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Well Characterized Biologicals

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Innovative Strategies and Regulatory Guidance for Characterizing Biological Products and Identifying and Controlling Variants and Impurities

November 03-04, 2014 · Washington Marriott at Metro Center · Washington, DC

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Agenda

Agenda

Monday, November 3, 2014

7:30
Registration and Coffee

8:25
Opening Remarks

Keynote Presentations

8:30
FDA Perspective
Lokesh Bhattacharyya, Ph.D. New FDA Draft Guidance on Analytical Procedures and Analytical Method Validation for Drugs and Biologics
CDER and CBER recently collaborated to create a new Guidance for Industry document entitled "Analytical Procedures and Methods Validation for Drugs and Biologics" which is published as a draft in February, 2014. This guidance was designed to update agency thinking on requirements for regulatory submission of analytical procedures and method validation data to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. The draft guidance supersedes the 2000 draft guidance for industry on Analytical Procedures and Methods Validation and, when finalized, will also replace the 1987 FDA guidance for industry on Submitting Samples and Analytical Data for Methods Validation. The agency also wanted to ensure this draft guidance would complement the International Conference on Harmonization (ICH) guidance documents, especially Q2 (R1) Validation of Analytical Procedures: Text and Methodology (Q2(R1)) for developing and validating analytical methods. In addition to assuring that guidance documents are current, the need for an updated guidance stems from the need to ensure analytical methodologies are consistent with changes to drug development and regulation seen with the concepts outlined in ICH Q8 (R2), Q9, Q10 and Q11.
Lokesh Bhattacharyya, Ph.D., Lab Chief, Laboratory of Analytical Chemistry and Blood Related Products, Division of Biological Standards and Quality Control, CBER, U.S. FDA

9:00
New Data
Edith Chang, Ph.D. New USP Chapter for N-glycan Analysis: <212> Oligosaccharide Analysis
USP has proposed a new General Chapter <212> in Pharmacopeia Forum 40(5) to provide qualitative analysis primarily for N-glycan chains with no or low levels of sialylated structures. In the meantime, an analytical procedure for analysis of multi-sialylated N-glycans is also developed. Total of four reference standards will be used to assess the system suitability for these analytical procedures. Details of this chapter are presented.
Edith Chang, Ph.D., Scientific Liaison, Biologics and Biotechnology, US Pharmacopeia

Technology Workshop

9:30
High-throughput and Validated Binding Kinetics Assay using Octet RED96 to Support Phase III Drug Product Release and Stability in Quality Control
Potency is an critical quality attribute in monoclonal antibody manufacturing and quality control. Binding kinetics assay measuring antigen-antibody interactions was originally evaluated in our facility using Surface Plasmon Resonance by Biacore. However, Biacore assay could not meet our needs with increased testing volume from Manufacturing scale-up when we began FDA-approved Pivotal Phase III clinical trial for Cachexia. We developed an innovative kinetics assay using ForteBio Octet RED96. Validation of this new method showed a precision of 17%, and it is also specific, accurate and robust enough to use as a QC drug product release and stability assay. The number of samples one operator can test per day using the new Octet method is significantly increased (8-fold) compared to the Biacore assay. Beside binding kinetics assay, we also use Octet RED96 to monitor cell culture titer in Manufacturing, which is also a validated QC assay.
Qian Wu, Ph.D., Director of Quality Control, XBiotech USA, Inc.

10:00
Networking Refreshment Break in Poster and Exhibit Hall

Track A

10:40
Chairman's Opening Remarks
Yves Aubin, Ph.D., Research Scientist, Centre for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Canada

Comparability Strategies for Biosimilars and Other Biotechnology Products

10:45
New Data
Characterization Strategies for Carbohydrate Biosimilars
The analysis of the glycoconjugates has become important for all comparability studies and in the quality control of therapeutic recombinant glycoproteins and polysaccharides. We will describe challenges in chromatography and mass spectrometry methods and procedures that are used for polysaccharide and glycoprotein biosimilar analysis in order to obtain regulatory approval. Details will be given on the pros and cons of certain methods from regulatory stand point. We will discuss procedures necessary for the complete structural elucidation of heparin, low molecular weight heparin and antibody products. Challenges in comparability study of low molecular heparin will be discussed. Examples of the methodologies will include data needed in different phases and currents analysis of biosimilars.
Parastoo Azadi, Ph.D., Technical Director, Complex Carbohydrate Research Center, University of Georgia

11:15
New Data
Application of NMR Spectral Fingerprinting for Structure Assessment of Monoclonal Antibody Therapeutics
High-resolution NMR methods can provide spectral 'fingerprints' of the higher order structure of protein therapeutics at atomic resolution. This presentation will report on the application of NMR methods for obtaining NMR 'fingerprints' of monoclonal antibody therapeutics and how these spectral 'fingerprints' can be used to establish consistency in drug manufacturing and for comparing a biosimilar to an innovator reference product.
John P. Marino, Ph.D., Leader, Biomolecular Structure & Function Group, NIST

11:45
Case StudyNew Data
Monitoring Effects of Excipients, Formulation Parameters and Mutations on the High Order Structure of Filgrastim by NMR
Filgrastim is the generic name for recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF). It is produced in E. coli in a non-glycosylated form. Here we show that NMR spectroscopy can be used to assess the three-dimensional structure of the active ingredient of formulated biosimilars. Recombinant metHuG-CSF was prepared in E. coli and isotopically enriched with 13C and 15N isotopes to study the effects of excipients such as pH, sorbitol, polysorbate-80, and ionic strength, on the conformation. Also, similar? Identical? NMR spectra were recorded for Neupogen®, a commercially available r-metHuG-CSF product purchased at a local pharmacy, thus showing that our labelled filgrastim has an identical conformation to this product. Therefore, NMR does provide residue specific information of the structure of the active ingredient of a product. In addition to current methods, the ability to assess the conformation with a high degree of resolution can greatly facilitate the comparability exercise.
Yves Aubin, Ph.D., Research Scientist, Centre for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Canada

12:15
Networking Luncheon in Poster and Exhibit Hall

1:25
Chairman's Opening Remarks
John P. Marino, Ph.D., Leader, Biomolecular Structure & Function Group, NIST

Analytical Methods and Characterization Strategies

1:30
Multi-Parameter Characterization of Biologics as a Tool for Aiding Development and Supporting Similarity
Characterization of proteins is essential to support claims of comparability or superiority in the development of follow on biologics. A fingerprinting approach that allows systematically building up a library of biophysical stability, conformation and aggregation information is demonstrated using a spectroscopic method typically used in the application of high throughput screening. Using a variety of orthogonal probes information can be determined about the way different proteins interact with each other under different conditions. In this presentation a family of data-rich instruments are used to develop a characteristic fingerprint of a therapeutic monoclonal antibody, providing the ability to gain detailed characterization information that helps control protein folding and aggregate formation while also providing a risk based assessment of the likelihood of particular formation under various conditions.
Daniel Lund, Ph.D., Product Manager, Avacta Analytical

2:00
High Throughput and High Resolution Glycan Analytics Using Multi-Capillary CE
Glycans represent a key quality attribute of biotherapeutics that requires analysis during several points in development and manufacturing. Key components of glycan analytics include sample preparation, glycan separation and data analysis. Current glycan methods are hampered by a laborious and time consuming sample preparation workflow coupled with a low throughput and/or low resolution data generating system. To address this analytical challenge, the sample preparation has been greatly simplified through a reduction in hands on time, pipetting and manipulations. Combined with analysis on a 24 capillary CE system, high quality relative quantitation glycan data for 96 samples can be generated from start to finish in less than 7 hours. This presentation describes the technology behind this method, with time to result, ease-of-use, reproducibility, sensitivity and benchmarking against existing glycan analysis platforms.
Wesley Straub, Senior Product Manager, BioProduction, Pharma Analytics, Life Science Solutions, Thermo Fisher Scientific

2:30
New Data
Discovery and Characterization of a Novel Post-Translational Modification in Recombinant Monoclonal Antibodies
Abstract Not Available.
Richard Beardsley, Scientist, Protein Analytical Chemistry, Genentech

3:00
Networking Refreshment Break in Poster and Exhibit Hall

3:40
Chairman's Opening Remarks
Richard Beardsley, Scientist, Protein Analytical Chemistry, Genentech

Analytical Strategies for Diverse Products

3:45
Case StudyNew Data
Monoclonal Antibody Reference Material for the Advancement of Characterization Technologies
Therapeutic monoclonal antibodies harness the highly evolved specificity of adaptive immunity to fight disease. Monoclonal antibody-based therapeutics have grown exponentially with the advent of mammalian cell culture, process, and formulation technology. At the same time, state-of-the-art and emerging analytical and biophysical methodology provides very detailed process and product information. Although such a battery of methodology and wealth of information is critical to product understanding; the accuracy, precision, robustness, and suitability of such techniques are also of critical importance. A representative and widely available material along with detailed historical data would greatly supplement characterization efforts throughout the drug product lifecycle. To this end, a first-of-its kind qualitative and quantitative biopharmaceutical Reference Material to supplement drug substance/product characterization is described. The NIST mAb IgG1κ is intended to provide a well characterized, longitudinally available test material that is expected to greatly facilitate development of originator and follow-on biologics for the foreseeable future. The RM is intended for a variety of uses including, but not necessarily limited to: system suitability tests, establishing method or instrument performance and variability, comparing changing analytical methods, assisting in method qualification, etc. Results from an ongoing round robin characterization study and book project including over 65 contributors from industry, academia, and regulatory agencies will also be discussed.
John Schiel, Ph.D., Research Chemist, National Institute of Standards and Technology

4:15
New Data
Measuring Trisulfides in Biologics: Methods for High Throughput Analysis of mAbs and Antibody Drug Conjugation Processes
A trisulfide bond is a previously known protein modification that was only recently found in recombinant monoclonal antibodies using mass-spectrometry. This modification introduces heterogeneity into the inter-chain disulfide linkages and can impact the reduction step involved in the manufacturing of cysteine-linked antibody-drug conjugates (ADCs). Several analytical methods with higher throughput than the original MS strategy have been developed to quantitate this product variant. These methods can be used to study trisulfide formation and to mitigate its impact on ADC manufacturing.
Chris R. Cornell, MSc., Technical Development Senior Research Associate, Protein Analytical Chemistry 3, Genentech Inc.

4:45
Case StudyNew Data
Predicting the Stability of Lyophilized Protein Formulations by Fluorescence Stokes Shift
Disaccharides such as trehalose and sucrose are commonly used to preserve therapeutic proteins in lyophilized formulations; however, there is currently no systematic and rational approach to predict the stability of protein formulations. We have shown firm evidence that protein stability in sugar-based glasses is directly linked to the high-frequency, local mobility of the sugar matrices, occurring on a timescale of nanosecond. In this talk, we present a new fluorescent instrument to probe the motions of lyophilized formulations. This technique will allow scientist in early development stage to rapidly screen and select suitable protein formulation candidates, and predict their long-term stabilities.
Ken K. Qian, Ph.D., Research Chemist, Biomaterials Group, NIST

5:15
Regulatory Challenges for Protein Therapeutics
Common regulatory challenges exist among protein therapeutics but there are unique concerns for novel molecules. This talk will present specific and general concerns for innovative non-mAb therapeutics which are becoming increasingly more important and are now in preclinical pipelines. Finally, the presentation will conclude with a case study highlighting a fusion protein which utilizes a nonstandard manufacturing process, illustrating the challenges with determining specifications, comparability and process validation for a novel molecule.
John Alvino, Senior Manager, Global Regulatory Affairs, AstraZeneca

5:45
Close of Day One

Track B

10:40
Chairman's Opening Remarks
Jonathan W. Cooper, Ph.D., Staff Scientist, Analytical Development, Vaccine Production Program Laboratory, Vaccine Research Center, NIAID, NIH

Assay Development Strategies for Vaccines and Other Therapeutics

10:45
FDA PerspectiveNew Data
Considerations for Use of Serologic Assays in Vaccine Development for Bacterial Diseases
The US Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Vaccines Research and Review (OVRR) evaluates the safety and efficacy of vaccines for therapeutic and vaccine preventable diseases in the U. S. Serologic assays may be used as correlates of protection to clinically evaluate effectiveness of a vaccine when disease cannot be measured. This presentation will review why, when, and how it is appropriate to develop serologic assays. Meningococcal vaccines (Neisseria meningitis) with use of the serum bactericidal activity (SBA) assay, and pneumococcal vaccines (Streptococcus pneumoniae) with the use of opsonophagocytic assay (OPA) will be presented as examples.
Cara Fiore, Ph.D., Microbiologist, Master Reviewer, Division of Vaccines and Related Products Applications OVRR, CBER, U.S. FDA

11:15
Potency Assay Strategies for Bispecific Antibodies
Abstract Not Available.
Kendall Carey, Ph.D., Scientist, Biological Technologies, Genentech, Inc.

11:45
FDA Perspective
Regulatory Considerations in the Safety Assessment of Vaccine Adjuvants and Adjuvanted Vaccines
The Office of Vaccines Research and Review (OVRR) is responsible for regulatory review of new Investigational New Drug Applications (INDs) and Biologics License Applications (BLAs) for preventive vaccines and therapeutic vaccines for infectious disease indications. Through this review process, OVRR ensures that vaccines are safe, effective, pure, and potent, as specified in Title 21 of the Code of Federal Regulations, Sections 312, 600, and 610. This presentation will review the key components in nonclinical and clinical safety assessment of investigational vaccines regulated by OVRR, with a focus on product testing and characterization and pharmacology and toxicology study design considerations for vaccines with novel adjuvants. In addition, updates on clinical trial design considerations, including demonstration of the "added benefit" of the adjuvant, adjuvant dose selection and safety monitoring will be discussed briefly.
Kirk C. Prutzman, Ph.D., Office of Vaccines Research and Review, Division of Vaccines and Related Products Applications, Regulatory Review Branch 3, CBER, U.S. FDA

12:15
Networking Luncheon in Poster and Exhibit Hall

1:25
Chairwoman's Opening Remarks
Cara Fiore, Ph.D., Microbiologist, Master Reviewer, Division of Vaccines and Related Products Applications OVRR, CBER, U.S. FDA

Assay Development Strategies for Vaccine and Other Therapeutic Development

Featured Presentation

1:30
Case StudyNew Data
Fab-Arm Exchange of IgG4 Therapeutic Antibodies In Vitro and In Vivo: An Industry Perspective
IgG4 isotype antibodies are prone to engage in Fab-arm exchange, a structural rearrangement that involves the swapping of a heavy-light chain unit between IgG4 molecules, resulting in bispecific hybrids in vitro and in vivo. A simple point mutation (S228P) at the core hinge region has been shown to be sufficient to stabilize the hinge disulfide bridges and prevent Fab-arm exchange from occurring. Propensity to engage in Fab-arm exchange is considered a potential critical quality attribute and thus needs to be tightly monitored during manufacturing and at the Drug Substance and Drug Product stages. This work will describe a strategy to monitor the presence of Fab arm exchange using multiple techniques both in vitro and in vivo.
Daisy Richardson, Ph.D., Director, Bioprocess Development, Merck

2:00
New Data
Platform Assays to Support Process Development, Release, and Characterization of Virus-Like Particles for Western, Eastern, and Venezuelan Equine Encephalitis Virus
The Vaccine Research Center at NIAID is developing a virus-like particle vaccine to protect from Western, Eastern, and Venezuelan equine encephalitis viruses due to their possible use as biological agents. Strategies for platform assays for CQAs, content, potency, purity, and residuals to support process development, release, and characterization for GMP production of the three VLPs will be discussed.
Jonathan W. Cooper, Ph.D., Staff Scientist, Analytical Development. Vaccine Production Program Laboratory, Vaccine Research Center, NIAID, NIH

2:30
FDA Perspective
Strategies of Potency Determination for New Generation Blood Products
Accurate and meaningful determination of potency is essential for the safe and effective use of blood products. Although most blood protein products are well characterized and international standards of their biological activity are often available, recent investigations have revealed discrepancies in potency assignment and post-infusion monitoring for both licensed and investigational coagulation factor products, especially the new generation products whose structures are modified in an attempt to improve treatment regimen. This lecture will discuss the issues related to potency assignment and post-infusion monitoring of these products, and strategies to address the problems.
Disclaimer: This is an informal communication and it represents authors' own best judgment. These comments do not bind or obligate FDA.
Mikhail V. Ovanesov, Ph.D., Visiting Scientist, Principal Investigator, Laboratory of Hemostasis/Division of Hematology, Office of Blood Research and Review, CBER, U.S. FDA

3:00
Networking Refreshment Break in Poster and Exhibit Hall

3:40
Chairman's Opening Remarks
Dong Xu, Ph.D., Scientist II, Analytical Development, Technical Development, Biogen Idec

Assay Development Strategies for Vaccines and Other Therapeutics

Featured Presentation

3:45
Characterization of Serum: Possibilities and Probabilities
This talk will introduce the International Serum Industry Association and provide an overview of history and areas of focus. Current programs around standardization of testing and traceability of origin and serum type will be discussed. The impact of new testing methods will be reviewed and the role going forward assessed.
Rosemary J. Versteegen, Ph.D., Chief Executive Officer, International Serum Industry Association

4:15
Reagent Management for Bioassay Development Group at Biogen Idec, Inc.
A reagent management system based on commercial software was established for bioassay development. Efforts to minimize the risk of mistaken information and provide users with secured and convenient accessibility to the program are discussed. In addition, the procedures and challenges associated with reagent production by CRO/CMOs are summarized for improvement on cost and time efficiency.
Dong Xu, Ph.D., Scientist II, Analytical Development, Technical Development, Biogen Idec

4:45
Case StudyNew Data
Improvement of a Sample Pretreatment Procedure for Immunogenicity Testing through Better Characterization of Cells, Positive Control Antibodies and Residual Drug Level
Biological therapeutics can induce an undesirable immune response resulting in the formation of anti-drug antibodies (ADAs), which can include neutralizing antibodies (NAbs). Functional (usually cell-based) assays are preferred to detect NAbs in patient serum samples, but cell-based bioassays are subject to interference from numerous serum factors such as growth factors, disease-related cytokines, as well as free drug. In this case study, a biotin extraction and acid dissociation (BEAD) procedure to isolate ADA was significantly improved through better characterization at multiple steps. First, we show that the cells used in the bioassay were extremely sensitive to a wide range of commonly used buffers in the acid extraction procedure, namely, Tris, glycine, acetic acid and citrate. Two different methods were identified to make the final extraction buffer compatible with even the most sensitive cell lines in the bioassay. We then discuss why some excellent NAb positive controls (PCs) could go awry upon acid treatment and propose a strategy for ADA or NAb PC characterization when they are intended to be used in acid extraction. Last, we show how LC/MS-MS played an instrumental role in the optimization of the extraction procedure by monitoring residual human monoclonal Ab drug levels in the final extraction, which contains an excess amount of endogenous human Abs. Lessons learned through this case study enabled the development and optimization of a universal ADA extraction method to minimize both drug and matrix interference for downstream ADA assay or functional cell-based NAb assays.
Weifeng Xu, Ph.D., Research Investigator, Bioanalytic and Analytic Science - Biologics (BAS-B), Bristol-Myers Squibb

5:15
Systematic Evaluation of In Vitro and In Vivo Adventitious Virus Assays for the Detection of Viral Contamination of Cell Banks and Biological Products
Viral vaccines and the cell substrates used to manufacture them are subjected to tests for adventitious agents, including viruses, contaminate. Some of the compendial methods (in vivo and in vitro in cell culture) were established in the mid-20th century. These methods have not been subjected to current assay validation, as new methods would need to be. This study was undertaken to provide insight into the breadth (selectivity) and sensitivity (limit of detection) of the routine methods, two such validation parameters. Sixteen viral stocks were prepared and characterized. These stocks were tested in serial dilutions by the routine methods to establish which viruses were detected by which methods and above what limit of detection. Sixteen out of sixteen viruses were detected in vitro, though one (bovine viral diarrhea virus) required special conditions to detect and another (rubella virus) was detected with low sensitivity. Many were detected at levels below 1 TCID50 or PFU (titers were established on the production cell line in most cases). In contrast, in vivo, only 6/11 viruses were detected, and 4 of these were detected only at amounts one or more logs above 1 TCID50 or PFU. Only influenza virus and vesicular stomatitis virus were detected at lower amounts in vivo than in vitro. Given the call to reduce, refine, or replace (3Rs) the use of animals in product safety testing and the emergence of new technologies for the detection of viruses, a re-examination of the current adventitious virus testing strategies seems warranted. Suggested pathways forward are offered.
Jim Gombold, Senior Director, Charles River Laboratories

5:45
Close of Day One

Tuesday, November 4, 2014

7:30
Registration and Coffee

8:25
Opening Remarks

Keynote Presentations

8:30
FDA Perspective
Santosh Nanda, Ph.D. Regulatory Considerations for Adventitious Agents and Host Contaminants in Vaccines
This talk covers ensuring vaccine safety; mitigation of adventitious agent risk; reduction of residual host cell material in final product: Cellular DNA and Protein; manufacturing challenges and control measures; designing product safety; and regulatory challenges.
Santosh Nanda, Ph.D., Interdisciplinary Scientist, CBER, U.S. FDA

9:00
FDA Perspective
Protein Aggregates and Other Particulates: Testing Methodologies and Regulatory Issues
Abstract Not Available.
Joseph Kotarek, Ph.D., ORISE Fellow, Office of Blood Research and Review, Division of Hematology, Laboratory of Plasma Derivatives, CBER, U.S., FDA

9:30
FDA Perspective
Characterization of Conjugate Vaccines from a Regulatory Perspective
Glycoconjugate vaccines are very effective at preventing diseases caused by encapsulated bacteria. The regulatory life of glycoconjugate vaccines begins in the development and IND stages and extends through post licensure for as long as the vaccines are a part of the drug supply. Characterization is essential throughout this life span. In this presentation we outline some of the goals for characterization of glycoconjugates and their intermediates. We present examples of methodology used to address these goals for characterization.
Tina Roecklein, M.S., Consumer Safety Officer, OVRR, DBPAP, CBER U.S. FDA

10:00
Networking Refreshment Break in Poster and Exhibit Hall

Track A

Identifying and Controlling Variants & Impurities

10:40
Chairman's Opening Remarks
Justin Sperry, Ph.D., Senior Principal Scientist, Analytical Research and Development, Senior Scientist, Pfizer Inc.

10:45
Case StudyNew Data
In-depth Examination of Interferon A-2 Products Using High-Resolution Separation Techniques
Interferons (IFNs) are some of the most frequently prescribed therapeutic proteins for the treatment of diseases such as hepatitis, multiple sclerosis and leukemia. Like other therapeutic proteins, however, IFNs are susceptible to a number of process and product-related modifications during preparation, formulation or storage. Such modifications may result in the loss of therapeutic efficacy or unwanted immune reactions. We have examined IFNα-2a and IFNα-2b products using methods based on high resolution separation techniques, in particular, capillary electrophoresis (CE) and high performance liquid chromatography (HPLC). Size-exclusion HPLC was used to assess the formation of dimers, aggregates and denatured IFNα-2. Ion-exchange chromatography as well as a CE enabled monitoring charge variants while reversed-phase HPLC enabled detection of oxidized products and other variants. In addition, a CE method was developed to directly assess the integrity of the active ingredient in finished products containing excipients such as human serum albumin or polysorbate. A brief overview of these methods will be presented.
Michel Girard, Ph.D., Research Scientist, Centre for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Canada

11:15
USP Analytical Methods and Monograph Approaches for Measuring Impurities in Biologics
USP's USP-NF contains General Chapters and monographs that support the quality, safety, and potency of drug substances and products. This talk will explain the strategies used to prepare suitable monographs containing impurity tests for biologics from multiple manufacturers. The talk will also highlight new test Chapters containing validated methods appropriate for many biologics. (PPVI)
Maura C. Kibbey, Ph.D., Senior Scientific Liaison, Biologics & Biotechnology, U.S. Pharmacopeia

11:45
Assessment of Small Molecule Impurities in Antibody Drug Conjugates
Currently there is little to no regulatory guidance for the treatment of small molecule impurities in an antibody drug conjugates. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) has developed a scientific rational that addresses this gap. The IQ's recommendation along with a case study will be presented.
Michael T. Jones, Ph.D., Research Fellow, Biotherapeutics Pharmaceutical Sciences, Analytical R&D, Pfizer

12:15
Networking Luncheon Break in Poster and Exhibit Hall

1:30
New Data
Control of Process Variants in Novel Vaccine Candidates
The insect cell-Baculovirus Expression Vector System (BEVS) is an established platform for the production of biological products and is used in the manufacture of commercial vaccines for human and veterinary use. Using BEVS, new viral antigens can be produced rapidly, without the need to produce live viral pathogens and without the need to qualify new cell banks for production of recombinant antigens. Applications of BEVS technology beyond the currently licensed products along with next generation products will be reviewed. Process variants and their control in the BEVS/insect cell system will discussed in the context of new vaccine candidates.
Clifton E. McPherson, Ph.D., Vice President, Product Development, Protein Sciences Corporation

Host Cell Protein Detection and Characterization

2:00
New Data
Characterization of Host Cell Proteins Using Mass Spectrometry
Sensitive detection and quantitation of residual host cell proteins (HCPs) during purification process development is critical in the design of robust and well-controlled manufacturing processes that yield high quality biotherapeutics. The enzyme-linked immunosorbent assay (ELISA) is the current standard assay for determining residual HCP levels in the purified biotherapeutic drug substance. Mass spectrometry-based methods are emerging as a routine approach for HCP analysis where residual HCPs can be detected, identified, and quantitated directly due to ever increasing instrument performance. In this study, we have developed proteomic approaches to identify and quantify residual HCPs in biotherapeutics derived from both mammalian and bacterial expression systems in an effort to complement ELISA results. Spiking studies were employed to determine the limits of quantitation and detection for a wide variety of possible HCPs. The proteomic method employs proteolytic digestion, one dimensional chromatographic separation by RP-HPLC, ultrahigh-resolution mass spectrometry, and database searching to definitively identify potential HCPs. A comparison of analytical approaches for HCP detection and quantitation will be discussed.
Justin Sperry, Ph.D., Senior Principal Scientist, Analytical Research and Development, Senior Scientist, Pfizer Inc.

2:30
Late-Breaking Presentation

Track B

QbD for Development

10:40
Chairman's Opening Remarks
Thomas A. Little, Ph.D., President, Thomas A. Little Consulting

10:45
FDA Perspective
QbD Approaches to Product Development
Summarizing case studies of where QbD filings have resulted in reduction of regulatory burden; from a regulatory perspective, how much data is needed to submit your filing.
Steve Kozlowski, MD, Director, Office of Biotechnology Products (OBP), CDER, U.S. FDA (Invited)

11:15
Essentials in Quality by Design for Modern Biologics Development
QbD is a systematic approach to development that begins with predefined development objectives and emphasizes product and process understanding and process control, based on sound science, data based decision making and quality risk management. Quality by Design as introduced by the FDA and EU brings modern drug development methodologies to CMC teams working on biologics, pharmaceuticals and vaccines. The presentation will discuss the application of QbD principles in the development, submission and manufacturing of drug product and drug substance. Most CMC development teams globally have little to no experience in generation of design space, selection of PAR/NOR ranges and preparing for Stage I Validation documentation and submission. This presentation will cover basic and advanced principles for the practical application of QbD in every phase of product development and control.
Thomas A. Little, Ph.D., President, Thomas A. Little Consulting

11:45
Practical Application of QbD for Method Development, Validation and Process Control
Abstract Not Available.
Andrea Coombs, Director Validation and Technical Transfer, Emergent Biosolutions

12:15
Networking Luncheon Break in Poster and Exhibit Hall

1:25
Chairman's Opening Remarks
Thomas A. Little, Ph.D., President, Thomas A. Little Consulting

QbD for Development Cont.

1:30
Case StudyNew Data
Establishing the Criticality of the Quality Attributes of an Fc Fusion Protein
One of the first steps in the QbD approach consists in identifying the Critical Quality Attributes (CQA), i.e. those quality attributes of the product that have an impact on its clinical efficacy and/or safety. According to ICH guidelines Q8/Q11, manufacturing process development should include at a minimum a number of elements, of one which is CQAs. CQAs are therefore expected in the submission for a commercial pharmaceutical product. The presentation describes how the potential CQAs of an Fc fusion protein were selected and covers the following steps:
  • Overview of the quality attributes of recombinant proteins expressed in mammalian cells
  • Risk assessment methodology to establish criticality
  • Application of risk assessment to an Fc fusion protein case study
  • Literature review of the impact of glycosylation on safety and efficacy
Alex Eon-Duval, Associate Project Manager, Biotech Process Sciences, Merck Serono S.A.

Technology Workshop

2:00
Case Studies in Biotherapeutic-Related Workflows with the Latest in Ultrahigh-Resolution Quadrupole Time-of-Flight (UHR-qTOF) Instrumentation"
Attendees of this technology seminar will hear about the latest advancements in ultrahigh-resolution time-of-flight hardware and their application to the analytical challenges facing innovators and biosimilar's characterization labs. Several biotech-relevant case studies will be presented to highlight: 1) The latest in high-mass detection and native MS, 2) The latest advancements in resolution and mass accuracy and, 3) Advancements in electron transfer dissociation (ETD) capabilities.
Jason S. Wood, Ph.D., Market Manager, Bruker Daltonics

2:30
Interactive Panel Discussion:
QbD Successes, Lessons Learned and Adaptation
Moderator:
Thomas A. Little, Ph.D., President, Thomas A. Little Consulting
Panelist:
Steve Kozlowski, MD, Director, Office of Biotechnology Products (OBP), CDER, U.S. FDA (Invited)
Andrea Coombs, Director Validation and Technical Transfer, Emergent Biosolutions
Alex Eon-Duval, Associate Project Manager, Biotech Process Sciences, Merck Serono S.A.

3:00
Networking Refreshment Break in Poster and Exhibit Hall

Analytical and Characterization Challenges for Marketed and High Protein Concentration Products

3:45
Case StudyNew Data
Analytical Control System Lifecycle Management Strategies for Marketed Protein Products
Although post-licensure control systems are often updated by modifying specific assays or revising individual acceptance criterion, a periodic, comprehensive and systematic evaluation and update is necessary to align commercial control systems with contemporary standards. To address this need, Genentech/Roche have developed a control system lifecycle management program for application to the portfolio of current and future licensed biological products. In this presentation, we will examine strategies for lifecycle management of biopharmaceutical product commercial control systems.
Minh Luu, Associate Program Director, Pharma, Technology and Regulatory, Genentech

4:15
New Data
Development and Qualification Strategy for Subvisible Particle Testing by Light Obscuration Method
Method development and qualification strategies will be discussed to address the challenges of using a light obscuration method to quantify subvisible particles in high protein concentration products in different drug product presentations.
Yoen Joo Kim, Associate Scientist II, MedImmune LLC

4:45
Characterization of Opalescence Behavior for High Concentration Monoclonal Antibody Solutions and Its Implications
Monoclonal antibody solutions are often opalescent at high protein concentrations. Multiple analytical techniques, including measurement of light scattering at 90° and transmission, Tyndall test, and microscopy, were deployed to examine the opalescence behavior for a monoclonal antibody in different conditions including temperature, protein concentration, salt concentration and pH. The experimental findings suggest that protein-protein interactions and phase diagram are key to understand the opalescence behavior.
Jifeng Zhang, Ph.D., Head of Combination Product Analytical Technology, Department of Analytical Biotechnology, MedImmune LLC

5:15
Close of Conference

BPI 2014