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`Eye Therapies Exhibit 2027, 5 of 25
`Slayback v. Eye Therapies - IPR2022-00142
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`

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`SpecificAtionS 9
`
`coMpendiA 9
`
`MonogrAphS 10
`
`Chapter 2
`Analysis of Medicinals
`
`Raymond D. Skwierczynski, PhD
`
`doSAge forMS—injectAbleS 16
`
`doSAge forMS—orAl drUg prodUctS 17
`
`AdditionAl doSAge forMS 19
`
`releASe And StAbility teSting 10
`
`fUtUre direction 19
`
`UniverSAl teStS 10
`
`Method vAlidAtion for UniverSAl teStS 11
`
`Appendix A 22
`
`Appendix b 24
`
`tAxonoMy 15
`
`The aim of this chapter is to provide the pharmaceutical sci-
`entist with a general overview of the analytical testing that is
`performed in order to release a medicinal product for clinical or
`commercial use and specifications that ensure the quality and
`performance of the medicinal product being released.
`
`SpecificAtionS
`
`The pharmaceutical manufacturer is responsible for ensuring
`the quality, purity, identity, and strength of each lot of drug
`product manufactured. One mandatory control strategy is to
`ensure that the lot “conforms to specification,” which means
`that the drug product (formulated preparation), when tested to
`the listed analytical procedures, will meet the listed acceptance
`criteria.1 Specifications are critical quality standards.
`A specification is a document that is defined as a list of tests,
`references to analytical procedures, and appropriate acceptance
`criteria (numerical range or limit).1 The pharmaceutical manu-
`facturer justifies the information on the specification, which is
`approved by regulatory authorities. Examples of specifications
`for hypothetical drug products are provided in Appendix A.
`Specifications can be categorized in a couple of manners.
`One way is by the intended use of the product. For example,
`is the medicinal an investigational product intended for use
`in a clinical study, or is it a commercial product that will be
`marketed? Let’s consider the evolution of a hypothetical oral
`drug product as it enters the clinic for single- and multiple-
`ascending dose safety studies during Phase 1 clinical studies,
`then multiple-ascending dose efficacy studies in Phase 2a, and
`confirmatory efficacy studies in Phase 2b and Phase 3. In order
`to enter the clinic rapidly, a simple drug product called a drug-
`in-capsule was chosen for Phase 1. This dosage form consists of
`neat drug (no excipients) that has been accurately weighed into
`gelatin capsules. The manufacturing process meets the volume
`demand for Phase 1, but the dosage form must be changed prior
`to scaling-up to Phase 2. Hence, the drug-in-capsule is a “lame
`duck” dosage form. Specifications for investigational products
`tend to have acceptance criteria that reflect the early life of
`the product. Here, the acceptance criteria for dissolution of our
`drug-in-capsule may be “record result.”
`Now let’s say that our drug-in-capsule drug product will be re-
`placed with a dosage form that is manufactured using a scalable
`manufacturing process — a tablet for Phase 2. The tablet will
`first be used in Phase 2 ascending-dose clinical studies, so sev-
`eral dose strengths will need to be manufactured. Let’s say that
`these dose strengths are 10, 25, and 100 mg. The acceptance
`criterion for the dissolution test may remain as “record result”
`because the dosage form is new, or the criterion may be a “di-
`saster check” criterion. Although the analytical chemist may
`
`not be able to assign a strict acceptance criterion because of the
`limited data, a slow-dissolving drug from an immediate-release
`tablet may jeopardize the interpretation of the clinical results.
`So a criterion like 70 percent of the drug dissolved after 60 min-
`utes may be appropriate for the 100-mg tablet. The lower dose
`strengths are usually assigned the same acceptance criterion.
`Finally, the tablet has entered late development and will be
`used for confirmatory studies. The dose ranging Phase 2a stud-
`ies determined that the efficacious dose was 60 mg, so a new 60-
`mg tablet was developed for use in the Phase 3 studies. During
`Phase 3, a robust manufacturing process has been developed at
`suitable scale, a robust dissolution test also has been developed
`and validated, and many lots of tablets have been manufactured
`and analyzed. Now, a suitable acceptance criterion at the time
`of NDA or MAA submission may be 70 percent of the drug dis-
`solved after 30 minutes.
`Another common categorization involves using different ac-
`ceptance criteria for release testing and stability testing in or-
`der to account for changes that may occur during the shelf life.
`For example, a topical cream may become less viscous upon
`storage at 25°C to 30°C for two years. The cream may be too
`fluid to apply when its viscosity is less than 1000 mPa·s. A suit-
`able acceptance criterion for a stability specification may be
`2000 mPa·s. Let’s say that the development data indicate that
`in order to ensure a viscosity of 2000 mPa·s at the end of the
`shelf life, the cream must have a viscosity of 10,000 mPa·s at
`the time of release. Therefore, the acceptance criteria for the
`release and stability specifications would be not less than (NLT)
`10,000 mPa·s and NLT 2000 mPa·s, respectively, in order to en-
`sure a quality product for its entire shelf life.
`
`coMpendiA
`
`All drug products, whether commercial or investigational, must
`meet standards that have been established by Pharmacopeial
`Conventions or Regulatory Agencies. The United States Phar-
`macopeial (USP) Convention is a scientific nonprofit organi-
`zation that sets standards for the quality, purity, identity, and
`strengths of medicines, food ingredients, and dietary supple-
`ments manufactured, distributed, and consumed worldwide.2–4
`USP drug standards are enforceable in the United States by the
`Food and Drug Administration, and these standards are devel-
`oped and relied upon in more than 130 countries.2,4
`The European Pharmacopeia (Ph. Eur.) Commission estab-
`lishes official standards that provide a legal and scientific basis
`for quality control during the development, production, and
`marketing of medicines in 37 signatory states of the conven-
`tion.5,6 In addition to the signatory states, which comprise 26
`countries and the European Union, there are a large number
`
`9
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`Eye Therapies Exhibit 2027, 6 of 25
`Slayback v. Eye Therapies - IPR2022-00142
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`

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`10
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`PHARMACEUTICAL ANALYSIS AND QUALITY CONTROL
`
`of observers of Ph. Eur. Twenty-two countries (including Aus-
`tralia, Brazil, Canada, China, the Russian Federation, and the
`United States) and the World Health Organization are listed as
`observers. Consequently, the standards developed by Ph. Eur.
`have an impact on the quality of medicines across the globe.5,6
`The USP and Ph. Eur. publish books of pharmacopeial stan-
`dards. The thirty-fourth revision of the USP and the twenty-
`ninth edition of the National Formulary, USP 34-NF29, became
`official on May 1, 2011. The USP-NF is continuously revised.
`Standard revisions are found in supplements to the USP-NF that
`are published twice yearly. Accelerated revisions are published
`in Pharmacopeial Forum (PF) and on the USP website, www.
`usp.org. A new edition of USP-NF becomes official each year
`on May 1. Chapters <1> through <999> are enforceable chap-
`ters, while Chapters <1000> through <1999> are informational
`chapters.3
`The seventh edition of the European Pharmacopeia (Ph. Eur
`7. 0) became official on January 1, 2011. This edition will be
`augmented with eight supplements over a three-year period.5
`The eighth edition of Ph. Eur. will become official on January
`1, 2014. The European Pharmacopeia is published in English
`and French.
`The British Pharmacopeia (BP) is the official collection of
`standards for UK medicinal products and pharmaceutical sub-
`stances.7 The standards are established by the British Pharma-
`copeia Commission. Canada and Australia also use the BP is as
`their official standards. The BP is recognized in over 100 coun-
`tries as an internationally acceptable standard and remains an
`essential reference for all individuals and organizations working
`within pharmaceutical research, development, manufacture,
`and testing across the globe.8 A new edition of the BP becomes
`official each year on January 1.
`Japan’s Ministry of Health, Labor, and Welfare (MHLW) pub-
`lishes The Japanese Pharmacopeia (JP), which provides an of-
`ficial standard to ensure the quality of medicines in Japan.9–11
`The Japanese Pharmacopeia, Sixteenth Edition (JP 16) became
`official on April 1, 2011. JP 16 is printed in Japanese only at the
`time of publication of this chapter. JP 15, however, is available
`in English. Both editions can be found on The Japanese Phar-
`macopeia website and are free of charge.
`
`MonogrAphS
`
`A monograph is written after a drug product has been registered
`and established in the marketplace and usually before its patent
`expires. The USP defines a monograph as a written standard
`that describes an article (e.g., drug substance, drug product,
`excipient, compounded preparation).12 A monograph published
`in any USP compendium provides the name of a substance; its
`definition; package, storage, and labeling requirement; and in-
`formation on tests needed to ensure the substance is of the ap-
`propriate identity, strength, quality, and purity.3 The later part
`of a monograph is similar in scope to a specification.
`The monograph gives manufacturers, governments, and sci-
`entists a public standard by which to judge an article’s quality.
`Monographs play an important role in meeting the USP’s mis-
`sion by providing standards for substances consumed in a glob-
`al marketplace—standards that help maintain public health.
`The USP-NF comprises more than 4000 monographs.12 The
`USP contains monographs for drug substances and preparations
`(drug products); excipient monographs are in the NF.
`The European Pharmacopeia contains more than 2000 gen-
`eral and specific monographs, including chemical substances,
`antibiotics, vaccines, dosage forms, herbal drugs, and homeo-
`pathic preparations.5 One major difference between the Ph.
`Eur. and USP is illustrated by this example: the USP has mono-
`graphs for tablets of a specific drug (e.g., amoxine), whereas Ph.
`Eur. will have only a general monograph for tablets. The BP and
`JP also contain monographs of drug substances and drug prod-
`ucts. The BP, which contains over 3000 monographs, incorpo-
`rates monographs of the European Pharmacopoeia.13
`
`releASe And StAbility teSting
`
`The release and stability testing can be classified in a couple of
`practical ways. One is by the nature of the testing performed:
`chemical, physical, and microbial. For example, the assay for
`the amount of active ingredient in a gel would be a chemical
`test, the viscosity measurement and the in vitro release test
`would be physical tests, and the microbial limits test would be
`a microbiological test. This classification system is often used
`in analytical laboratories that are specialized by the type of test
`being performed. The chapters in pharmacopeia are also orga-
`nized by the nature of the test.3,5,9,10
`Another classification system that is used is based on the at-
`tribute that is being tested. For example, the ICH Guidances and
`the USP provide two categories for the system: analytical tests
`and acceptance criteria for assessing (1) general quality attri-
`butes and (2) product performance.1,14-17 Using the previous gel
`example, the assay, viscosity, and microbial limits tests would
`be examples of tests that assess general quality attributes while
`the in vitro release test would assess product performance.
`
`UniverSAl teStS
`
`There are four tests that are generally applicable to all drug
`products: description, identification, assay, and impurities.
`
`deScription
`This test is often called “appearance” on a specification and is a
`qualitative description of the dosage form. For example, the de-
`scription of a tablet on a specification may read: white, round,
`biconvex, film-coated tablet, imprinted with “400” on one side.
`
`identificAtion
`The purpose of an identification or identity test is to verify the
`identity of the active pharmaceutical ingredient(s) (API) in
`the dosage form. This test should be able to discriminate be-
`tween compounds of closely related structure that are likely to
`be present. Infrared and Raman spectroscopy are commonly
`used techniques. A more practical technique, however, is high-
`performance liquid chromatography because the identity and
`assay can be determined using the same analytical method.
`The ICH Q6A Guidance, however, does not regard identifica-
`tion solely by a single chromatographic retention time as being
`specific, the definition of which is the ability of the method to
`assess unequivocally the analyte in the presence of the sam-
`ple matrix (excipients, impurities, and degradation products).
`Thus, some laboratories will couple a diode array or mass spec-
`trometric (MS) detector to the HPLC system. The diode array
`detector provides a UV spectrum of the drug; the MS detector
`gives the nominal mass of the drug.
`
`ASSAy
`This test determines the strength or content of the API in the
`dosage form and is sometimes called a content test. The method
`should be stability-indicating, which means that the method is
`quantitative and specific and can detect chemical changes with
`respect to time, so that the quantity of the active ingredient(s)
`can be accurately and precisely measured in the presence of
`the sample matrix. HPLC is the most common technique used
`for stability-indicating methods.
`
`iMpUritieS
`ICH Guidance Q6A defines an impurity in a drug product as any
`component that is not the API or an excipient. The most com-
`mon type of impurities that are measured is related substances,
`which are process impurities from the new drug substance syn-
`thesis, degradation products of the API, or both. The test for re-
`lated substances is often referred to as a purity test and must be
`stability indicating. The method can be the same as that used
`for assay, or it can be a different method that has been devel-
`oped for measuring low-level impurities. An additional method
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`Eye Therapies Exhibit 2027, 7 of 25
`Slayback v. Eye Therapies - IPR2022-00142
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`

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`to measure chiral purity may be used to quantify enantiomeric
`impurities in the drug product. In cases in which an organic
`solvent is used during the manufacture of the drug product, a
`method for measuring residual solvents is also used.
`
`Method vAlidAtion for UniverSAl teStS
`
`The objective of validation of an analytical method is to dem-
`onstrate that it is suitable for its intended purpose.3,5,18,19
`Therefore, the objective of the analytical method will govern
`the validation characteristics that need to be evaluated. Typical
`validation characteristics are specificity, accuracy, precision,
`linearity, range, robustness, detection limit, quantitation limit,
`and sample and standard stability. Well-characterized reference
`materials, with documented purity, should be used throughout
`the validation study.19 A validation protocol that describes the
`validation experiments to be performed and their pre-deter-
`mined validation performance criteria is required. In early de-
`velopment, a department Standard Operating Procedure (SOP)
`can be used instead of a protocol, provided that the SOP clearly
`outlines the validation experiments and validation performance
`criteria. Let’s examine the characteristics evaluated for each of
`the four universal tests and typical acceptance criteria that ac-
`company each test on the specification.
`
`ASSAy
`
`Acceptance criteria
`The results from an assay are usually expressed as a percentage
`of the label claim with acceptance criteria that are typically in
`the range from 90.0 to 110.0 percent label claim. For example,
`a manufactured lot of 500-mg aspirin tablets with these accep-
`tance criteria would have an average assay value between 450
`and 550 mg. The width of these limits is to allow for manufac-
`turing variability and shelf-life stability. In some cases, such as
`narrow-therapeutic drugs, the acceptance criteria may be from
`95.0 to 105.0 percent label claim.
`
`validation characteristics
`Assay methods are validated for specificity, linearity, range, ac-
`curacy, precision, robustness, and sample and standard stabil-
`ity.18,19 Validation of detection limit and quantitation limit is
`not needed unless the same method is used to quantify related
`substances.
`
`SPEcificity
`Most assays are performed using HPLC. Specificity can be dem-
`onstrated in a number of ways. A common approach is to spike
`each impurity and excipient into the analytical solution at an
`appropriate level and compare the results of the spiked sam-
`ples against those of the unspiked samples to demonstrate that
`the presence of the impurities or excipients does not affect the
`assay result. Of course, this approach works only if authentic
`samples of the impurities are available.
`If the impurities are not available, the API, or the dosage
`form, is subjected to forced degradation conditions, and the de-
`gradants and synthetic process impurities are separated from
`the API, using the method that is being validated, as well as
`other methods that make use of different stationary phases
`(chromatographic columns) and chromatographic conditions
`(mobile phase components and gradients, flow rate). Diode ar-
`ray or MS detection is often used. The goal here is to demon-
`strate that no impurity co-elutes with the API in the validated
`method.
`The forced degradation conditions that are often used in
`the analytical laboratory for method development and valida-
`tion are dissolving the API (with or without excipients) in an
`aqueous or aqueous-organic solvent and exposing the solution
`to acidic, basic, and nucleophilic and free radical oxidation
`conditions. It is important to control the degradation to less
`than about 10 percent in order to make the forced degradation
`
`ANALYSIS Of MEDICINALS
`
`11
`
`experiments representative of the degradation that might be
`seen during the shelf-life of the drug product and to decrease
`the probability of the degradants reacting with each other or
`degradants reacting with the API.
`In addition, the API and the dosage form should be exposed
`to a variety of moderately stressed stability conditions, such
`as light and prudently selected combinations of heat and hu-
`midity in order to degrade the material “purposefully.” Some
`common storage conditions for purposeful degradation of a sol-
`id-dosage form include 40°C and 75 percent relative humidity
`(40/75) in high-density polyethylene (HDPE) bottles, 40/75 in
`an open dish (containerless), 60/75 in HDPE bottles, and 60/75
`in an open dish. Some pharmaceutical companies have formed
`purposeful-degradation groups that are tasked with identifying
`“soft spots” on API molecules, understanding the degradation
`chemistry, identifying impurities, conducting purposeful degra-
`dation studies, and proposing stabilization strategies to prevent
`or inhibit chemical degradation.20
`If the API is volatile, gas chromatography (GC) can be used
`for the assay test. Just as with HPLC, more than one method
`should be used to demonstrate specificity. Gas chromatography
`with mass spectrometric detection (GC-MS) is useful to accom-
`plish this goal. In cases in which a non-specific assay, such as
`titrimetry or UV spectrophotometry, is used, other supporting
`methods and knowledge of the degradation chemistry can be
`used to demonstrate overall specificity. The use of non-specific
`methods to determine assay, however, is not recommended,
`given the advances in chromatographic and detection technol-
`ogy. The USP is actively modernizing official USP-NF mono-
`graphs for small-molecule API and their dosage forms that use
`outdated analytical technology or have non-specific identifica-
`tion and assay tests.21
`
`LinEarity and rangE
`A linear relationship should be evaluated across the range of
`the analytical method. For a drug product that has assay ac-
`ceptance criteria of 90.0 to 110.0 percent label claim, linearity
`is usually demonstrated minimally from 80.0 to 120.0 percent.
`Some companies have a policy to demonstrate linearity over an
`expanded range from 70.0 to 130.0 percent. The linearity can
`be demonstrated directly on the API or on separate weighings
`of API and excipient mixtures.
`
`accuracy
`The accuracy of an analytical method expresses the closeness
`of agreement between the value found using the method and
`either an accepted reference value or a conventional true value.
`Accuracy is also termed trueness. A common way that accu-
`racy of a method is evaluated is by performing “spike and re-
`covery” experiments. Here, a known quantity of drug substance
`is spiked into a placebo matrix and compared to a reference
`solution that contains a known amount of drug substance. The
`compatibility of the analyte with the filter used during sample
`preparation is often formally evaluated at this time. Another
`common way to validate the accuracy of a method is to com-
`pare the results obtained from the method being validated to
`those obtained from a second well-characterized procedure.
`Accuracy should be assessed using at least nine determi-
`nations over a minimum of three concentration levels (three
`different concentrations with three replicates of each concen-
`tration) that cover the specified range.
`Accuracy can be inferred once precision, linearity, and speci-
`ficity have been established. This approach is more common in
`early development activities, such as IND-enabling toxicology
`studies or Phase 1 clinical studies.
`
`PrEciSion
`The precision of an analytical method expresses the closeness
`of agreement between a series of measurements obtained from
`multiple samplings of the same homogeneous sample under the
`prescribed conditions.18,19 The precision of a method is best
`
`Eye Therapies Exhibit 2027, 8 of 25
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`12
`
`PHARMACEUTICAL ANALYSIS AND QUALITY CONTROL
`
`evaluated using authentic homogeneous samples. If authentic
`samples are not available, artificially prepared samples or a
`sample solution may be used.
`Precision is considered at three levels: repeatability, inter-
`mediate precision, and reproducibility, which are intra-assay,
`within-laboratory, and inter-laboratory measurements, respec-
`tively. Repeatability is measured in one of two ways. One is to
`perform a minimum of six determinations at 100 percent of the
`test concentration. The other is to perform at least nine deter-
`minations over a minimum of three concentration levels (three
`different concentrations with three replicates of each concen-
`tration) that cover the specified range. Depending on company
`policy, repeatability and intermediate precision may be the
`only precision evaluation made in early development. Interme-
`diate precision in its simplest sense is a comparison of results
`obtained by two analytical chemists from the same department
`(laboratory), preferably using two different chromatographic
`systems. Intermediate precision, however, can also be a design
`of experiments (DOE) in which variables such as analytical
`chemists, chromatographic systems, and days are examined.
`Reproducibility is usually assessed prior to or during regis-
`tration stability studies. A DOE is often used. Variable studies
`are similar to those used in intermediate precision, except that
`multiple analytical chemists and chromatographic systems are
`from two laboratories. These laboratories are often the labo-
`ratory that developed the method and the laboratory that will
`perform the release testing of the drug product.
`
`robuStnESS
`The robustness of an analytical method is evaluated prior to or
`during registration stability studies. The robustness evaluation
`shows the reliability of the method with respect to deliberate
`changes made to the method. For example, consider an HPLC
`assay method for which the pH of the aqueous buffer used in
`the mobile phase is 4.5. Experiments may be performed using
`buffers at pH 4.0 and 5.0 in order to evaluate the criticality of
`mobile phase pH on the assay results. Other variables that may
`be evaluated in robustness experiments for assay methods are
`flow rate, injection volume, column temperature, sample tray
`temperature, column manufacturer, mobile phase composition,
`extraction time for sample preparation, and solvent (diluents)
`composition for sample preparation. The numbers of variables
`can be large, and the variables may be interdependent, so a
`DOE approach to evaluate robustness is encouraged.
`
`SamPLE and Standard StabiLity
`Regardless of the phase of development, the analytical samples
`and standards need to be stable for the duration of the analy-
`sis. This stability needs to be evaluated formally during method
`validation.
`
`iMpUritieS: relAted SUbStAnceS
`Acceptance criteria
`The acceptance criteria for related substances on a drug prod-
`uct specification are expressed as less than or equal to a numer-
`ical value and are provided for individual impurities and total
`impurities. The purity results are reported as a percentage, with
`respect to either the peak area of the API in the drug product
`or the sum of the integrated peaks on the chromatogram. Pu-
`rity methods must be stability-indicating. Related substances
`arising during drug product manufacturing and from the degra-
`dation of the drug substance must be monitored. Process impu-
`rities originating during the synthesis of the API are normally
`controlled during drug substance testing and are not listed on
`the drug product specification unless the synthesis impurity is
`also a degradation product in the drug product.
`The magnitude of the acceptance criterion and how the im-
`purity is listed on the specification are determined by the total
`daily dose, the dose at which the impurity was qualified in a
`toxicology study, manufacturing capability, and stability of the
`
`drug product.22 If the daily dose is not more than (NMT) 1.0 g,
`impurities greater than 0.1 percent must be reported on the
`Certificate of Analysis (CofA). For daily doses greater than 1.0 g,
`the impurities greater than 0.05 percent must be reported. The
`values for all of the reported impurities will be summed, and this
`sum must meet the acceptance criterion for total impurities.
`Some individual impurities are listed on the specification
`and limited in order to ensure the quality of the drug product.
`These impurities are called specified impurities. If the level of
`a specified impurity exceeds the identification threshold listed
`in ICH Guidance Q3B, then this impurity must be identified us-
`ing a combination of mass spectrometric and nuclear magnetic
`resonance (NMR) spectrophotometric techniques. Such impu-
`rities are called specified identified impurities. If the level of a
`specified impurity does not exceed the identification threshold,
`it does not have to be identified. This specified, unidentified
`impurity is listed on the specification by its relative retention
`time, which is calculated by dividing the retention of the impu-
`rity by the retention time of the API. Identification thresholds
`are determined by the maximum daily dose and the total daily
`intake of the impurity and are provided in Table 2-1. Two ex-
`amples are provided to help interpret the use of this table.
`
`• Example 1: Consider a tablet for which the maximum
`daily dose is 750 μg. One percent of the maximum daily
`dose is 7.5 μg, which is greater than the 5 μg total daily
`intake (TDI) limit. Therefore, any impurity greater than
`5 μg or 0.67 percent must be identified.
`• Example 2: Consider a tablet for which the maximum
`daily dose is 200 μg. One percent of the maximum daily
`dose is 2 μg, which is lower than 5 μg TDI. Therefore, any
`impurity greater than 1.0 percent must be identified.
`
`If a specified, identified impurity exceeds the qualification
`thresholds provided in Table 2-2, the impurity must be quali-
`fied in a toxicology study. The qualification threshold calcula-
`tions from the information in Table 2-2 are analogous to those
`performed for determining identification thresholds. The ac-
`ceptance criterion for an individual impurity should not exceed
`the amount that has been qualified in a toxicology study.
`How are meaningful limits set for each impurity? ICH Guid-
`ance Q6A recommends that the acceptance criteria be based
`on safety and efficacy data at hand at the time of filing. The
`Guidance recognizes that the amount of data batch history data
`at the time of filing is likely insufficient to assess manufacturing
`
`Table 2-1. identification thresholds
`Maximum Daily Dose
`Threshold
`< 1 mg
`1.0% or 5 μg TDI, whichever
`is lower
`0.5% or 20 μg TDI, whichever
`is lower
`0.2% or 2 mg TDI, whichever
`is lower
`0.10%
`
`≥ 1 mg and ≤ 10 mg
`
`> 1 mg and ≤ 2000 mg
`
`> 2000 mg
`
`Table 2-2. Qualification thresholds
`Maximum Daily Dose
`Threshold
`< 10 mg
`1.0% or 50 μg TDI, whichever
`is lower
`0.5% or 200 μg TDI,
`whichever is lower
`0.2% or 3 mg TDI, whichever
`is lower
`0.15%
`
`≥ 10 mg and ≤ 100 mg
`
`> 100 mg and ≤ 2000 mg
`
`> 2000 mg
`
`Eye Therapies Exhibit 2027, 9 of 25
`Slayback v. Eye Therapies - IPR2022-00142
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`

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`process capability and recommends that limits do not tightly
`encompass the batch data that are available at the time of filing.
`The acceptance criteria for individual impurities that are
`degradation products are determined by extrapolating the sta-
`bility data that are available at the time of filing and setting the
`limit using a statistical analysis that usually involves calculating
`the upper 95 percent confidence limit.
`The acceptance criterion for total impurities is usually es-
`tablished by taking the acceptance criteria for individual im-
`purities into account. If degradation does not occur in the drug
`product, acceptance criterion for total impurities is set at 2.0 or
`3.0 percent. If degradation does occur, this acceptance criterion
`can be as high as 5.0 or 7.0 percent.
`The Guidance, however, recognizes that the development
`stability data are incomplete at the time of filing and allows for
`the limit to be raised through a qualification toxicology study.
`Likewise, the limit can be lowered to a value that is less than
`the qualified amount if stability data indicate that a lower value
`is justifiable. As more batch history is obtained, process capa-
`bility should be re-evaluated. The Guidance allows for the lim-
`its to be raised or lowered based on sufficient commercial batch
`history.
`
`validation characteristics
`Impurity methods for related substances are validated for
`specificity, linearity, range, accuracy, precision, robustness,
`sample and standard stability, and quantitation limit.18,19 Usu-
`ally detection limit is also a validation characteristic that is also
`determined.
`
`SPEcificity
`The validation of a related substances impurity method is simi-
`lar to that for an assay method, regardless if the method is com-
`bined with the assay method or a stand-alone impurity method.
`The USP is actively modernizing official USP-NF monographs
`for small-molecule API and their dosage forms that do not have
`a stability-indicating impurity method for related substances.
`
`LinEarity and rangE
`A linear relationship should be evaluated across the range of
`the analytical method. For a drug product, linearity is assessed
`from the reporting level of an impurity to 120 percent of the
`specification limit.
`
`accuracy
`Accuracy of an impurity method is evaluated by performing
`“spike and recovery” experiments. If reference material for the
`impurities is not available, it is acceptable in early development
`to spike drug substance into a placebo matrix and compare the
`value obtained to a reference solution that contains a known
`amount of drug substance. The amount of drug substance or
`impurity reference material spiked should be representative of
`the expected range for the im