Current USP Approaches to Biologics Issues

1
Current USP Approaches to Biologics Issues

• Anthony J. DeStefano, Ph.D.
• Vice President, General Chapters
• Tina S. Morris, Ph.D.
• Director, Biologics and Biotechnology

2
USP Mission Statement

• USP promotes the public health and benefits
  practitioners and patients by disseminating
  authoritative standards and information developed
  by its volunteers for medicines, other healthcare
  technologies, and related practices used to
  maintain and improve health and promote optimal
  healthcare delivery.
• USP is a practitioner-based compendiumthe only
  one in the world

3
USP Milestones and Legislation

• 1820 USP founded
• 1848 - Drug Import Act USP legislatively
  mandated
• 1880s 1890s - State Boards recognize USP as the
  legal standard for composition and formulation of
  drugs
• 1902 - PHS Act regulates biologicsUSP not
  mentioned (no parenterals)
• 1906 - Federal Food and Drugs ActFDA enforces
  certain aspects of the USP quality standards for
  biological articles.
• 1938 - Federal Food, Drug, and Cosmetic Act USP
  and NF standards recognized as official standards
  of quality

4
USP Milestones and Legislation

• 1941 - As the patent protection for insulin was
  about to end, Congress gave FDA certification
  authority and stated that FDA must enforce USP
  standard for insulin
• 1965 Social Security Act Drugs and biologics
  provided in a physicians office must be in the
  USP for reimbursement to occur.
• 1997 - FDAMA indicates that FDC Act applies to
  biologics regulated under the PHS Act.
• 2003 MMA calls for USP to develop a list of
  drug categories and classes.

5
Recognition of USP Standards in Federal Food Drug
and Cosmetic Act (FDCA)

• Section 501(b) - Adulterated Drugs and Devices
• A drug or device shall be deemed to be
  adulterated if it purports to be or is
  represented as a drug the name of which is
  recognized in an official compendium, and its
  strength differs from, or its quality or purity
  falls below, the standards set forth in such
  compendium.
• Such determination as to strength, quality, or
  purity shall be made in accordance with the tests
  or methods of assay set forth in such compendium
• Section 502(g) Misbranded Drugs and Devices
• A drug or device shall be deemed to be misbranded
  if it purports to be a drug the name of which is
  recognized in an official compendium, unless it
  is packaged and labeled as prescribed therein.

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Provisions of the FDCA apply to biologics
regulated under PHS Act

• PHS ACT (42 USC 262)
• 262(j) Application of FDCA
• The Federal Food, Drug, and Cosmetic Act
  applies to a biological product subject to
  regulation under this section, except that a
  product for which a license has been approved
  under subsection (a) shall not be required to
  have an approved application under section 505 of
  such Act (21 U.S.C. 355)
• Biological products approved under the PHS Act
  are subject to the adulteration and misbranding
  provisions of FDCA
• If an official monograph in USP-NF is available,
  the biological product, including a generic
  biologic, should conform

7
Council of Experts

• Scientific Policy Body
• Chairs of Expert Committees
• Develops Standards and Information
• Assisted by Expert Committees
• Chair of the Council, Roger L. Williams, M.D.

8
USP and Biologics

• 1985 - Convention Resolution Feasibility and
  Advisability of Compendial Monographs for
  Macromolecular Drugs Derived from
  Biotechnological Processes
• 1987 - USP Biotechnology Program
• 1990 - Proposed monographs on Alteplase,
  Interferons, Somatrem, and Somatropin
• Biologics and Biotechnology related general
  chapters in USP
• 1992 PF - USP Rationale for Development of
  Public Standards for Biological Products Licensed
  by CBER
• 1995 - USP Subcommittee on Biotechnology and
  Biopolymers

9
USP and Biologics

• 2000 - Expert Committees on
• Biotechnology and Natural Therapeutics and
  Diagnostics
• Vaccine, Virology, and Immunology
• Blood and Blood Products
• Gene Therapy, Cell Therapy, and Tissue
  Engineering
• Complex Actives Department in ISD
• 2005 Biologics and Biotechnology Department Formed

10
Biologics and Biotechnology

• Division of Documentary Standards- Chief Science
  Officer Darrel Abernethy
• Biologics and Biotechnology-Director Tina Morris
• Expert Committees in BB
• Cell Therapy, Gene Therapy, and Tissue
  Engineering Fouad Atouf/William Tente
• Blood and Blood Products Anita Szajek/Jean
  Huxsoll
• Proteins and Polysaccharides Larry Callahan/Lynn
  Yeoman
• Vaccines and Virology Victor Lu/Barry Garfinkle
• Committee Chairs form BB Collaborative Group

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Expert Committees and Advisory Panels in
Biologics Biotechnology
Biologics Biotechnology Collaborative Group
Blood Blood Products
Vaccines Virology
Proteins Polysaccharides
Cell, Gene Tissue Therapies
Bioassay analysis
Human Plasma
Vaccine Tests
Flow Cytometry
Bioassay Development
Heparin
Virology Tests
Test Kit Validation
Immunology Tests
Plasma Analytical
Bioassay Validation
Cell Therapy
NAT
Gene Therapy
Monoclonal Antibodies
Viral Clearance
Bovine Serum
Viral Testing Plasma
Protein A
Glycans
Enzymes
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Importance of USP Standards in Biotechnology Today

• Biotech Products are the most expensive drug
  products on the market today.
• Biotech products are often the target of
  counterfeiters
• Public standards can help identify and deter
  counterfeiting.
• Biotech products are inherently heterogeneous.
• Biotech products are often unstable.
• Biotech product can have complex methods of
  analysis (need for horizontal standards).

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Importance of USP Standards in Biotechnology Today

• USP Standards are market standards enforceable
  from production to consumption
• Monographs are tied to products not manufacturers
• USP standards can be flexible-take into account
  different methods of production
• Public monographs and national primary reference
  materials are government responsibilities that
  came to USP historically
• Public process improves quality and provides
  transparency
• A public documentary standard (monograph) and
  national primary reference material are key to
  maintaining unitage within and across products.
• This is critical to practitioners to understand
  dosing and switching

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Impact of USP Monographs

• USP Monographs are enforced both in the US and
  foreign countries
• Product and API Specifications Must Fall Within
  the USP Monograph Specifications Throughout the
  Entire Lifetime of Product or API
• US-FDA Can and Often Does Require Additional
  Tests That are not in a Monograph for the Release
  of Products
• It is not Necessary to do Every Test In a USP
  Monograph but the Product Must Pass Every Test if
  Tested
• Methods in USP Monographs are Considered
  Validated

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USP Monograph for Biotech API (Typical
Requirements)

• ID Tests
• Peptide Map
• Retention Time from Assay
• Purity Test
• HPLC (Reverse Phase)
• Electrophoresis
• Limit on HMW Species (SEC)
• Glycan analysis (if glycosylated)
• Assay
• HPLC-HIC-SEC-RP
• Enzyme
• Bioassay-Bioidentity (Potency)
• If defined 3D structure exists
• Cellular preferred over animal

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USP Monograph for Biotech Product (Typical
Requirements)

• ID Tests
• Retention Time from Assay
• Packaging
• Endotoxin
• Sterility
• Total Protein Test
• Purity Test
• HPLC (Reverse Phase)
• Limit on HMW Species (SEC)
• Assay
• HPLC-SEC-RP
• Bioassay-Bioidentity (Potency)
• If defined 3D structure exists
• Cellular preferred over animal
• If not performed on API

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Biologics and Biotechnology Initiatives

• Develop and Revise New General Chapters
• Develop Procedural (Horizontal) Standards
• Develop Ancillary Materials Monographs and
  Standards
• Revise Current Monographs with Modern Techniques
• Bioassays
• Replace animal assays where possible
• Develop Separate Chapters for the Development and
  Design, Analysis and Validation of Bioassays
• Develop criteria for when a bioassay needs to be
  included in a monograph
• Develop Monographs for High Value Products to
  Combat Counterfeiting and Diversion.

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Challenges of Monographs for Biotech Products

• Should Monographs be Product Specific or Type
  Specific
• Should each interferon have a separate monograph
• Comparability Equivalence Challenge-
• Somatropin produced in bacteria, yeast and
  mammalian cells
• Epoetin different CHO cell lines different
  glycosylation.
• Complexity Challenge
• Biotech Products are Inherently Heterogenous
• Glycosylation/Glycation
• Deamidation, Oxidation, Proteolysis
• Complex Biology
• Produced by complex processes
• Technology-Analysis Challenge
• Accessibility (cost, expertise, time)

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Insulin Historical Overview

• 1921 Discovery of insulinic function (dog
  pancreatic tissue) for the treatment of diabetes
• 1922 Amelioration of diabetic condition in human
  by using injections of bovine pancreatic extracts
  
• Insulin injection also induced side effects
  including formation of abscesses, probably due to
  impurities, e.g., endotoxin.
• Further research helped improve purity of the
  extracts, but also showed that too much of the
  pancreatic extract could induce hypoglycemia,
  introducing the notion of potency

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Insulin Monograph- Historical Overview, cont.

• 1942 (USP XII), First monograph for extracted
  insulin
• 1980s, First monograph for human recombinant
  insulin was developed
• New monographs to cover new analogs or delivery
  systems are developed (rapid- long-acting
  insulin, inhaled insulin)
• Monograph specifications evolved with technology
  innovations

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USP Monographs for Insulin

• Different monographs reflecting
• Different formulations
• Nature of the stabilizing complex (Isophane,
  Zinc)
• Slow and fast release forms (Prompt, extended)
• Recombinant, extracted, synthetic, analog
• USP monographs, today!
• Insulin Injection
• Insulin Human
• Insulin Human Injection
• Human Insulin Isophane Suspension and Human
  Insulin Injection
• Insulin Lispro
• Insulin Lispro Injection
• Isophane Insulin Suspension
• Isophane Insulin Human Suspension
• Insulin Zinc Suspension
• Extended Insulin Zinc Suspension
• Prompt Insulin Zinc Suspension
• Insulin Human Zinc Suspension

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Key Requirements for Insulin Monographs

• Limits on high molecular weight insulin species
• Stability indicating
• Limits immunogenicity
• Limits on Zinc
• Zinc interacts with insulin
• Impact on formation of hexameric structures
• Affects insulin release
• Purity Test
• Deamidation, oxidation and disulfide scrambling
  occurs over time.
• Gradient is necessary to resolve all peptide
  related impurities.
• Assay
• Stability indicating
• Takes into account the activity of main degradent
  (A-21 desamido)
• Amount of different forms (soluble, amorphous)
• Soluble insulin can stick to crystals
• Amorphous form can turn into crystalline forms
  over time

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When Are Bioassays Needed in a Monograph

• Bioassays are a probe of the 3-D conformation or
  a method for measuring the potency of complex
  products where activity may be attributable to
  more than one component
• EP and USP Differ
• Somatropin (Bioidentity Test)
• EP No Bioassay
• USP Rat weight gain assay
• Insulin (Bioidentity Test)
• EP No Bioassay
• USP Rabbit blood glucose

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Bioassay Continuum
Steven Kozlowski, USFDA
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Product-Specific Bioassay Chapters

• Official
• lt121gt Insulin Assays
• Under development
• Somatropin Assays
• Glucagon Assays
• Insulin Cell Based Assays
• These will include cell-based potency tests that
  replace animal assays

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Erythropoetin Monograph

• Kidney derived hormone, role in maintaining
  erythrocyte maturation in vivo
• 165 amino acids glycoprotein with three (3)
  N-linked and one (1) O-linked glycosylation sites
• EP monograph
• WHO designated two INNs (Epoetin-alpha and
  Epoetin-beta) on the basis that they might have
  different glycosylation sites

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Why General Chapters for Biotechnology?

• Biotechnology manufacturing is process-driven
• Many considerations apply to a wide range of
  products
• Analytical and testing is more complex than for
  small molecules
• Comprehensive General Chapters facilitate the
  development of monographs for these products

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USP General Chapters Related to Biotechnology

• General Chapters are written to provide common
  methods for monographs and/or for informational
  purposes.
• Chapters over 1000 are for informational purposes
  unless mentioned in a monograph.
• If over 1000 and mentioned in a monograph the
  chapter is official for that monograph.
• General Biotech Chapters Official (Revision
  Needed)
• lt1041gt BIOLOGICS
• lt1045gtBIOTECHNOLOGY-DERIVED ARTICLES
• Bioassay Chapters
• lt111gtAnalysis of Bioassays (Major Revision)
• lt1032gtDevelopment of Bioassays (In Development)
• lt1033gtValidation of Bioassays (In Development)

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General Chapters Official

• Protein/Peptide Analysis Official Harmonized
• lt503gtACETIC ACID IN PEPTIDES
• lt1052gtAMINO ACID ANALYSIS
• lt1053gtCAPILLARY ELECTROPHORESIS
• lt1054gtISOELECTRIC FOCUSING
• lt1055gtPEPTIDE MAPPING (UNDER REVISION)
• lt1056gtPOLYACRYLAMIDE GEL ELECTROPHORESIS (IN
  NEED OF REVISION)
• lt1057gtTOTAL PROTEIN ASSAY

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General Chapters Under Development

• lt130gt PROTEIN A QUALITY ATTRIBUTES
• lt131gt RESIDUAL PROTEIN A TESTING
• lt1084gt GLYCOPROTEIN AND GLYCAN ANALYSIS --
  INTRODUCTION AND CHOICE OF ANALYSIS STRATEGIES
• lt1085gt GLYCOPROTEIN AND GLYCAN ANALYSIS --
  DEGLYCOSYLATION OF GLYCOPROTEINS
• lt1094gt GLYCOPROTEIN AND GLYCAN ANALYSIS --
  MONOSACCHARIDE ANALYSIS
• lt1095gt GLYCOPROTEIN AND GLYCAN ANALYSIS --
  OLIGOSACCHARIDE ANALYSIS
• lt1260gt MONOCLONAL ANTIBODIES

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The new Chapter lt111gt, out for public comment
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Participate!
To register http//ems.intellor.com/?p201821do
registert12
33
Ancillary Materials

• lt1043gt Ancillary Materials for Cell, Gene and
  Tissue Engineered Products
• Biochemical substances that are used to
  manufacture cell therapy, gene therapy or
  tissue-engineered products or therapeutics
  derived from cell culture (e.g., vaccines,
  proteins) but are not intended to be in final
  product.
• Include raw materials, processing and
  purification aids or agents used during
  manufacture.

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Ancillary Materials

• Ancillary material chapters are intended to help
  standardize these items
• These chapters can specify reference standards
  that help demonstrate compliance to compendial
  tests.
• Reference standards can also be qualified for use
  as procedural standards and calibrants in limit
  tests

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lt130gt Protein A Quality Attributes

• Contains specifications for
• Protein A
• rProtein A, C-Cys
• rProtein A
• rProtein A, B4, C-Cys
• Is accompanied by 4 USP
• Ancillary Materials RS

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The USP Glycoprotein and Glycan Chapter Family
and Associated Standards
lt1084gt Glycoprotein and Glycan Analysis
Introduction and Choice of Analysis Methods
Human a Acid Glycoprotein
Single oligosaccharides
Single monosaccharides
Mixes 14
Mixes 14
Fetuin
RNAse B
Human IgG
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Procedural Reference Standards

• Procedural Reference Standards are horizontal
  standards
• To be Used in Analytical Methods Development and
  Validation of Procedures
• To be Used in Routine Analysis as
• Positive Controls
• Method Optimization, qualification and Validation
• System Suitability Establishment
• Training
• Troubleshooting
• Reagent Qualification

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Procedural Reference Standards Monosaccharide
Mixtures

• Use of Mixture 1 for system suitability in
  HPAEC-PAD analysis, PA 10 method

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Impurity Matrix From lt1045gtBIOTECHNOLOGY-DERIVED
ARTICLES
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Impurity Matrix From lt1045gtBIOTECHNOLOGY-DERIVED
ARTICLES
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Conclusions

• Biotechnology products are complex from both
  biological and compendial perspectives
• Monograph development and general chapters
  designed to help
• Analytical methods can be used as surrogate for
  functionality assays
• Development of cell based assays will help
  tighten the monograph specifications and increase
  the precision of the assays.
• Public standards play a key role in assessing
  product quality in an emerging global market of
  increasing product diversity (biogenerics/biosimil
  ars)

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Extractables and Leachables

• Broad topic that impacts many small molecule and
  biologics and biotechnology Expert Committees.
• It likely will call for chapters that are
  specific to the areas of interest (e.g.,
  aerosols, water, biologics/parenterals).
• USP needs input to develop chapters. It does not
  have a mechanism to work on these issues alone.
  Industry input in developing a framework is
  critical.
• USP works with organizations that can help, such
  as PDA and PQRI.

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Extractables and Leachables

• USP has worked with PQRI on extractables and
  leachables in orally inhaled and nasal drug
  products report (over 270 pages).
• The Aerosols Expert Committee is currently
  drafting a chapter to address this area.
• PQRI has set up a committee to work on
  extractables and leachables in parenteral and
  ocular drug products.
• USP will have membership on this committee to
  make transition of a report to a chapter more
  seamless.

44
Extractables and Leachables in Biologics

• Extractables and leachables can cause problems
  unique to biologics
• USP needs a group to draft a proposed chapter
• A strong tie to existing and future monographs is
  needed
• The tests proposed need to be able to
  meaningfully detect known issues

45
Quality by Design?

• Quality is never an accident.It is always
  the result of intelligent effort. There must be
  the will to produce a superior thing.John
  Ruskin (1819-1900)

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What is Quality by Design?

• The application of formal risk-analysis
  techniques to the manufacture and control of
  drugs
• Application of advanced technologies to better
  predict risks
• Application of advanced data handling techniques
  to evaluate risks
• Application of advanced systems to reduce and
  control risks
• Definition of regions of acceptable risk in the
  manufacturing design space

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Risk

• Which/Whose Risk?
• Patient Risk?
• Practitioner Risk?
• Manufacturer Risk?
• What Risk?
• Risk of producing a bad product
• Unsafe
• Ineffective
• Non-compliant
• Risk of variable manufacture

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Where is/can QbD be applied?

• Manufacturing
• Feedback loops
• Re-defined unit operations
• Change control
• Analytical
• Multivariate Design of Experiments
• Change control
• Regulatory Affairs
• Question-based review
• Change control

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Change control

• Change?
• Specification of raw material
• Specification of excipient
• Specification of manufacture route
• Process for manufacture
• Compared to what?
• Initial Specification?
• Pivotal trial material?
• Critical control parameter

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USP Perspective on QbD

• Represents
• Good science done for the right reasons
• Enhanced dialogs
• Meaningful specifications
• A better standard
• May not
• Be financial sound (not our issue)
• Produce better product
• Increase quality, safety or efficacy
• We support QbD for product registration
• But private specifications must move to public
  specifications

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What are USPs roles in QbD

• Final public standard (traditional role)
• National primary standards
• General guidance chapters
• Standards of equivalency
• Ancillary and procedural standards

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Effects of QbD on USP

• New concepts on
• General Test Chapters
• Near-IR
• Raman
• Heavy Metals
• Residual solvents?
• Equivalency testing
• Flexible monograph
• Performance standards
• Certified Reference Materials

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Measurement Science, QbD, PAT

• Improved manufacturing/manufacturing controls
  (QbD, PAT) reduce uncertainty (variation in
  ingredient and product attributes relative to
  specification)
• Measurement science identifies and controls
  analytical uncertainty
• USPs reference materials (national primary
  standards) add uncertaintyUSP should control
  this and tell you what it is
• Buffers (acceptance criteria) help assure that
  specification is met

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