AAPS Annual Meeting, San Diego, CA November 12, 2017 Short Course. Pharmaceutical Excipients: Biopharmaceutical, QC and Regulatory Considerations

Transcription

1 AAPS Annual Meeting, San Diego, CA November 12, 2017 Short Course Pharmaceutical Excipients: Biopharmaceutical, QC and Regulatory Considerations

2 Updating USP-NF Excipient Monographs: Challenges and Opportunities Catherine Sheehan, Sr. Director, Science Excipients United States Pharmacopeia

3 Presentation outline An introduction to USP Introduction to USP Standards Setting Process Why do Excipient Monographs Need Updating? Excipient Up-to-date Initiative Introduction to Excipient Performance <1059> Opportunities for Stakeholder Collaboration Summary/Conclusions

4 Almost 200 years of building and advancing the USP vision 1820 Today 217 medicines covered Over 5,000 monographs covering pharmaceuticals, food ingredients, herbal medicines and dietary supplements No formal legal recognition The Pharmacopeia U.S. focused Standards legally recognized in many jurisdictions and used in more than 140 countries Expanded offerings: 3,600+ Reference Standards 50,000 professionals trained Verification program Global Health Impact Programs Global presence, with facilities in India, China, Brazil, Switzerland, Ghana, Ethiopia, Nigeria, Indonesia and the Philippines

5 What is USP today? We are an independent, scientific, global non-profit that: Establishes quality standards Established through independent scientific experts Provides reference standards Physical standards associated with monographs for product quality testing Especially important when medicines have multiple sources

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7 USP Standards Setting Process Pascal Anger 7

8 Expert Committees for Excipients Expert Committees Excipient Subcommittee (SC) Monographs/ Chapters Expert Panels (EP) /Joint Subcommittees (SC) Excipient Monograph 1 SC A- Simple molecules (179) SC B- Polymers, Proteins, Clays (124) SC C- Oils, Fats, Waxes and Plants (117) Excipient Related General Chapters (8) 420 / 8 Joint EP: <1059> Excipient Performance Joint SC: Impurities in Excipients Joint SC: Excipient Nomenclature Excipient Monograph 2 (PDG harmonization) SC D (Cellulosics) SC E (inorganic mineral/salts) SC F (organic alcohols/glycols) SC G (Povidones) SC H (starches) SC I (sweeteners) SC J (water) SC K (waxes, organic polymers, stearates) 67 / 0 Joint EP: <1059> Excipient Performance Joint SC: Impurities in Excipients Joint SC: Excipient Nomenclature Glycerin EP Povidones EP Talc Methods EP General Chapters Chem Analysis/ Phys Analysis/ Microbiology Excipient related general chapters PDG related general chapters 0 / 15 0 / 4 HQS Nomenclature and Labeling Joint SC: Excipient Nomenclature

9 USP Standards Setting Process

10 FDA Participation is Integrated Into the USP Standard Setting Process Provides Government Liaisons - FDA appoints staff as liaisons to USP s committees and panels Reviews and Comments - FDA Reviews Proposed Standards and Provides Comments Appoints Delegates to USP Convention - Provides Members to Governing Body and Introduces Resolutions Engages in USP Workshops/Stakeholder Forums Collaborates in Discussion Groups - Special topics such as OTC monograph modernization and compounding

11 Why Excipient Monographs Need Updating... To introduce specific identification (ID) tests (where possible) To introduce specific assays (where possible and necessary) To better understand excipient composition Impacts Quality-by-Design (QbD) To replace older, less specific methods To augment supply chain security To reflect best pharmacopeial practices

12 Challenges with Pharmaceutical Excipients Those developed and manufactured specifically for pharma use sometimes have: Special grade or grades available e.g., MCC, Magnesium stearate Multisource suppliers of the same grade Lot-to-lot / batch-to-batch / supplier inequivalence or variability Variability in excipient properties impacts consistent performance Vast diversity of excipient applications exist in product development

13 Challenges with Pharmaceutical Excipients IID Search Results for sucrose and cellulose cder/iig/index.cfm

14 Excipient Monographs Up-to-Date Initiative External Drivers Questions to be addressed Increasing complexity and global scope of pharmaceutical supply chains Concerns about lack of excipient supply chain integrity Desire to improve characterization of excipient composition Use of complex excipients in highly specialized drug delivery systems Does the USP-NF excipient monograph reflect the quality of excipients currently used in drugs on the US market? Does the USP-NF excipient monograph include all possible manufacturers/manufacturing processes for that excipient? To what extent can monographs help promote fit for pharmaceutical use? How to better characterize/define the excipient composition? How should we define and address impurities versus other components - concomitant components, added substances (processing aids)?

15 USP Expert Committee Criteria for Updating Excipient Monographs Universality of test procedure application Simplicity of procedure simpler tests are preferable to tests whose methodology is more complex and challenging Ease of adoption use of existing equipment and methodology to the greatest extent possible Specificity any test or combination of orthogonal tests must uniquely identify the excipient and exclude the presence of other related substances Sufficient specificity to differentiate between an authentic excipient and an excipient adulterated of inferior quality Introduce specific ID and Assay tests when possible - preferably use one method to cover identity and assay

16 USP Standard Setting Strategies for Excipients Donor model ( externally sourced ) USP laboratories ( internally sourced ) Sponsors are encouraged to submit supporting data Challenging to acquire adequate procedures for Identification tests, Assay, and Impurities for excipients Extensive testing facilities for procedure development Collaborative testing sites in US, India, China and Brazil Challenging to set impurity specifications

17 USP s Current State of Excipient Monographs There are about 480 excipient monographs in the USP-NF Primary goal of excipient monographs ensure safety and quality of excipients Challenges: Many excipients do not have a specific ID test Many excipients do not have an adequate assay Not possible to monitor the composition of many excipients Characterization of polymers is generally poor

18 USP NF Excipient Monograph Structure Title Definition Other Components (Concomitant Contains chemical definition and added substances) with content limits, or describes Impurities the substance and the source(s) Specific Tests from which it is obtained. Additional Requirements May refer to the method of Packaging and Storage manufacture Labeling Any permitted additives will also Other Requirements be indicated. USP Reference Standards Identification Assay (or Composition) Note: Not every excipient monograph will contain every section

19 Excipient Monograph Development Process Regulatory status e.g., permitted for use in an FDA regulated drug product, listed in IID Also use as a resource, NIH Daily Med ) Rationale (for revisions) Proposed tests, procedures and acceptance criteria Identification test(s) Assay test (preferably stability-indicating) Impurity test(s)

20 Monograph Development/Update Process Validation data Packaging, storage, and labeling requirements Reference Standard commitments or Statement on suitability for use of any existing USP Reference Standards Typical timeline: 18 to 24 months from submission to official adoption (but it can take longer) Impacted by Review/evaluation of public comments Obtaining additional information Testing in USP s laboratories Availability of reference materials

21 USP Excipient Monograph Title is Evolving Nomenclature Expert Committee approves NF article titles Title is becoming more specific Average molecular weight is indicated on a monograph title Polyethylene Glycol 3350 Monomer repeating unit number is indicated on a monograph title Polyglyceryl 3 Diisostearate Polyoxyl 10 Oleyl Ether Polyoxyl 15 Hydroxystearate Polyoxyl 20 Cetostearyl Ether Polyoxyl 35 Castor Oil Polyoxyl 40 Hydrogenated Castor Oil Composition is indicated in a monograph title Glyceryl Behanate (Title for this monograph not to change until December 1, 2019)» Glyceryl Dibehanate (Title for this monograph becomes official December 1, 2019) Butyl Palmitostearate Butyl Stearate

22 Definitions for Excipients (Examples) Lauric Acid NF Lauric Acid contains NLT 98.0% and NMT 102.0% of dodecanoic acid (C 12 H 24 O 2 ), calculated on the anhydrous basis. Olive Oil NF Olive Oil is the refined fixed oil obtained from the ripe fruit of Olea europaea Linné (Fam. Oleaceae). It may contain suitable antioxidants Microcrystalline Cellulose NF Microcrystalline Cellulose is purified, partially depolymerized cellulose prepared by treating alpha cellulose, obtained as a pulp from fibrous plant material, with mineral acids.

23 Identification (ID) Tests Traditionally wet chemical test procedures relating to color changes, solubility, or precipitation are used Many wet chemical methods are targeting test sample s functional groups - not specific for the particular molecules Modernization introduced instrumental analyses Orthogonal approach - Spectroscopic methodology and separation science used together provide greater assurance of uniquely identifying an excipient Infrared Absorption spectroscopy fingerprinting identity Chromatographic Identity (retention time against that of USP Reference Standard)

24 Assays: Recent Updates Replaced non-specific titrimetric procedures with stability-indicating LC or GC procedures Introduced LC or GC assays in many small molecular excipients Introduced LC assays for lipid mixtures such as Lecithin, Sesame Oil, Castor Oil, and Hydrogenated Castor Oil Introduced size exclusion chromatography (SEC) in polymeric (polyethylene glycol 3350) and protein based excipients (Alpha-Lactalbumin) Streamlined analytical testing across multiple family monographs GC Assay for 6 fatty alcohols (Myristyl, Cetyl, Cetostearyl, Stearyl, Oleyl alcohol, and Octyldodecanol) HPLC Assay for fatty acids (Myristic and Palmitic acid) HPLC Assay for 3 sugar excipients (Compressible Sugar, Confectioner's Sugar, and Sugar Spheres) HPLC Assay for gum products (Guar Gum, Locust Bean Gum)

25 Introduction to Excipient Performance <1059> Excipients manufactured for pharmaceutical use are supplied to comply with existing compendial standards. Because of the vast diversity of the application of excipients in product development, it is impossible to include all performance test methods/procedures in the compendial monograph.

26 Introduction to Excipient Performance <1059> The emphasis of compendial tests for an excipient relate to specifications for Identity, Strength, Quality and Purity Tests for some (but not all) physical and chemical properties of the material appear in the excipient monograph, e.g., Specifications Identification Universal Tests Specific Tests ph Optional Tests (Performance Related Tests) Assay Impurities Description (Reference Tables) Loss on Drying Or other Microbial Limits Bacterial Endotoxins

27 Excipient Performance tests in the Pharmacopeias Should they be mandatory or non-mandatory? The performance of an excipient will be linked to how it is used (type of dosage form, what it is used for) Too many possibilities to make all tests mandatory. Non-mandatory testing in the pharmacopeias In the monograph or elsewhere? European Pharmacopoeia Non-mandatory section of the monograph Functionality-Related Characteristics Emphasis on typical uses of the excipient. United States Pharmacopeia Non-mandatory General Chapter <1059> Excipient Performance Emphasis on how the excipient is used

28 General Chapter <1059> Excipient Performance Introduction the effects of excipient properties on the critical quality attributes (CQAs) of a drug product are unique to each formulation and process and may depend on properties of excipients that are not evaluated in USP or NF monographs the effects of variations in excipient material attributes depend on the role of an excipient in a formulation and the CQAs of the drug product A critical material attribute (CMA) is a physical, chemical, biological, or microbiological property of a material that must be within an appropriate limit, range, or distribution to ensure that drug product CMAs are maintained through the product life cycle Manufacturers should anticipate lot-to-lot and supplier-to-supplier variability in excipient properties and should have in place appropriate control measures to ensure that CMAs are maintained within the required limits

29 Introduction to USP Excipient Performance <1059> Excipient functional category: Sometimes described as functionality, is the general purpose or utility of an excipient in a formulation (e.g., diluent, lubricant, glidant). Often identified in CMC Composition of Drug Product Table Excipient performance: Determined by the physical, chemical or mechanical properties that influence an excipient's ability to perform its intended functional purpose in a formulation. Excipient performance test methods: Quantitative physical, chemical, or mechanical test methods that assess properties of an excipient that influence its ability to perform the intended function in a formulation. Ingredient Amount (mg) per unit dose Functional Category API 20 Active Lactose monohydrate, NF 50 Diluent Microcrystalline cellulose, NF 40 Diluent Magnesium Stearate, NF 1 Lubricant

30 Layout of General Chapter <1059> Divided into Dosage Forms (tablets, oral liquids, etc.) Divided into Functional Category Diluent Wet binder Lubricant Disintegrant etc. For each specific functional category Description Functional Mechanism Physical Properties Chemical Properties General Chapters Additional Information

31 <1059> Excipient Performance - LAYOUT Functional Category Description Functional Mechanism Physical Properties Chemical Properties General Chapters Other Information TABLETS AND CAPSULES Functional Category: Diluent Description: Components incorporated into tablet or capsule dosage forms to increase dosage form volume or weight may be considered diluents. Sometimes referred to as fillers, they often comprise a significant proportion of the dosage form and the quantity and type of diluent selected is often dependent upon its physical and chemical properties. Because the diluent may comprise a large portion of the dosage form, successful and robust manufacturing and dosage form performance is dependent upon the measurement and control of the critical attributes. Functional Mechanism: Among the most important functional roles diluents play is to impart desirable manufacturing properties (eg: powder flow, tablet compaction strength, wet or dry granule formation, homogeneity) and performance (eg: content uniformity, disintegration, dissolution, tablet integrity, friability, physical and chemical stability). Some diluents (eg: microcrystalline cellulose) are occasionally referred to as dry binders because of the high degree of tablet strength they impart to the final compressed tablet dosage form. Physical Properties: The primary physical properties relevant to tablet/capsule diluents are those properties that can have a direct effect on diluent and formulation performance. These include: (1) particle size and size distribution, (2) particle shape, (3) bulk / tapped / true density, (4) crystallinity, (5) moisture content, (6) specific surface area, (7) powder flow, (8) solubility and (9) compaction properties for tablet dosage forms. Chemical Properties: Tablet diluents comprise a large and diverse group of materials that include inorganics (eg: dibasic calcium phosphate, calcium carbonate), single component organic materials (eg: lactose monohydrate, mannitol) and multicomponent or complex organics (eg: microcrystalline cellulose, starch). They may be soluble or insoluble in water, and they may be neutral, acidic or alkaline in nature. These chemical properties need to be considered in selecting diluents that will not negatively affect active ingredient physical or chemical stability and performance. Appropriate selection of excipients with desirable physical and chemical properties can enhance the physical and chemical stability as well as the performance of the active ingredient. The detailed composition of an excipient may be important as excipient function may be influenced by the presence of minor concomitant components that are essential for proper performance. The presence of undesirable components (e.g. heavy metals, peroxides) may also need to be controlled to assure adequate dosage form stability and performance. General Chapters: The following General Chapters may be useful in developing tests and specifications to assure consistent excipient performance: <616> Bulk and Tapped Density, <699> Density, <695> Crystallinity, <696> Crystallinity Determination by Solution Calorimetry, <731> Loss on Drying, <921> Water Determination, <776> Optical Microscopy, <786> Particle Size Distribution Estimation by Analytical Sieving, <429> Light Diffraction Measurement of Particle Size, <811> Powder Fineness, <846> Specific Surface Area,, <1174> Powder Flow.

32 <1059> Excipient Performance - How can the Pharmacopeia help? By providing guidance as to which properties might be important for a particular material in a particular application. By providing standard methods that can be used by both manufacturers and users: Makes communication more straightforward between the two Avoids an unnecessary plethora of test variations for a particular parameter. By keeping the tests non-mandatory. By avoiding confusion with mandatory tests and labeling tests. By not imposing limits/specifications. Provides a framework for applying Quality by Design concept to excipient quality control.

33 Opportunities for Stakeholder Participation Attend Excipient round-table meetings, stakeholder forums, and workshops Visit USP Excipient Webpage for upcoming events Face to face Excipients Stakeholders Forum November 29, Comment on revision proposals in Pharmacopeial Forum Collaborate on New Monographs & Revisions: Submission Guidelines and Lists

34 Summary/Conclusions USP continues to rely on support from external sponsors as well as USP laboratories and input/comments from the Expert Committee and stakeholders to ensure that the excipient standards are Up-to-Date and current. Monograph/chapter development (modernization) process is a collaborative effort. Because of the vast diversity of the application of excipients in product development, it is impossible to include all performance test methods/procedures in the compendial monograph. The <1059> Excipient Performance chapter provides an overview of the key functional categories of excipients identified in USP NF along with those tests that may relate to excipient performance. <1059> draws a more direct link between excipient properties and product performance. 34

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