PPQ-to-Approval Timelines—

Acceleration Approaches at BMS

Marcus Boyer Kristen Manchester

Bristol-Myers Squibb Bristol-Myers Squibb
Associate Director Sr. Engineer
Process Life-cycle Management Drug Substance Process Champion
Syracuse, NY Syracuse, NY
USA USA
Discussion Points

• Distinction between continuous and ongoing or

continued process verification
• How does continuous process verification differ from
traditional process validation?
• Advantages and challenges of continuous process
verification
• BMS case-studies: Departure from traditional process
validation

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 Continuous versus Ongoing Process Verification
Continuous Ongoing or Continued
Process Verification Process Verification
• An alternative approach to • Assuring that during routine
process validation in which production the process remains
manufacturing process in a state of control.
(EU Draft Guideline on process validation for the
performance is continuously manufacture of biotechnology-derived active
monitored and evaluated. substances and data to be provided in the
(ICH Q8) regulatory submission) (FDA Guidance for
Industry; Process Validation: General Principles
and Practices)

Quality Target Process

Product Profile Reproducibility

Critical Quality
Attributes

Manufacturing
Control
Strategy http://cdex-inc.com/
http://cmc-
consultants.com/2014/10/stat
http://vietnaminvestigat
istical-process-control/
ion.com/verification/ http://www.acdlabs.com/solutions
/pharma/verification_nmr/
3
Traditional Process Validation (Eudralex Annex 15)
• Use of a minimum of three consecutive batches
manufactured under routine conditions to confirm
reproducibility during process performance
qualification (PPQ) is generally considered
acceptable.
• A process validation protocol should leverage
development data or documented process
knowledge to define:
• Critical quality attributes
• Critical process parameters
• Associated acceptance criteria

4
Continuous Process Verification (Eudralex Annex 15)
• Alternative approaches may be justified where the
control strategy demonstrated that the process is
capable of consistently delivering quality product with a
high degree of assurance during development.
• The control strategy should define:
• Incoming materials
• Critical quality attributes
• Critical process parameters
• Regular evaluation of the control strategy
• Process Analytical Technology and multivariate
statistical process control may be used as tools for
verification.
5
Challenges of Continuous Process Verification
• Manufacturers and regulators share the goal of increasing the
speed of getting drug to patients
Process
Knowledge Risk-Based Speed
+ Continuous to
Robust Verification Patients
Monitoring

• True continuous process verification may be difficult to

implement, especially for accelerated programs due to:
• Limited time for process development and characterization
• Limited manufacturing experience to set meaningful statistical
process control limits
• Maturity of data collection and monitoring systems
• Concurrent review and accelerated approval timelines may
limit launch supplies
Departure from Traditional Process Validation
• BMS has recently commercialized multiple molecules with
“breakthrough” or “fast track” designation; working with
Health Authorities on low-risk acceleration within the
traditional framework
• Extension of risk-based acceleration begins to approach
the continuous process verification paradigm
• A hybrid approach requires a substantial amount of
product and process knowledge from manufacturing
experience
• Use of platform technology to support development
• Widespread implementation of statistical process
control program(s) for ongoing process verification
• Especially useful for post-commercial process and facility
changes
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Equipment Grouping

CASE STUDY 1

8
BMS Case Study 1: Equipment Grouping
3x 1x 1x 3x 1x 1x
Risk-based
Approach

1x 1x 1x Equivalency: N/A N/A N/A

• Design and installation data

Traditional “n+2” • Operability data (temp
Grouping
Approach: 8 PPQ profiles, addition volumes, Approach:
kLa)
Runs 5 PPQ Runs
• Data from previous products

• BMS has submitted applications with process performance

qualification (PPQ) data from a subset of bioreactors, plus
equipment equivalency data.
• US approval of first such submission for a new facility
resulted in post-marketing commitments to provide additional
data.
• Data could have been monitored or reported under an
ongoing process verification plan.
Extension of Equipment Grouping Strategy
• No requirement for all bioreactors, no replication
within one train
• 8-lot campaign becomes 3, preserving the 3-lot
paradigm
• Justification for this approach may be stronger
when the facility has been previously qualified for
other product(s)

3x 1x 1x 1x 1x 1x
Risk-based
Approach

1x 1x 1x Equivalency: N/A N/A N/A

• Design and installation data

Traditional “n+2” • Operability data (temp
Grouping
Approach: 8 PPQ profiles, addition volumes, Approach:
kLa)
Runs 3 PPQ Runs
• Data from previous products
Prospective Capacity Expansion Planning

CASE STUDY 2

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BMS Case Study 2: Prospective Capacity Expansion Planning

• Manufacturing capacity expansion often necessary as demand grows

• Variations for expansion require significant time
• Initial file might be accelerated if the path to expansion is smoothed
• BMS proactively discussed within-site expansion with FDA during
initial review
• FDA agreed to inspect manufacturing area not included in initial file
• Supplement was ready and agency expected submission as soon
as initial approval was granted

http://www.bluearbor.com/blog/tag/fact
ory-workers-jacksonville-nc/
Extension of Proactive Capacity Expansion Planning
• Within-site expansion using continuous process verification
• Limit the scope of initial full-scale demonstration to speed completion
• Comparable equipment, people, and analytical tests across site
• Leverage ongoing process verification knowledge from statistical
process monitoring program
• Approval based on a continuous process verification protocol would be
low-risk
• Post-approval scale up or tech transfer using continuous process
verification
• Example: launching at clinical scale speeds initial file
• Continuous process verification protocol for post-approval scale-up or
transfer measured against clinical and launch lots

http://www.bluearbor.com/blog/tag/fa http://videohero.com/easy-
ctory-workers-jacksonville-nc/ video-sales-letter-is-easy/
Risk-Based Stability Requirement

CASE STUDY 3

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BMS Case Study 3: Risk-based Stability Requirement

• Drug substance (DS) and drug product (DP)

stability data often on the critical path for CMC
file
• A year may pass between start of DS
production and 6 month stability data http://www.binaryoptionswire.com/launching-risk-
based-supervision-framework-cysec/

• Especially for capacity expansion filings, stability profile may be

well established and favorable
• Low risk that comparable DS material from new site will have a
different stability profile
• Even lower risk that unchanged DP process will interact with
new DS site to produce a different stability profile
• BMS submitted a new DS site without DP stability data
• Data collection in parallel with review
Extension of Risk-based Stability Requirement
• A comparable product has a
low risk of a different stability
profile
• Submit variation based on time
zero data (release and
characterization results)
• Example: No DS stability data
at time of filing for DS site
http://www.bigvisible.com/wp-content/uploads/2013/08/
change
• No DP data
Conclusions

• To accelerate approval of exciting new drugs, BMS

has employed risk-based compression of traditional
process validation data requirements.
• These modest departures remain within the current
paradigm, but offer tangible timeline benefits.
• Further defendable options for acceleration exist
which begin to approach the continuous process
verification paradigm.