alsante et al. / Advanced Drug Delivery Reviews 59 (2007) 29–37
`
`mulations change. The tables in Appendices A and B outline
`general protocol of tests and conditions that may be used to gene-
`rate data for regulatory submissions.
`
`4.1. API
`
`The specified stress conditions should result in approximately
`5–20% degradation of the API or represent a reasonable maxi-
`mum condition achievable for the API. The specific conditions
`(intensity and duration) used will depend on the chemical
`characteristics of the API. The stressed sample should be
`compared to the unstressed sample (control) and the appropriate
`blank. A compound may not necessarily degrade under a given
`stress condition. No further stressing is advised in these cases [2].
`
`4.1.1. Acid
`Example acids include HCl or H2SO4 (0.1–1 mol/L
`solution). Studies should be carried out in the solution state.
`For certain APIs that are partially soluble or insoluble in the
`described acidic solution, addition of an appropriate co-solvent,
`or adjustment of solution pH in the acidic range may be required
`to achieve dissolution; or the APIs can be run as suspensions
`[2]. Special attention to the API structure should be paid when
`choosing the appropriate co-solvent (i.e. do not use alcohols for
`acidic conditions due to their reactivity). Dimethylsulfoxide,
`acetic acid and propionic acid are useful under acidic
`conditions. Additionally,
`the sample may be heated for a
`defined time/temperature to accelerate degradation, depending
`on the API sensitivity to heat.
`
`4.1.2. Base
`Example bases include NaOH, LiOH or KOH (0.1–1 mol/L
`solution). Studies should be carried out in the solution state. For
`certain APIs which are partially soluble or insoluble in the
`described basic solution, addition of an appropriate co-solvent, or
`adjustment of solution pH may be required to achieve dissolution;
`or the APIs can be run as suspensions. Glyme and 1, 4-dioxane
`facilitate reactions in basic conditions [7]. Additionally, the sample
`may be heated for a defined time/temperature to accelerate
`degradation, depending on the API sensitivity to heat.
`
`4.1.3. Oxidation
`Oxidation can be carried out under an oxygen atmosphere or
`in the presence of peroxides. The use of oxygen is a more
`realistic model. Free radical initiators may be used to accelerate
`oxidation. Generally, a free radical initiator and peroxide will
`produce all primary oxidation degradation products observed
`on real-time stability. Therefore, free radical and/or hydrogen
`peroxide conditions are strongly recommended at all stages of
`development.
`For solution state stress conditions, dissolve the API utilizing
`an appropriate solvent, add 5–20 mol% of a free radical initiator
`at atmospheric pressure. To increase the solubility of oxygen in
`the solution, the reaction can be performed in a reaction vessel
`pressurized at 50–300 psi with molecular oxygen. Additionally,
`the system is heated to accelerate degradation. The temperature
`depends on the free radical initiator selected.
`
`Fig. 1. Forced degradation process flow map — prediction to documentation in
`a structure searchable global degradation database.
`
`key product observed in actual degradation or ICH stability
`studies. It is also likely that certain products predicted can
`undergo further decomposition. Due to these limitations with
`this prediction program, tracking historical degradation data
`in terms of functional groups along with CAMEO prediction
`data provides a more thorough approach to degradation predic-
`tion exercises.
`
`4. Experimental approach tools
`
`Forced degradation studies of API and DP include appropriate
`solid state and solution state stress conditions (e.g. acid/base
`hydrolysis, heat, oxidation, and light exposure) in accordance
`with ICH guidelines (Fig. 1, Steps 2 and 3: Design protocol and
`perform experiments) [1,6]. Forced degradation studies should be
`conducted whenever a stability indicating method is required.
`Studies may need to be repeated as methods, processes, or for-
`
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`K.M. Alsante et al. / Advanced Drug Delivery Reviews 59 (2007) 29–37
`
`33
`
`For peroxide conditions, hydrogen peroxide reagent (up to
`3%) can be used. As previously indicated, the addition of an
`appropriate co-solvent may be necessary, depending on API
`solubility. Hydrogen peroxide stress testing can be useful in DP
`studies where hydrogen peroxide is an impurity in an excipient.
`Solid-state stress conditions may be similarly investigated by
`placing the API (as is) in suitable closed containers filled with an
`oxygen headspace versus an argon or nitrogen control headspace.
`Additionally, the sample may be heated for a defined time/
`temperature to accelerate degradation, depending on the API
`sensitivity to heat.
`For later stage development compounds when more time and
`effort can be focused on mechanistic understanding,
`the
`following oxidation conditions can be applied. The addition
`of metal ions to solutions of API can indicate whether there is a
`tendency for the API to be catalytically oxidized. Iron and
`copper ions are routinely found in APIs and formulation
`excipients [8]. Transition metal ions can also reduce peroxide to
`generate hydroxyl
`radicals in a Fenton-type reaction.
`In
`addition,
`light can also effect oxidation reactions. Light
`absorbed by a photosensitizer can react with molecular oxygen
`to form the more reactive singlet oxygen species.
`
`4.1.4. Thermal/humidity
`Solid state stability can be evaluated utilizing accelerated
`storage temperatures in general greater than 50 °C and N75%
`relative humidity. The duration of exposure is dependent on the
`API sensitivity. If the forced degradation thermal/humidity
`conditions produce a phase change, it is recommended to also
`run thermal/humidity conditions below the critical thermal/
`humidity that produces the phase change.
`Arrhenius kinetics may be used to establish an appropriate
`temperature and maximum duration of thermal degradation
`studies. Using an appropriate assumption of activation energy,
`the duration of controlled room temperature storage that is
`simulated by the study can be estimated. The table in Appendix
`C provides a guide to that conversion. In general, an activation
`energy assumption of 15 kcal/mol is recommended. In certain
`preclinical
`through phase 2 studies, an activation energy
`assumption between the recommended 15 kcal/mol assumption
`and an aggressive assumption of 18 kcal/mol might be
`appropriate. In studies where particular concerns exist, an
`activation energy assumption between the recommended
`15 kcal/mol assumption and a conservative assumption of
`12 kcal/mol might be appropriate. Deviation from Arrhenius
`kinetics is increasingly expected above 70–80 °C, and the
`impact of this should be considered during experimental design.
`
`4.1.5. Photostability
`Perform studies in accordance with ICH photostability
`guidelines [9]. Option 1 and/or Option 2 conditions can be
`used. According to the ICH guideline, “the design of the forced
`degradation experiments is left
`to the applicant's discretion
`although the exposure levels should be justified. The recom-
`mended exposures for confirmatory stability studies are an
`overall illumination of not less than 1.2 million lux hours and an
`integrated near ultraviolet energy of not less than 200 W-h/m2.
`
`For forced degradation studies, the samples should be exposed to
`at least 2× the ICH exposure length to ensure adequate exposure
`of the sample. For solution studies, acetonitrile is the co-solvent
`of choice. Methanol can produce more artifact degradation
`products from methoxy radicals produced from light exposure.
`
`4.2. Drug product
`
`Drug product (DP) degradation cannot be predicted solely
`from the stability studies of the API in the solid state or solution.
`The non-active pharmaceutical ingredients can also react with
`the API or catalyze degradation reactions. Impurities in the
`excipients can also lead to degradation in the DP not originally
`observed in the API. For DP formulations, heat, light, and
`humidity are often used. The DP stress conditions should result
`in approximately 5–20% degradation of the API or represent a
`reasonable maximum condition achievable for a given formu-
`lation. The specific conditions used will depend on the chemical
`characteristics of the DP. For a solid DP, key experiments are
`thermal, humidity, photostability and oxidation, if applicable.
`For solution formulations, key experiments are thermal, acid/
`base hydrolysis, oxidation and photostability. It
`is recom-
`mended to compare stressed samples with unstressed samples
`and an appropriate blank. For DP studies, the blank sample is an
`appropriate placebo. The stressed placebo sample will provide
`information about excipient compatibility.
`It is advised to take kinetic time points along the reaction
`pathway for API and DP degradation studies to determine primary
`degradants and a better understanding of the degradation pathway.
`
`5. Stability-indicating method development
`
`A stability-indicating method is defined as an analytical method
`that accurately quantitates the active ingredients without interfer-
`ence from degradation products, process impurities, excipients, or
`other potential impurities. A method that accurately quantitates
`significant degradants may also be considered stability-indicating.
`A proactive approach to developing a stability indicating HPLC
`method should involve forced degradation at the early stages of
`development with the key degradation samples used in the method
`development process (Fig. 1, Step 4: Challenge methodology).
`Forced degradation should be the first step in method development.
`If forced degradation studies are performed early, method
`development and identification of primary degradation products
`and unknown impurities can be run in parallel. Using this process,
`a validated HPLC analytical assay, mechanisms of degradation,
`and the impurity/degradant
`information for filing can all be
`generated without delays in the project timeline.
`
`5.1. Mass balance
`
`Mass balance is defined in the 1999 ICH Guidelines as
`“adding together the assay value and levels of degradation
`products to see how closely these add up to 100 percent of the
`initial value, with due consideration of the margin of analytical
`error”. Assessment of mass balance may be informative in
`assuring that
`the chosen analytical strategy controls all
`
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`

`34
`
`K.M. Alsante et al. / Advanced Drug Delivery Reviews 59 (2007) 29–37
`
`significant degradants (Fig. 1, Step 5: Evaluate purity/potency).
`The Guidelines recognize that it can be difficult to determine
`mass balance due to unknown analytical precision and
`differences in response factor. Additional guidance on helping
`the analyst obtain or approximate mass balance is given by
`Baertschi et al. [10].
`
`5.2. Key degradation sample set
`
`The key degradation-impurity sample set (Fig. 1, Step 6:
`Select key degradants/track peaks) for a given compound is
`equal to the significant degradants plus process impurities
`which can include intermediates, starting materials, and by-
`products. Process related impurities and known degradation
`products might be available as reference standards for use in
`method development. Unknown degradation products can
`also be critical
`in the development of a stability specific
`method.
`Forced degradation studies may generate complex mixtures
`of degradants, but method development should consider only
`significant degradants. Although project-specific factors may
`influence judgments of degradant significance, Table 2
`describes guidelines that may generally be applied, considering
`the stage of development. A degradant in a degraded sample
`may be judged not significant, and hence discounted, if it fails
`to exceed either threshold described.
`Example 1: A degraded sample from an exploratory API
`forced degradation study shows 25% main band loss. Analysis
`shows a major degradant (16%), a second degradant (3%) and
`several further degradants at levels NMT 2%.
`
`performed to identify the unknown significant degradants, as
`appropriate. The integrity of these analyte peaks can be verified
`by LC/MS selective ion monitoring. The purity of the peaks can
`also be verified by collecting the peak of
`interest and
`chromatographing it by another method (TLC, GC, or a second
`HPLC system). Usually key predictive samples can be gener-
`ated on a large-scale basis for preparative isolation. Small-scale
`synthesis is also an option when a likely structure is identified
`and the chemistry can be accomplished in a few short steps.
`
`5.3. Stereochemical stability
`
`Chiral APIs should be assessed for their stereochemical
`stability during forced degradation studies on a case-by-case
`basis. CAMEO analysis should be reviewed for concerns with
`racemization of chiral centers in the API. If the degradation
`prediction suggests racemization to be likely by any condition,
`stereochemical stability should be explored. APIs with one or
`two chiral centers should be analyzed with a chiral method.
`Based on predictive data and chemical knowledge, choose
`degradation conditions that are most
`likely to convert
`the
`molecule. If the chosen conditions do not invert or racemize the
`API, then chiral analysis does not need to be part of further
`forced degradation protocols. APIs with three or more chiral
`centers most likely convert to diastereoisomers and could be
`analyzed with an achiral method. Stereoisomers should be
`treated like any other API related impurity with respect to quan-
`titation, identification and qualification thresholds, etc. [11].
`
`5.4. Physiochemical stability
`
`• The 16% peak is the largest degradant, representing N60% of
`total degradation is judged significant.
`• Although the 3% component comprises more than 10% of
`total degradation, its level is less than 25% that of the largest
`degradant and is thus judged not-significant.
`• The components at or below 2% are less than 10% of total
`degradation, as well as being less than 25% the level of the
`largest degradant. All are thus judged not significant.
`
`A polymorph appearing in the late stage of drug develop-
`ment may require reformulation, redevelopment of analytical
`method and change of manufacturing procedures. In addition to
`this, some physical form change only occurs in the solid state
`[12]. For these reasons,
`the solid form change should be
`monitored during forced degradation studies. In order to insure
`the solvolysis of the API, solvates and hydrates should be
`stressed in closed and open containers.
`
`Example 2: A forced photodegradation experiment results in
`10% main band loss. Many individual degradants are observed,
`of which the largest is 0.8%.
`
`• Since no individual impurity exceeds 10% total degradation,
`none is judged significant.
`
`Fig. 1 details the process involved in the key degradation-
`impurity sample generation and selection. Work should then be
`
`Table 2
`Significance judgment guidelines for forced degradation studies
`Pre-clinical — Phase 2
`Phase 2 — registration
`
`% of largest degradant
`% of total degradation
`
`API
`
`25%
`10%
`
`Drug product
`
`10%
`10%
`
`API
`
`10%
`10%
`
`Drug product
`
`10%
`10%
`
`5.5. Identify degradants
`
`Degradants structure elucidation is a collaborative effort
`involving the analytical chemist, process chemist and/or
`formulator, as well as the degradation, mass spectrometry and
`NMR experts (Fig. 1, Step 7: Identify degradants) [13].
`Typically, the focus will be on collecting LC/MS data only
`through the Phase 1 clinical stage. At the Phase 2 clinical stage
`and beyond, more time is invested in isolation, synthesis and
`structural
`identity using NMR characterization of
`forced
`degradation products of concern.
`
`6. Degradation database
`
`A structure-searchable degradation profile database has
`been created to compile API/DP degradation data and share
`degradation knowledge globally at Pfizer (Fig. 1, Step 8:
`
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`

`K.M. Alsante et al. / Advanced Drug Delivery Reviews 59 (2007) 29–37
`
`35
`
`Appendix B (continued)
`Acid/base hydrolysis
`API
`Duration
`
`5–20% degradation or 14 days maximum
`
`DP (not necessary if DP is not solution form)
`API
`Formulation dependent (usually at formulation
`concentration
`API concentration)
`+/−2 pH units around the target pH
`pH range
`pH adjustment HCl for low range and NaOH for high range
`Co-solvents
`Not applicable
`(if needed)
`Temperature
`Duration
`
`70 °C
`5–20% degradation or (3 weeks maximum)
`see activation energy chart
`risk level
`to
`compare with correlation to shelf life
`
`Oxidative degradation
`
`API
`⁎Radical
`chain
`initiators
`
`Initiator
`
`API
`concentration
`Initiator
`concentration
`Solvent
`Temperature
`Duration
`
`AIBN (40–60 °C) —
`organic soluble
`initiator; ACVA
`(40–60 °C) or VA-044
`(RT — 40 °C) —
`water soluble initiators
`0.1–20 mg/ml
`
`5–20 mol% of
`API concentration
`Acetonitrile/water
`Ambient — 60 °C
`5–20% degradation or
`14 day maximum
`
`Document degradants and mechanisms) [14]. The database is a
`web-based system. It was developed to address certain key
`goals including: improve communication, minimize duplication
`of effort, and establish a proactive approach to drug stability,
`predict problems and identify trends in data. With the
`degradation profile database, an analyst can search by structure
`and produce tabulated results of all the identified degradants
`observed under each degradation condition. The database also
`contains a substructure search function that allows the analyst to
`retrieve all records on compounds with similar structure. This
`function is extremely powerful
`in that
`it enables better
`prediction of degradation reactions and better use of our library
`of degradation studies previously performed. The following
`data is tracked in the database: compound number, notebook
`reference, salt form, parent structures, degradant structures,
`molecular weights of degradants, degradation experimental
`conditions, HPLC procedure references, conditions for
`performing degradant HPLC screening analysis, structure
`elucidation data, report references, links to electronic report
`files, and proposed mechanisms for degradants.
`
`Appendix A. General protocol of API and DP degradation
`experiments
`
`Condition
`
`API
`
`DP
`
`Solid Solution/
`suspension
`
`Solid (tablets,
`capsules,
`blends)
`
`+
`+
`o
`
`Acid