Implementation of Quality by Design:

Implementation of Quality by Design: An Office of Biotechnology Products Perspective Steven Kozlowski, M.D., Director Office of Biotechnology Products OPS/CDER ACPS 10/5/06

Overview • OBP Products & Quality by Design • Relevant Product Attributes • Manufacturing Process • Implementation Plans

Office of Biotechnology Products • Therapeutic Proteins • Growth Factors • Enzymes • Cytokines • Chemokines • Angiogenic factors • Toxins • Soluble Receptors/Receptor antagonists • Monoclonal antibodies • Related Products

Office of Biotechnology Products • These proteins are usually produced from: • Cell culture • Recombinant & non-recombinant • Mammalian, bacterial, yeast, etc. • Transgenic plants & animals • Products transferred from CBER to CDER in October 2003 • ONDQA regulates some protein products

Fab = ~1/3 mAb Statin o 11 A o 87 A Statin MW ~400 Da PDB 2IG2, 1HW8 Structure of complex molecules • 1 structure • higher order structure • post-translational modifications • heterogeneity Monoclonal Ab MW ~150,000 Da

Relationships Safety Efficacy (SE) Manufact. Process (P) Quality Attributes (A)

Product Method Validation Release Testing Characterization Stability Testing • Facilities and Equipment • Control of Raw Materials • In-Process Testing (PAT) • In-Process Controls • Process Robustness (FED) • Process Validation • cGMPs (QC/QA) Comprehensive QbC Strategy Process

What is “Quality by Design”? • Quality • “Good pharmaceutical quality represents an acceptably low risk of failing to achieve the desired clinical attributes.” • Quality by Design (QbD) • “Means that product and process performance characteristics are scientifically designed to meet specific objectives, not merely empirically derived from performance of test batches.” Janet Woodcock (2004)

Process Understanding Continuous Improvement Product Knowledge Product Quality Attributes Process Controls Process Parameters Product Specifications Product Design Unit operations, control strategy, etc. Process Design Desired Product Performance Dosage form, stability, formulation, etc. Process Performance Cpk, robustness, etc. SE SE P P A A Quality by Design Moheb Nasr

Release tests ? • Process How Much of the Iceberg (Quality Attributes) Can We See? • Characterization

Release tests • Process ? How Much of the Iceberg (Quality Attributes) Can We See? • Characterization • MS, NMR • Orthogonal methods

pyro-E pyro-E • Pyro-Glu (2) O O O D D D D • Deamidation (3 x 2) D O • Methionine oxidation (2 x 2) G D • Glycation (2 x 2) • High mannose, G0, G1, G1, G2 (5) G G G • Sialylation (5) K K • C-term Lys (2) Attributes & Combinatorics • (9600)2≈ 108 • 2 x 6 x 4 x 4 x 5 x 5 x 2 = 9600

… those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product (Q6B) Can these attributes be defined? Often difficult Default is to look at many attributes SE P A Relevant Attributes • Biological Characterization • Structure/function

One to some lots Purified/Induced Variants Clinical Lot Extremes Developmental Lots Many lots Stressed Lots Clinical Lots Multiple Binding/Cellular Assays Small Animal/Complex Bioassay Clinical Pharmacology (PK/PD) Clinical Studies Validated Bioassay Biological Activity Matrix

Charge Glycoform 2 Glycoform 1 SE P A CQA Multivariate Range

The Desired Product • Desired attributes of the API (Focus for Biotech) • Opportunity for rational protein engineering • Customize quality • Increase attributes that are desirable • Limit attributes that negatively impact product quality (via process or product) • Understanding structure/function relationships is critical for this approach

Protein Engineering • Reduce tendency for aggregation • Block free sulfhydryl groups • Alter amino acid sequence based on computational predictions • Glycine repeats or proline insertions • Maintenance of net charge • Alternate polar and non polar residues • Clusters of hydrophobic residues • Human Calcitonin (Zurdo et al PNAS 2005) • Immunogenicity considerations

QSE…by Design • Safety & Efficacy by Design • Improving function/new properties • Increasing Bioavailability • Reducing immunogenicity • Selective technologies in development such as phage, ribosome and yeast display • Quality by design • These strategies can also be used to select for product quality and manufacturability

SE P • Release tests A • Process ? What is the Relationship Between Attributes & Process? • Characterization • MS, NMR • Orthogonal methods

SE P • Release tests • Release tests A What is the Relationship Between Attributes & Process? • Characterization • Characterization • MS, NMR • Orthogonal methods • MS, NMR • Orthogonal methods • Process ?

SE SE P P Charge Time Glycoform 2 A A Media Glycoform 1 Agitation Critical Product Attributes Critical Process Parameters Translating CQA to a Manufacturing Design Space

The Desired Process • Desired attributes of the API or drug product • Opportunity for rational process design • Choose unit operations that select for • select for desired product attributes • minimize impurities/contaminants • are robust • Order unit operations to maximize efficiency • minimize buffer changes • consider impurities introduced by each step • Process control • consider impact of variable inputs • parameters set based on maximizing multiple variables • for critical steps- ideally real time & based on a knowledge base (PAT)

Examples of Problematic Process Designs • Processes that promote product variability • Heat treatment step added after aggregate clearance step • Process performed at room temperature with negative impact on quality • Recloning is used to establish new WCB • Processes that are difficult to control • Roller bottle processes (open, multiple fermentations difficult to control) • Poor formulation (stability & interactions)

Focus on “small steps” for biotech…………………. Implementation of QbD • Benefit from other OPS knowledge on implementation • e.g. ONDQA pilot • OBP participation in agency CRADAs to facilitate QbD • OBP Structure • Mixture of research/reviewers and full time reviewers • Experience with new technologies, fermentation/purification • Expertise in biological characterization • Encourage industry to engineer proteins for quality as well as safety and efficacy • “desired product” • Encourage industry to consider “desired process”

Small Steps • Product Testing • If no likely impact on S and E don’t include as a specification (no rejection limit) • use as a process consistency measure, where exceeding a limit initiates an investigation • if not a consistency measure, drop the test entirely • Need to discuss more extensive in-house reviewer training • Process Changes • Strategy to assess risk • Select classes of change based on • supplement load • variable risk to product • FDA/industry forums targeted to create risk map for a single class of change • Publication as white papers

Small Steps (cont.) • Complex API pilot • Encourage manufacturers to generate and submit data on characterization of structural attributes • the use of multiple biological assays for characterization • the generation of a product attribute space • consideration of associated relief (e.g. greater flexibility for comparability protocols) • Need to consider & discuss further • Platform Strategies • monoclonal antibodies may share a great deal of structure • efficient use of prior knowledge • long history of a regulatory path for modular/generic validation (Mab PTC) • underutilized • currently of interest to many biotech companies • conference to put interested parties together

Question to ACPS • Should FDA develop a pilot program and/or initiative to explore specific QbD issues that are important for biotechnology products? • Such a program could focus on issues such as: • (1) general approaches to CQA for complex API • (2) platform approaches/extrapolation for highly related complex APIs.

Quality Life Cycle Definitions? Knowledge Base Product-specific Process-specific Quality Risks Identify (Critical/ Key Parameters/ & Ranges) Design -Evaluation Propose (Desired Attributes/Process) Development Studies (DOE) Optimize (Continuous Improvement Innovation) Confirm (Control/ Predict) Monitor Conformance Lots “Validation Studies” Post-Approval Commercial Production

Credits • Barry Cherney • Patrick Swann • Moheb Nasr • Keith Webber • Ajaz Hussain

Implementation of Quality by Design: