The Role of Mass Spectrometry for Developing Biotherapeutics: Regulatory Perspectives

Transcription

1 The Role of Mass Spectrometry for Developing Biotherapeutics: Regulatory Perspectives Jun Park, Ph.D. Division of Monoclonal Antibodies Office of Biotechnology Products CDER/FDA CASSS, Applications of Mass Spectrometry in the Biotechnology Industry Napa, California, September 9-12,

2 The content reflects the views of the speaker and does not necessarily reflect official opinions of the FDA. 2

3 Outline Introduction Laws, Regulation, and Guidance Protein Structures/ Characteristics Examples Comparability/Similarity Assays for Host Cell Proteins Establishing Clonal Cell Lines Questions 3

4 Drug Development: FDA/CDER Perspective Approval IND Submission Clinical Hold NDA/BLA Submission Regulatory Briefing Supplements PMR/PMC... Pre- Human Studies NDA/BLA Phase 1 Phase 2 Phase 3 Review Phase 4 IND Review Supplement Review Pre-IND Meeting EOP2 Meeting Advisory Committee Meeting Generics, Biosimilars 4

5 US Federal Laws Federal Food, Drug, and Cosmetics Act (FD&C) in 1938 giving authority to the FDA to oversee the safety of food, drugs, and cosmetics Public Health Service Act (PHS) in 1944 including Regulation of Biological Products (BLA) Prescription Drug User Fee Act (PDUFA): Allows the FDA to accept user fees from drug and biologic companies in return for committing to review a new drug and/or biologic product within certain time frames Biologics Price Competition and Innovation Act (BPCI) in 2010 creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product. 5

6 Federal Regulations Federal regulations are interpretations of laws and are therefore binding like laws as well Draft and final regulations are published in the Federal Register (FR) 21 CFR 210, 211 cgmps 21 CFR New drug applications 21 CFR 312 IND submission requirements 21 CFR part Biological product definition 21 CFR part 601 Biologic License Application (BLA) 21 CFR 610 product standards and tests specific for biopharmaceuticals 6

7 FDA Guidance and Points to Consider Guidance documents that reflect the FDA s current thinking on a particular topic and not a law Provide specific detail that is not included in the relevant statues and regulations Examples: Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use, FDA 1997 Scientific Considerations In Demonstrating That A Proposed Protein Product Is Biosimilar To A Reference Product: Draft Guidance,

8 International Conference on Harmonization (ICH) Association of industry and regulatory agencies from the USA, Europe, and Japan Goal is to harmonize the interpretation, application, and product registration in order to effectively and safely carry out the development of new medicines Guidance topics include quality (Q), safety (S), efficacy (E), and multidisciplinary (M) Examples Q2A&B (analytical method validation) Q5A (viral safety) Q5C (product stability) Q6B (biopharmaceutical specifications) 8

9 Examples: The inspection revealed significant deviations of cgmp in the manufacture... These violations of the cgmps render the product adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act. The inspection and your failure to notify FDA prior to your implementation of production process changes as required by 21 CFR ( a warning letter from FDA Website) Per CFR (a)(7)(iv)(c), the IND submission is required to contain a brief general description of the composition... of placebo 9

10 Examples: There is insufficient CMC information contained... The IND submission for a Phase I trial should contain sufficient CMC information as outlined in Points to Consider in the Manufacture and Testing of Monoclonal Antibodies for Human Use (1997) The current manufacturing process provides little excess retroviral clearance... You will need to develop and provide a more robust retroviral safety factor with sufficient clearance Please see ICH Guideline Q5a Viral Safety Evaluation of Biotechnology Products 10

11 What do FDA/CDER reviewers do? Write reviews Document decisions and provide rationale Allows future reviewers to understand the regulatory history of the product Proactive interactions with the industry Meetings to address concerns before and after submission of a marketing application Communications to stakeholders Letters, labeling, and promotional materials Guidance and MaPP development 11

12 Typical IND/NDA/BLA Reviews Team Regulatory Project Manager (RPM) Product Quality Reviewer (CMC review) Pharm/Tox Reviewer (non-clinical study review) Clinical Reviewer Clinical Pharmacology (CP) Reviewer Biostatistics Reviewer Medical errors/proprietary name reviewer Scientific Investigator (CMC, clinical and CP study) Risk Management Reviewer (REMS review) Drug Advertising Reviewer (labeling review) CDRH Reviewers (e.g., PFS and autoinjector review) 12

13 Protein Structures/ Characteristics 13

14 Structural and Functional Complexity Fab-region Antigen binding Statin o Fc-region Fc-receptor binding (ADCC) C1q binding (CDC) FcRn-receptor binding (serum half-life) Jefferis et al. Immunology Letters (2002) 82; & PDB 2IG2, 1FC1

15 Post-Translational Heterogeneity Aggregation/particulates Fragmentation Arthur J Chirino & Anthony Mire-Sluis Nature Biotechnology 22, (2004) Process related impurities Host Cell Proteins Host Cell DNA etc.

16 Hierarchy of protein structure Emily Shacter, 2012 CASSS Mass Spectrometry Conference 16

17 Emily Shacter, 2012 CASSS Mass Spectrometry Conference 17

18 ICH Q6B: Specifications for Biotechnology Products Mass Spectrometry - Peptide map - Sulfhydryl group(s) and disulfide bridges - Molecular weight or size - Product-related impurities: deamidated, isomerized, mismatched S-S linked, oxidized or altered conjugated forms (e.g., glycosylation, phosphorylation) New analytical technology and modifications to existing technology are continually being developed and should be utilized when appropriate.

19 Orthogonal approaches for higher order structure changes by Far UV CD, FTIR, and 10 0 CD Signal Cloudy Clear Wavelength (nm) Li Shi, Genzyme, 2009 ACS 19

20 Examples/ Case Studies Comparability/Similarity Assays for Host Cell Proteins Establishing Clonal Cell Lines 20

21 Comparability/Similarity Intact Molecular Mass for Antibodies Product 1 Peak Glycans Theoretical Mass (Da) Product 1 Product 2 A G0F/G0F B G0F/G0F & K C G0F/G1F Product 2 D G1F/G1F E G1F/G2F Not Measured Is Product 1 comparable to Product 2? Quantification? 21

22 How close is close enough? Monitoring batches of an approved mab for glycosylation profile & ADCC potency Shift in glycosylation pattern results in different potency Unfucosylated G0 (% of glycans) Glycan profile ADCC Potency Martin Schiestl et al., Nature Biotechnology, 29, ,

23 Host Cell Protein Assays 1. ELISA (or Western blot) assaya) Process-specific assay: The anti-hcp antiserum is raised against a host cell protein pool that is derived from the cell line used for production. Generally a vector transfected parental cell line is used. b) Commercial assay: The anti-hcp antiserum is raised against host cell proteins derived from a generic cell line (CHO, NSO, E. coli). 2. Characterization assays: 2D-Difference Gel Electrophoresis (DIGE), Mass Spectrometry

24 Process Specific versus Commercial HCP Assays Silver stain of HCP assay standards Western blots Commercial Assay Process Specific Assay

25 In House vs. Specific HCP Assays Process Specific Assay Commercial Assay Release specification: Requested a 2-fold increase in the acceptance criterion when using the in-house assay compared to the commercial assay.

26 Establishing Clonal Cell Lines FDA concerns regarding assurance of monoclonality One round of cloning is likely not sufficient without extremely good supporting data. 90% probability of clonality with no supporting data/information is not sufficient. Animal-derived reagents used in manufacturing of the cell banks or products Contamination from equipment used with multiple cell lines Support for clonality Genetic stability clonality Sequencing of gene of interest clonality 26

27 Establishing Clonal Cell Lines Adaptation should be performed prior to cloning. Sufficient information/data should be provided to verify the capability of the method used to establish a clonal line. If clonality has not been assured, additional controls on manufacturing and other aspects of the product quality control strategy will be required. Application of Mass spectrometry techniques to characterize potential variants of protein products (e.g., sequence variants, glycosylation changes, etc.) 27

28 Acknowledgements Sarah Kennett, Division of Monoclonal Antibodies/ Office of Biotechnology Products/CDER/FDA Authors of cited papers Presentations from Industry

29 Questions and Further Discussion? 29