WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
Control, Context, and Commitment to Continuous Improvement in Biopharmaceutical Manufacturing
1
Jeffrey C. Baker, Ph.D.
Deputy Director,
Office of Biotechnology Products, CDER
United States Food & Drug Administration
WCBP 2015, Washington, DC
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The Disclaimer
This presentation represents the views and perspectives of the speaker and should not be viewed or acted upon as FDA Policy or assumed to be an all inclusive list of FDA requirements.
For official policy and guidance, contributors are directed to http://www.fda.gov/
The speaker may be contacted at [email protected]
WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
Regulation of biological products in the US
Biological products are a subset of drugs and are therefore regulated under the Food, Drug, & Cosmetic Act.
Biological products are licensed for marketing in the United States under section 351 of the Public Health Service (PHS) Act.
The PHS Act also provides authority to immediately suspend licenses in situations where there exists a danger to public health.
WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
Licensure is based upon scientific, data driven assertions
The drug is safe.
The drug is pure.
The drug is potent.
The process and facilities used to manufacture safe, pure, and potent drug are very likely to
do so reproducibly and predictably.
A BLA submission is an exercise in technical, data driven advocacy of quality assurance.
WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
“A planned set of
controls, derived
from current product
and process
understanding, that
assures process
performance and
product quality”
(ICH Q10)
Process Control Strategy
Raw Material Control
Process Monitoring
Release and Stability Testing
Training
Equipment and Facility SOPs
Inherent Material
Variability
Environmental
Stresses
Process
Capability
Critical Quality
Attributes
Quality
Assurance
Adapted from Dr. Michael Pikal, University of Connecticut
WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
Reality gets more complicated
Raw Material Control
Process Monitoring
Release and Stability Testing
Training
Equipment and Facility SOPs
Inherent Material
Variability
Environmental
Stresses
Process
Capability Quality
Assurance
Across all sites and types of business relationships!
Across All Geographies
Across the product
portfolio!
Across the product
lifecycle with continuous
improvement and learning!
Across the process train as a whole !
Critical Quality
Attributes
Across changing business drivers!
WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
Aspiration to technical excellence in an atmosphere of operational tension adds additional complexity and constraint.
WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
Risk and Complexity Drive Behaviors
Immediate
Long Term
Me Us Them
WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
Is knowledge compression risk management or a stress response?
Controlling a multivariate, probabilized, risk based design space in a Quality System that is binary: “pass’ or “fail”
Applying “Lean Principles” to management of a knowledge space leads to binary keep/drop (critical/non-critical) approach to knowledge.
Applying FMEA to communication practices compromises transparency : “there is no upside to telling them… only two things can happen: nothing and something bad. Every disclosure is a failure mode.
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WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
A good map anticipates options, paths, and outcomes and provides reproducible experiences
In order to manage residual uncertainties, an effective bioprocessing control strategy maps a performance space.
A process in control is a process that reproducibly meets expectations.
Define Demonstrate Document Maintain
WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
A control strategy is an alarm-control system
Data is tracked and monitored
Variability is sorted as relevant or not relevant
There is a predetermined response to a signal relevant t product quality
A decision is made. The merits of an alarm-control system rest not in the number of alarms or the trigger points but in the responses to the signals.
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WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
Quality
Systems
Sound Science and Effective Engineering
Lab
Data
Pilot
Data
Site
Mfg
Data
Development
Program
Tech Transfer
Package
Validation
Master Plan
The Process Flow Document
Assurance of Predictable, High
Quality Product and Process
“Architecture of Assurance”
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BLA review and the CGMP program
The original product development, process design and initial process qualification studies are evaluated as part of the BLA application review.
During a surveillance inspection investigators determine if the current manufacturing process is performing as planned and predicted.
> Is the control strategy properly targeted and working as intended?
> Is the state of control established and maintained?
> Is the identity, strength, quality, purity and potency of product on the market assured?
> How does current production compare with submitted data and predictions ?
Risk based assessment of process changes associated with continuous learning and improvement should be fully captured and accommodated by the Production Quality System.
WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
Clear understanding and communication of purpose and intent
The BLA is an exercise in data driven technical advocacy.
This advocacy needs to be data driven, risk based, patient centered, and compelling to reviewers and inspectors.
Successful sponsors focus on effective communication of relevant science and engineering practices.
“The ability to tell a good story is a competitive advantage.”
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WCBP 2015 J.C. Baker, OBP/OPS/CDER FDA
Medicine matters.
We don’t have time to wander around the valley.