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USP Standards for Biologics Tina S. Morris, Ph.D., Vice President, Biologics & Biotechnology USP-NF Fouad Atouf, Ph.D., Director, Biologics & Biotechnology,

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Presentation on theme: "USP Standards for Biologics Tina S. Morris, Ph.D., Vice President, Biologics & Biotechnology USP-NF Fouad Atouf, Ph.D., Director, Biologics & Biotechnology,"— Presentation transcript:

1 USP Standards for Biologics Tina S. Morris, Ph.D., Vice President, Biologics & Biotechnology USP-NF Fouad Atouf, Ph.D., Director, Biologics & Biotechnology, USP-NF User Forum January 17 th, 2013 Istanbul, Turkey

2 USP Standards—Biologicals

3 Major B&B Themes and Initiatives for  Modernization of Monographs  Outreach to Industry for New Monographs  Procedural Chapters and Characterization/Measurement of Ancillary and Process Materials  Growing the portfolio to support all biologics  Modernization of analytical approaches  Biological Potency Tests:  Implementation of new USP Chapters  Assay transitions: animal to cell, cell to binding, activity to amount of substance – questions of equivalence and units  Product Class Chapters:  Monoclonal antibodies  Glycoconjugate vaccines

4 Vertical Standards – Monographs Role and Use:  Clearly define identity, strength and purity, as well as other important quality attributes at the product level  Allow independent testing and verification based on a public standard Considerations for Standard Development:  Complexity of specifications and system suitability criteria  Biological potency assignments and unit maintenance –Across manufacturers –Internationally  Product- specific vs. common product class requirements  For well-characterized and legacy products: inclusion and bridging to new analytical technology

5 Official USP Biologics Monographs by Product Class Product Class Number of monographs peptide47 enzyme12 complex extract11 carbohydrate11 glycosaminoglycan9 other5 Tissue product6 IgG/serum9 Blood component/protein 5 Vaccine3

6 Current Biologics in the US Market From Kozlowski et al., NEJM 265;5, 2011

7 Biologics with no official USP Monograph

8 Current Key New Monograph Development Projects  BB1: –Insulin Glargine –Fondaparinux –Dalteparin Sodium –Epoetin –Octreotide  Soon in ballot: –Filgrastim  BB2: –Factor IX, plasma derived  Soon in ballot: Sipuleucel T

9 Current Key Monograph Modernization Projects  BB1: –Heparin Sodium, stage 3 –Menotropins –Pancreatin/pancrelipase –Insulins

10 Horizontal Standards - Procedural Benefits:  Access to validated procedures and procedure performance criteria early in development  Solid anchor point for product characterization  Facilitate comparability during all development stages  Directly apply ICH guidance, including: –Q5E –Q6B  Establish consistency in analytical expectations

11 From General to Specific - Procedures Glycoprotein and Glycan Analysis – Introduction and Choice of Analysis Methods Oligosaccharide Analysis Monosaccharide Analysis Monosaccharide Mixes 1–4 Oligosaccharide mixtures from -Human α acid Glycoprotein -Fetuin -RNAse B -Human IgG Single Monosaccharides Guidance & Information Procedures & Performance Criteria Procedural (Horizontal) Standards for System Suitability & Validation

12 - Glycoprotein Analysis Strategies

13 Glycoprotein Analysis Strategies

14 Test Chapters – Current Major InitiativesImpurities Residual DNA Physicochemical Tests Oligosaccharide Analysis Monosaccharide Analysis Insulin Physicochemical Analysis Low Molecular Weight Heparin Molecular Weight Determinations Collagen Potency Assays and Content Measurement Protein Determination Procedures Glucagon Bioidentity Tests Epoetin Bioassays Somatropin Bioassays Anti-Factor IIa and Xa Assays for Unfractionated and Low Molecular Weight Heparins

15 Vaccine Chapters Vaccines for Human Use (completed) Bacterial Vaccines (completed) Viral Vaccines (in progress) Toxins/Toxoids Sub- Analytical Chapters for Key Quality Attributes and RS Possible PC Chapters Polysaccharide and Glycoconjugate Live Attenuated Other Subunit Live Attenuated Killed Viruses Subunit Vaccines

16 Analytical Procedures for Recombinant Therapeutic Monoclonal Antibodies  Will contain a collection of validated compendial procedures with established system suitability criteria for therapeutic MAbs  Will be accompanied by USP MAb System Suitability RS  Will not contain product or class specific acceptance criteria  Will be supported by a suite of >1000 Information Chapters that discuss quality attributes, manufacturing and quality control aspects for MAbs

17 Benefits:  Quality specifications and standards for complex ancillary and process materials –Give access to process ingredients of consistent quality –Control process variability –Facilitate testing of process intermediates and bulks Challenges in Standard Development:  Fast evolution of process materials: –Serum-free, proprietary custom media –Engineered 2 nd and 3 rd generation materials, e.g. Protein A  Defining key quality attributes for complex materials, e.g. Fetal Bovine Serum (FBS) Horizontal Standards– Ancillary & Process Materials

18 Raw/Ancillary Materials  Raw materials may or may not remain in the final therapeutic product as active substances or excipients –Ancillary materials are a subset of raw materials  Ancillary products may exert an effect on a therapeutic substance –(e.g. a cytokine may activate a population of cells), but they are not intended to be in final formulation  Concerns related to raw materials qualification have been amplified by recent materials supply issues: –Glycerin, Heparin, Melamine –Animal derived material (serum) used in manufacturing of some biologics  Some components are more critical than others! Risk assessment strategies are required to ensure quality –A critical material will come in contact with cells with a potential to alter either the growth characteristics of the cells or the ability of the cell culture to meet lot release specifications.

19 Ancillary Materials Standards: USP Approach Ancillary Materials for Cell-, Gene-, and Tissue-Engineered Products Specific AM Chapters FBS Quality Attributes Cytokines and Growth Factors Quality Attributes Reference Standards: - FBS - Interleukin-4 - FGF-2 - Transferrin - G-CSF General Information Chapter (Guidance) Ancillary Material Requirements for Specific AMs Ancillary Material Reference Standards

20 Tier 1 – Low-Risk, Highly Qualified Materials with Intended Use as Therapeutic Drug or Biologic, Medical Device, or Implantable Material Tier 2 – Low-Risk, Well Characterized Materials with Intended Use as AMs, Produced in Compliance with GMPs Tier 3 – Moderate-Risk Materials Not Intended for Use as AMs (frequently produced for in vitro diagnostic use or reagent grade materials) Tier 4 – High-Risk Materials, Materials not Produced in Compliance with cGMPs and materials not intended to be used in cell manufacturing Risk-based Classification of Ancillary Materials

21 Risk-based Qualification – USP Elements of Qualification and/or Risk Reduction Activities Tier 1Tier 2Tier 3Tier 4 Master File cross referenceXXXX Certificate of analysisXXXX lot-to-lot effect on process performanceXXXX Removal from finished productXXXX Stability as stored and used in specific processXXXX Confirm Certificate Analysis TestXXX Vendor AuditXXX Upgrade Manufacturing to GMP levelXX Develop internal specificationsXX Lot to lot comparability may be neededXX Testing for adventitious agents may be neededXX Traceability to country of origin, safety from animal diseasesX Adventitious agent testing for animal source-relevant viruses X

22 Recombinant Human Interleukin 4 -USP  Interleukin-4 Standard Requirement –Specific Activity: Not less than 0.5 x 10 7 USP Units /mg of total protein Labeled potency of RS will be based on bioactivity using TF-1 cell line –Purity: 98% (SDS-PAGE and silver stain) –Identity: N-term protein sequencing (10 residues) and Western Blot  Associated Reference Standard –Lyophilized powder –Calibrated against International Standard (WHO)  How is the standard used? –Preparation of IL-4 for which the activity was determined by calibration against the USP standard, will provide consistency in the manufacturing of the cell therapy product, by way of using the right amount of material.

23  Fetal Bovine Serum – Quality Attributes and Functionality Tests  Official uses of the USP FBS Reference Standard –Identification – Radial Immunodiffusion –FBS Functionality Tests – Growth Promotion Curve Five cell lines are recommended for use Functionality tests are performed on 3 cell lines ○Two from the recommended cell line list ○Third is cell line relevant to the user’s application USP General Chapter

24 Fetal Bovine Serum (FBS)- USP  FBS Standard Requirements –Osmolality: mOsm/Kg –Total Protein: mg/mL –pH: –Endotoxin: Not more than 10 units/mL –Hemoglobin level: Not more than 30 mg/dL –Identification: Radial Immunodiffusion (RID): species ID, IgG levels –Functionality Assays (Growth Curve and Clonal Assay)  Associated Reference Standard (RS), under development –Liquid frozen, 10 mL –Collaborative study to include several laboratories to test: Identification (FBS sample positive for bovine IgG and content is < 500 mg/L) Growth curve (doubling time in test sample is not less than 90% compared to RS)

25 How the FBS Standard is Used: Growth Curve Challenges: Cell Line, Cell Density, Cell Counting, Days in Culture  Three cell densities, determine viable cell counts on days 0,1,2,3,4, and 7. Select the cell density that exhibit a growth curve with 3 phases: Lag, Log, Stationary; and linear over 3 time points or more  Use the selected cell density to assess the test FBS side by side with the reference standard FBS  Doubling time is estimated using a growth curve that is linear over three or more time points.  Acceptance Criteria: R 2 ≥ 0.98 Doubling time of test sample should be not less than 90% of doubling time of RS

26  Growth Factors and Cytokines – additions to. –Next revision adds FGF  Standards for enzymes as ancillary material s –Trypsin, others?  Second and third generation identification tests for complex, naturally derived materials: –Application of modern immunology and proteomics approaches? Future Directions for USP Ancillary Materials Standards

27 Thank you!


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