Technology transfer: CMC activities for the manufacture of ... · Technology Transfer: CMC...
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BioProcess Technology Consultants www.bptc.com Technology Transfer: CMC Activities for the Manufacture of Monoclonal Antibodies Patricia Seymour BioProcess Technology Consultants, Inc. IBC’s 7th International Outsourcing Manufacturing of Biopharmaceuticals Bellevue, WA March 14-15, 2011
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Transcript of Technology transfer: CMC activities for the manufacture of ... · Technology Transfer: CMC...
BioProcess Technology Consultantswww.bptc.com
Technology Transfer: CMC Activities for the Manufacture of Monoclonal Antibodies
Patricia SeymourBioProcess Technology Consultants, Inc.IBC’s 7th InternationalOutsourcing Manufacturing of BiopharmaceuticalsBellevue, WAMarch 14-15, 2011
Comprehensive review, in‐depth analysis, and recommendations for all aspects of CMC from initial discovery through First‐In‐Human clinical trials
Additional information on strategic and regulatory considerations for late‐stage product development and commercialization
Published February 2010
Basis for presentation
From Clone to Commercial®2
Why Develop Monoclonal Antibodies
US healthcare spending by 2015 forecast to be ~15% GDP (~$4T)
Prescription pharmaceuticals in 2015 forecast to be ~$446B (>10% total healthcare expense)
Biologics drug expenditure• already accounts for >14%
pharmaceutical spend• >33% of all drugs in
development
Program Administration
7%
Prescription Drugs10%
Investment7%
Nursing Home Care6%
Dental Services
4%Hospital Care31%
Physician & Clinical
Services21% Other
Spending*14%
* Other spending: Other professional services, other personal healthcare, home healthcare, durable medical products, government public health activities
Source: Center for Medicare & Medicaid Services
From Clone to Commercial®3
MAb Approvals
The number of monoclonal antibody product approvals continues to grow• Approximately 65% of all biopharmaceutical products in
development are monoclonal antibody‐related products• 2009 revenue >$40B
0
20
40
60
80
100
120
Pre-1995
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Year
No.
Pro
duct
s
EU Non-MAbsEU MAbs
US Non-MAbsUS MAbs
From Clone to Commercial®4
MAb CMC Development Program Management of MAb product development requires technical expertise
in a wide range of CMC areas Develop detailed activity plans for each major CMC function
• Analytical Method Development• Upstream Process• Downstream Process• Formulation Development• Drug Substance Manufacturing• Drug Product Manufacturing• Clinical Supplies• Regulatory
Define what is “good enough” to accelerate timelines and delay major CMC expenditures until proof‐of‐concept achieved
From Clone to Commercial®5
Timelines: CMC Development Program
1. Analytical MethodsPreliminary Development Assays & StandardsAnalytical Methods DevelopmentAssay Qualification & Transfer to QCProduct CharacterizationClinical Reference Standards
2. Upstream ProcessExpression VectorCell Line Selection & OptimizationCell Banking & CharacterizationInitial Media & Bioreactor Process Development
3. Downstream ProcessPurification Process DevelopmentInitial Viral Validation Studies
4. Formulation DevelopmentPre-Formulation DevelopmentClinical Formulation Development
5. Drug Substance ManufacturingProcess & Analytical DocumentationPreclinical/Engineering Drug Substance ProductionPhase I (GMP) Drug Substance ProductionPreliminary Drug Substance Stability Studies
6. Drug Product ManufacturingClinical Fill/Finish Process DevelopmentProcess & Analytical DocumentationPreclinical/Engineering Drug Product ProductionPhase I (GMP) Drug Product ProductionPreliminary Drug Product Stability Studies
7. RegulatoryIND Filing Preparation - CMC Section
IND Filing
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18Months from start of program
Techno
logy Transfers
From Clone to Commercial®6Platform Process
Multiple Technology Transfers Points Transition of knowledge and processes from Research to
Development Early phase Development to late phase Development groups Transition from Development to Commercial Manufacturing Transfer to, or receiving from, a third party (licensed
product/CMO)
Sending Unit Receiving UnitSending Unit Receiving Unit
From Clone to Commercial®7
Technology Transfer Considerations
TT plan driven by the target product profile (TPP)• Understand product’s intended use and quality targets
• Ensure product development and transfers start with end product in mind
• Define those critical product characteristics that must be maintained or met during technology transfer
From Clone to Commercial®8
Early Stage Technology Transfers Identify Critical Quality Attributes (CQA) and
the Critical Process Parameters (CPP) that define the process and need to be controlled• CQAs unlikely to be established yet
―Definition of what product attributes should be can be based on general properties of antibodies and on established safety parameters for all biopharmaceutical products
• CPPs likely to affect quality attributes not well defined yet
• Early stage transfers trickier since thereis not a robust data set to refer to for trouble shooting
• TPP serves as a guide to capture product attributes as they emerge
From Clone to Commercial®9
Overall Technology Transfer Strategy
Outline all transfer activities in detail• Timing of initiation and completion of each transfer activity
• Roles and responsibilities• Interdependencies of different activities
• Phase appropriate criteria for determining successful technology transfer
From Clone to Commercial®10
Governance and Management
Outline governance structure to oversee transfer activities and to ensure information is shared over the course of the transfer process• Identify relationship manager, project manager, functional contacts
• Assign a team who can support the transfer and a senior management steering committee
• Establish clear RACI matrix
From Clone to Commercial®11
Determine Gaps in Technology Transfer Strategy
Define what skill sets and capabilities are needed• Determine what necessary skill sets exist at both the sending and receiving sites
• Determine what necessary capabilities and capacities exist at the facility
From Clone to Commercial®12
Regulatory Expectations for Technology Transfer
Define what are the regulatory expectations of the transfer• Identify what regulatory submissions will be required as a result of the transfer ―IND amendments, Type II variations, PAS, CBE‐30, Annual Report
• Identify who will be responsible for the preparation of these regulatory documents
• Use either TT Plan or Quality/Technical Agreement to solidify these responsibilities
From Clone to Commercial®13
Identify Risks in Technology Transfer Strategy
Develop a risk profile to track and highlight scientific, operational and business risk and corresponding mitigations
From Clone to Commercial®14
Risk Ranking and Filtering
Low
Medium
High
Severity
Prob
abili
ty
Hig
h
Low
Med
ium
Risk Class ONE
Risk Class TWO
Risk Class THREE
Risk Ranking
Three
Two
One
DetectionRi
sk
Clas
sific
atio
n
Hig
h
Low
Med
ium
HIGH priority
MEDIUM priority
LOW priority
Risk Filtering
From Clone to Commercial®15
Risk Control and Review
Identify risk control procedures
Complete risk review
From Clone to Commercial®16
Begin the Technology Transfer Assemble summary of all prior knowledge about the cell line,
analytical methods, product, or process that is being transferred
Development Reports
Batch Records SOPs
Sending Party
Receiving Party
Materials Procurement
QC/QA Preparations
Process Engineering & Validation
Manufacturing Preparations
Materials Specifications
Process Transfer Package
Cell LineAnalytical Methods
From Clone to Commercial®17Make Product
Comparability Decision Tree
Working Cell Bank (WCB)
Formulation
Polishing
Purification
Primary Recovery
Production Bioreactor
Inoculum Preparation
Drug Substance (API)
From Clone to Commercial®18
Comparability Risk Following Technology Transfer
From Clone to Commercial®19
Technology transfers are a necessary component of monoclonal antibody product development
Smooth and successful technology transfer process depends on several factors• Sending and receiving parties must be well aligned in expectations and plan
• Process and product understood in terms of CQAs and CPPs• Take the time for detailed planning, including checklists and phase appropriate criteria
• Risks identified and controlled as best as possible.
Summary
From Clone to Commercial®20
BioProcess Technology Consultantswww.bptc.com
Thank you!
Patricia SeymourBioProcess Technology Consultants, Inc.12 Gill Street, Suite 5450Woburn, MA [email protected]
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