Draft - Not for ImplementationX:\CDERGUID\2180DFT.WPDNovember 13, 1998Guidance for IndustryMetered Dose Inhaler (MDI) andDry Powder Inhaler (DPI) DrugProductsChemistry, Manufacturing, and ControlsDocumentationDRAFT GUIDANCEThis document is being distributed for comment purposes only.
`
`U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)October 1998CMC
`
`Comments and suggestions regarding this draft document should be submitted within 90 days of
`the draft guidance.
`publication in the Federal Register of the notice announcing the availability of
`Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration,
`5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the
`docket number listed in the notice of availability that publishes in the Federal Register.
`
`For questions regarding this draft document, contact Guirag Poochikian, Ph.D., (301) 827-1050.
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`Page 1 of 65
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` Insys Exhibit 2003
`CFAD v. Insys
`IPR2015-01797
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`Draft - Not for ImplementationX:\CDERGUID\2180DFT.WPDNovember 13, 1998Guidance for IndustryMetered Dose Inhaler (MDI) andDry Powder Inhaler (DPI) DrugProductsChemistry, Manufacturing, and ControlsDocumentation
`
`U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)October 1998CMC
`
`Additional copies are available from:
`
`Drug Information Branch (HFD-210)
`Center for Drug Evaluation and Research (CDER)
`5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573
`Internet at http://www.fda.gov/cder/guidance/index.htm
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`III. DRUG PRODUCT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`A. Components. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..6
`B. Composition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..6
`1.
`MDIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.
`DPIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`C. Specifications for the Formulation Components. . . . . . . . . . . . . . . . . . . . . ..7
`1.
`Active Ingredient(s). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.
`Excipients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`D. Manufacturers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..14
`E. Method(s) of Manufacture and Packaging. . . . . . . . . . . . . . . . . . . . . . . . ..14
`F. Specifications for the Drug Product. . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..15
`1.
`MDIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.
`DPIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`G. Container and Closure Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1.
`MDIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.
`DPIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`H. Drug Product Stability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..37
`
`IV. DRUG PRODUCT CHARACTERIZATION STUDIES. . . . . . . . . . . . . . . . . . . ..41
`A. MDIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`B. DPIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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`II. BACKGROUND. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`A. Metered-Dose Inhalers (MDIs). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`B. Dry Powder Inhalers (DPIs). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..4
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`Draft - Not for ImplementationX:\CDERGUID\2180DFT.WPDNovember 13, 1998 iTable of ContentsI. INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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`V. LABELING CONSIDERATIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..52
`A. MDIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`B. DPIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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`GLOSSARY OF TERMS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..60
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`ABBREVIATIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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`GUIDANCE FOR INDUSTRY1MDI and DPI Drug ProductsChemistry, Manufacturing, and Controls Documentation(Due to the length and complexity of this draft guidance, please identify specific comment by line number.)I.INTRODUCTION1
`
`This document provides guidance for industry on the chemistry, manufacturing, and controls
`(CMC) documentation to be submitted in new drug applications (NDAs) and abbreviated new
`drug applications (ANDAs) for metered dose inhalation aerosols and metered dose nasal aerosols
`(also known as oral and nasal metered dose inhalers respectively or MDIs) and inhalation powders
`(also known as dry powder inhalers or DPIs). This guidance also covers CMC information
`recommended for inclusion in the application regarding the components, manufacturing process,
`and controls associated with each of these areas. The recommendations in this guidance should
`also be considered for investigational drug applications (INDs). The guidance does not address
`inhalation solutions and aqueous nasal sprays.
`
`The guidance sets forth information that should be provided to ensure continuing drug product
`quality and performance characteristics for MDIs and DPIs. The guidance does not impose
`mandatory requirements but does put forth acceptable approaches for submitting CMC-related
`regulatory information. Alternative approaches may be used. Applicants are encouraged to
`discuss significant departures from the approaches outlined in this guidance with the appropriate
`Agency division before implementation to avoid expending resources on development avenues
`that may later be deemed unacceptable.
`
`Reference to information in Drug Master Files (DMFs) for the CMC section of the application is
`acceptable if the DMF holder provides written authorization that includes specific reference (e.g.,
`submission date, page number, item name and number) to the pertinent and up-to-date
`information (21 CFR 314.420(d)). Refer to FDA's Guideline for Drug Master Files (September
`1989) for more information about DMFs.
`
`This guidance has been prepared by the Inhalation Drug Products Working Group of the Chemistry,
`Manufacturing and Controls Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research
`(CDER) at the Food and Drug Administration (FDA). This guidance represents the Agency’s current thinking on
`inhalation drug products. It does not create or confer any rights for or on any person and does not operate to bind FDA
`or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute,
`regulations, or both.
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`II.BACKGROUND23A.Metered-Dose Inhalers (MDIs)24
`
`Metered-dose inhalers have grown in popularity since their introduction in the late 1950s,
`and they are currently used by over 25 million Americans for a variety of diseases, such as
`asthma, chronic obstructive pulmonary disease (COPD), and other lung diseases
`characterized by obstruction of airflow and shortness of breath.
`
`Metered-dose inhaler products contain therapeutically active ingredients dissolved or
`suspended in a propellant, a mixture of propellants, or a mixture of solvents, propellants,
`and/or other excipients in compact pressurized aerosol dispensers. An MDI product may
`discharge up to several hundred metered doses of one or more drug substances.
`Depending on the product, each actuation may contain from a few micrograms (mcg) up
`to milligrams (mg) of the active ingredients delivered in a volume typically between 25 and
`100 microliters.
`
`Although similar in many features to other drug products, MDIs have unique differences
`with respect to formulation, container, closure, manufacturing, in-process and final
`controls, and stability. These differences need to be considered during the development
`program because they can affect the ability of the product to deliver reproducible doses to
`patients over the life of the product as well as the product's efficacy. Some of the unique
`features of MDIs are listed below:
`
`1.
`
`The container, the valve, the actuator, the formulation, any associated accessories
`(e.g., spacers), and protective packaging collectively constitute the drug product.
`Unlike most other drug products, the dosing and performance and, therefore, the
`clinical efficacy of a MDI may be directly dependent on the design of the container
`and closure system (CCS).
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`2.
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`The fraction of the formulation delivered to the patient consists of a mixture of
`micronized (or solubilized) drug substance in the desired physical form, which may
`be within a residual matrix of oily excipient material, propellant, and/or solvent.
`
`3.
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`Fixed portions of medication from a multidose container can be directly
`administered to the patient without contamination or exposure of the remaining
`material under normal use conditions. Conversely, portions of the immediate
`container’s content cannot be removed from a pressurized container for further
`modification or manipulation.
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`2
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`4.
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`5.
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`The aerosolization of materials from a pressurized container is a complex and rapid
`sequence of events. When the content of the metering chamber is released, it
`undergoes volume expansion and forms a mixture of gas and liquid before being
`discharged as a jet through the orifice of the actuator. Within the expanding jet,
`the droplets undergo a series of processes. Subsequent to the aerosolization and
`dispersion of the drug product into a multitude of droplets, and during the
`propulsion of these droplets from the actuator to the biological target, the drug
`substance particles in the droplets become progressively more concentrated due to
`rapid evaporation of the volatile propellant components.
`
`The concept of classical bioequivalence and bioavailability is usually not applicable
`for oral inhalation aerosols. The dose administered is typically so small that blood
`or serum concentrations are generally undetectable by routine analytical methods.
`Moreover, bioequivalency studies are complicated by the fact that only
`approximately 10–15 percent of the dose reaches the biological target. The
`remainder of the dose, trapped in the mouth and pharynx, is swallowed and
`absorbed through the gastrointestinal (GI) tract. Thus, even if determination of
`blood or serum concentrations were possible, additional and more extensive
`studies would be necessary to distinguish the contributions of the drug absorbed
`from the pulmonary, buccal, and GI routes.
`
`Clinical efficacy assessment of inhalation aerosols requires consideration of several
`parameters, such as:
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`6.
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`!
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`!
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`!
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`!
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`Variability in the disease itself (ventilatory and anatomic or pathologic
`factors);
`Administration skills and practices, for example, breath holding and its
`duration, patient inspiratory flow rate, discharging either via closed lips
`around the mouthpiece or into the open mouth, coordination of aerosol
`discharge (actuate and breathe) and inhalation by the patient, add-on
`devices (e.g., spacers, chambers), proper priming of the valve and cleaning
`practices for the actuator, proper handling and fitting of the actuator to the
`valve stem;
`Presence of other drugs (i.e., when disease states require a multidrug
`treatment) which may exacerbate differences between products;
`Drug product variability due to physical characteristics and controls of the
`drug substance, optimized formulation, valve and actuator design,
`manufacturing process and in-process controls, and so on.
`
`3
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`1.
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`2.
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`3.
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`4
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`At present, dry powder inhalers are not used as commonly in the United States as are
`MDIs. Technical challenges have resulted in a greater variety in design and function of
`DPIs relative to MDIs. Current designs include pre-metered and
`device-metered DPIs,
`both of which can be driven by patient inspiration alone or with power-assistance of some
`type. Pre-metered DPIs contain previously measured doses or dose fractions in some type
`of units (e.g., single or multiple presentations in blisters, capsules, or other cavities) that
`are subsequently inserted into the device during manufacture or by the patient before use.
`Thereafter, the dose may be inhaled directly from the pre-metered unit or it may be
`transferred to a chamber before being inhaled by the patient. Device-metered DPIs have
`an internal reservoir containing sufficient formulation for multiple doses that are metered
`by the device itself during actuation by the patient. The wide array of DPI designs, many
`with characteristics unique to the design, will present challenges in developing information
`in support of an application. Regardless of the DPI design, the most crucial attributes are
`the reproducibility of the dose and particle size distribution. Maintaining these qualities
`through the expiration dating period and ensuring the functionality of the device through
`its lifetime under patient-use conditions will probably present the most formidable
`challenge.
`
`DPIs are complex drug products that differ in many aspects from more conventional drug
`products as well as from MDIs. The unique characteristics of DPIs should be considered
`during development, particularly with respect to formulation, manufacturing, container
`and closure system or device, and both in-process and final controls. Several key
`distinctions of DPIs are listed below:
`
`The device with all of its parts, including any protective packaging (e.g.,
`overwrap), and the formulation together constitute the drug product. Unlike most
`other drug products, the dosing and performance and therefore the clinical efficacy
`of a DPI may be directly dependent on the design of the device.
`
`The portion of the formulation that is delivered by inhalation to the patient consists
`of the neat drug substance controlled to a suitable particle size distribution (e.g.,
`micronized, spray-dried) or the drug substance contained within a matrix of
`excipients.
`
`Energy is required for dispersion and aerosolization of the formulation and the
`drug substance. Whereas MDIs use energy stored in a liquefied gas propellant
`under pressure for aerosolization and dispersion, DPIs may rely on several energy
`sources, including energy from patient inspiration, from compressed gas, or from a
`motor-driven impeller.
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`B.Dry Powder Inhalers (DPIs)90
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`4.
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`5.
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`Whereas MDIs administer doses of the drug substance formulation to the patient
`without contamination of the remaining formulation under normal use conditions,
`this is not necessarily the case with DPIs. In particular, device-metered DPIs can
`be susceptible to contamination (e.g., moisture, microbial) of the remaining doses.
`Contamination aspects under both in-use and abuse conditions should be
`considered during development of the drug product.
`
`In DPIs, complex and subtle interactions may occur between the drug substance,
`carrier(s), and components of the container and closure system that significantly
`affect the safety and effectiveness of the drug product. For example, gravitational,
`fluid dynamic, and other interactive forces, such as electrostatic, van der Waals,
`and capillary forces, together are responsible for different fluidization behaviors
`exhibited by different powders in an inhaler. Electrostatic charge interactions
`influence the overall efficiency of a DPI, since such forces are considered to be
`significant for attraction and adhesion between the drug substance particles,
`excipient particles, and device surface. Additionally, particle size distribution,
`particle morphology, and moisture content can greatly influence the bulk
`properties of the formulation and the product performance.
`
`The issues of classical bioequivalence and bioavailability (point 5 in section II.A)
`and clinical efficacy assessment (point 6 in section II.A) that were discussed for
`MDIs apply equally to DPIs.
`
`6.
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`Draft - Not for ImplementationX:\CDERGUID\2180DFT.WPDNovember 13, 1998
`
`In summary, MDIs and DPIs have many distinctive features that should be considered
`when developing documentation supporting an application. Furthermore, modification or
`alteration of these products due to changes in components of the drug product or changes
`in the manufacturers or manufacturing process should be carefully evaluated for effect on
`the safety, clinical effectiveness, and stability of the product. The type and extent of
`scientific supportive information needed for such changes could be more extensive than
`that needed for similar changes in more conventional drug products.
`
`The remaining portion of this guidance will focus on specific chemistry, manufacturing,
`and controls information recommended for inclusion in the drug product section of
`applications for MDI and DPI drug products.
`
`155III.DRUG PRODUCT156
`
`MDIs and DPIs are complex units, the quality and reproducibility of which can be better ensured
`by appropriate controls of all components (active ingredients, excipients, device components,
`protective packaging) used in the drug product, controls during manufacture of the drug product,
`
`5
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`
`and controls for the drug product. In particular, consistent dosing and particle size distribution
`for these products should be maintained throughout the expiration dating period.
`161A.Components162
`
`A list of all components (i.e., ingredients) used in the manufacture of the drug product
`formulation, regardless of whether they undergo chemical change or are removed during
`manufacture, should be included in the application. Each component should be identified
`by its established name, if any, and by its complete chemical name, using structural
`formulas when necessary for specific identification. If proprietary preparations or other
`mixtures are used as components, their identity should be fully described including a
`complete statement of their composition and other information that will properly identify
`the material.
`
`170B.Composition
`
`
`
`MDIs
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`Draft - Not for ImplementationX:\CDERGUID\2180DFT.WPDNovember 13, 1998
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`1.
`
`The composition of an MDI formulation is crucial, particularly in defining the
`physical stability and the performance characteristics of a suspension MDI. In
`suspension inhalation aerosols, the drug substance can float or settle depending on
`the relative densities of the drug substance and the liquid phase of the formulation.
`Moreover, the formulation composition will have a direct effect on the degree or
`extent of agglomeration or suspendibility of the drug substance particles.
`Preferential interaction of the suspended drug substance with the various internal
`container and closure system components (e.g., adherence of the drug substance to
`the walls of the container or valve components) may also contribute to a
`nonhomogeneous distribution of drug substance. The above mentioned
`phenomena, which may be exacerbated with time, can contribute to inconsistent
`medication dose delivery and particle size distribution. Additionally, in a typical
`MDI, the propellant(s) and cosolvent(s) constitute the majority of the formulation
`composition, and the type and amount of these components determine the internal
`pressure of an inhalation aerosol, a critical parameter related to the MDI
`performance.
`
`The application should include a statement of the quantitative composition of the
`unit formula of the drug product, specifying the name and amount of each active
`ingredient and excipient contained in a stated quantity of the drug product. These
`amounts should be expressed in concentration (i.e., amount per unit volume or
`weight), as well as amount per container and per actuation delivered at the valve.
`The amount of active ingredient delivered per actuation from the mouthpiece
`
`6
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`should be provided. The target container fill weight should also be indicated.
`Similarly, a production batch formula representative of the one to be employed in
`the manufacture of the drug product should be included. Any calculated excess for
`an ingredient should be designated as such, the percent excess shown, scientifically
`justified, and documented. Information on the density of the formulation should be
`included. Any intended change in the formulation from that used in the submitted
`batches (e.g., clinical, biobatch, primary stability, production) should be clearly
`indicated.
`
`2.
`
`The composition of the formulation of a DPI has a direct effect on the stability of
`the formulation as well as on the dosing performance of the product. A carrier
`may be used for a DPI, for example, as a bulking agent to enhance reproducible
`dose metering. The suitability of a carrier is dependent on its chemical and
`physical characteristics, which can have direct effect on the performance of the
`product (e.g., ease of entrainment of the formulation, energy input necessary for
`dispersion and aerosolization of the active ingredient from the carrier,
`hygroscopicity of the formulation). Hygroscopicity can result in uptake of
`moisture by the formulation which may affect the particle size distribution of the
`emitted drug substance, the stability of the drug substance, the dose hold-up in the
`device, and hence the delivered dose.
`
`The application should include a statement of the quantitative composition of the
`drug product, specifying the name and amount of each active and excipient
`contained in a stated quantity of the formulation. These amounts should be
`expressed in concentration (i.e., amount per unit weight), as well as amount per
`metered dose and emitted dose at the mouthpiece under defined test conditions
`(e.g., flow rate, duration). For device-metered DPIs, the target formulation fill
`weight should also be indicated. A production batch formula representative of the
`one to be employed in the manufacture of the drug product should be included.
`Any calculated excess for an ingredient should be designated as such, the percent
`excess shown, scientifically justified, and documented in the submission.
`
`DPIs
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`225C.Specifications for the Formulation Components226
`
`1.
`
`Active Ingredient(s)
`
`Information regarding the comprehensive characterization of the physical and
`chemical properties of the drug substance to be used in inhalation drug products
`should be included in the application. Important properties of the drug substance
`
`7
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`may include, but are not necessarily limited to, density, particle size distribution,
`particle morphology, solvates and hydrates, clathrates, morphic forms, amorphous
`forms, solubility profile, moisture and/or residual solvent content, microbial
`quality, pH profile and pKa(s), and specific rotation.
`
`Appropriate acceptance criteria and tests should be instituted to control those drug
`substance parameters considered key to ensuring reproducibility of the
`physicochemical properties of the drug substance. Key specification parameters
`may include color, appearance (visual and microscopic), specific identification,
`moisture, residue on ignition, specific rotation, assay, microbial limits (10 g sample
`size, USP <61>), melting range, particle size distribution, surface area, crystalline
`form(s), residual solvents, and heavy metals. Micronized drug substance is
`typically used in DPIs or MDIs containing a suspension of drug substance.
`Specifications for control of particle size distribution and crystalline forms (e.g.,
`shape, texture, surface) of the drug substance, parameters often critical for
`reproducible drug product performance, should be included in the application.
`
`The purity of the drug substance and its impurity profile should be characterized
`and controlled with appropriate specifications. Important impurity-related
`parameters may include organic volatile impurities and/or residual solvents, heavy
`metals, residual organics and inorganics (e.g., reagents, catalysts), and related
`substances (synthetic and degradants). Any recurring impurity found in the drug
`substance at a concentration of 0.1 percent or greater, relative to the parent drug
`substance, should be identified and qualified. In addition to toxicological
`considerations, justification of acceptance criteria for the drug substance impurities
`should be based on levels of impurities found in the submitted batches (e.g.,
`clinical, biobatch, primary stability, production). For additional guidance on
`toxicological qualification, the applicant is encouraged to contact the responsible
`review division.
`
`In general, acceptance criteria for all parameters defining the physicochemical
`properties should be based on historical data, thereby providing continuity of
`quality and reproducible performance of future batches of the drug substance.
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`Excipients
`
`2.
`
`For most MDIs and DPIs, excipients (when used) comprise a significant portion of
`the formulation content by weight and their quality has a substantial effect on the
`safety, quality, stability, performance, and effectiveness of such drug products.
`The sensitive nature of the patient population warrants complete characterization
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`
`and strict quality control of these excipients to ensure consistency in the above
`properties.
`
`The source of each excipient should be identified in the application. Each source
`should be assessed, and the material supplied should meet appropriate acceptance
`criteria based on test results for several batches of excipients that were used in
`preparing the submitted batches of drug product (e.g., clinical, biobatch, primary
`stability, production). Likewise, when the supplier of an excipient is changed, the
`new supplier's ability to provide material that meets the same acceptance criteria
`should be assessed.
`
`Adequate DMFs with appropriate authorization should be submitted to the agency
`for major (e.g., propellant, carriers) and noncompendial excipients. A full
`description of the acceptance criteria and the test methods used to ensure the
`identity, assay, functionality, quality, and purity of each excipient should be
`submitted. If these materials are accepted based upon certificates of analysis from
`the manufacturers with a specific identification test, the applicant should also
`develop validated methods or have access to all of the manufacturer’s analytical
`and other test methods to allow the applicant to verify the reliability of the test
`results at appropriate intervals (21 CFR 211.84).
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`Draft - Not for ImplementationX:\CDERGUID\2180DFT.WPDNovember 13, 1998
`
`The suitability of excipients to be administered by the inhalation route should be
`thoroughly investigated and documented in terms of the physicochemical
`properties. Toxicological qualification of these excipients may be appropriate
`under various circumstances including (1) increased concentration of an excipient
`above that previously used in inhalation drug products, (2) excipients used
`previously in humans but not by the inhalation route, and (3) novel excipients not
`previously used in humans. The extent of toxicological investigation needed to
`qualify the use of an excipient under such circumstances will vary, and the
`applicant is encouraged to contact the responsible review division to discuss an
`appropriate strategy for toxicological qualification.
`
`National Formulary (NF)
`When United States Pharmacopeia (USP) or
`monograph materials are used and the associated specifications do not provide
`adequate assurance for inhalation use with regard to the assay, quality,
`performance, and purity, the monograph specifications should be supplemented
`with additional appropriate acceptance criteria and tests to ensure lot-to-lot
`reproducibility of the components. For example,
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`
`When Dehydrated Alcohol, USP is used as a cosolvent in MDIs, additional
`discriminatory specifications for water content (e.g., Karl Fischer) and
`impurities should be included.
`
`!
`
`When Lecithin, NF, a surfactant, is used in MDI formulations, additional
`acceptance criteria and tests controlling the complete compositional profile
`should be used (e.g., levels of phosphatidyl choline, phosphatidyl
`ethanolamine, phosphatidyl inositol, lysophosphatidyl choline, phosphatidic
`acid, triglycerides, fatty acids, carbohydrates).
`
`!
`
`!
`
`!
`
`!
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`Draft - Not for ImplementationX:\CDERGUID\2180DFT.WPDNovember 13, 1998
`
`When Oleic Acid, NF is used as a surfactant in MDI formulations,
`additional specifications should be included for identification, assay, and for
`characterization and control of the compositional profile of impurities (e.g.,
`individual specified fatty acids, unknowns).
`
`Compendial propellants (e.g., CFC-11, CFC-12, and CFC-114) should be
`completely controlled by additional acceptance criteria and validated test
`methods for assay and related impurities (based on historical data). See
`recommendations in Table I.
`
`Lactose Monohydrate, a commonly used carrier excipient for DPIs, is
`covered by a National Formulary monograph. However, the monograph
`acceptance criteria and tests alone are not adequate for controlling key
`physicochemical characteristics of this excipient and should be
`supplemented if this excipient is used in the formulation of an inhalation
`drug product. For example, lactose carrier particles with low surface
`roughness may more effectively redisperse drug particles in an inhaled
`stream. Similarly, different morphic and amorphous forms of lactose may
`adhere differently to the drug substance particles and produce varying
`aerosolization behavior. Because the compendial monograph does not
`address the control for particle morphology and amorphous content, it
`should be supplemented with appropriate acceptance criteria and tests for
`control of these parameters in the application. Moreover, other additional
`recommended parameters for lactose include particle size distribution,
`quantitative color and clarity, assay, impurities and degradants, solvents,
`water content, microbial limits (total aerobic count, total mold and yeast,
`absence of pathogens), pyrogens, and/or bacterial endotoxins test, and
`specific and quantitative protein content. Protein determination may be
`performed by an adequate combination of specific and/or general methods
`(e.g., ELISA, Western Blot, amino acid analysis, Kjeldahl, Lowry,
`spectrophotometric assay).
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