2. Outline
• Defining process change
• Assessing and implementing proposed
process changes
• Reducing the frequency of process
changes
• What went wrong? (Case studies)
• Conclusions
2
3. (Charles Darwin, 1809 – 1882)
“It is not the strongest of the species that survives, nor
the most intelligent that survives. It is the one that is the
most adaptable to change.”
3
5. Drug Development Lifecycle
Discovery
Process Transfer
and Design Process Scale-Up Process Scale-up #2
and prelim. optimization and Optimization
Preparation for Commercialization
Clinical Trials
PreClinical Studies CommercializationPhase IIIPhase IIPhase I
Research
Process Development
Manufacturing
Drug Development
6. Willingness to change a process
depends on the stage of the product
6
PD/preclin. Phase I/II Phase III Commercial Scale
Flexibility
To Change
7. Changes
• Corrective Action
• Out of spec product (OOS)
• Scale-up/design issues
• Continuous Improvement
• Evolutionary process improvements
• New production platform
• Technology transfer from another company
• Improved process quality (cost)
• New administration method/packaging
• Innovation
• New technologies, scientific advances
7
9. Typical Protein Manufacturing Process
4
Fermentor
Capture Column Purification 1 Purification 2
Clarification
UF
Sterile filtration
Bulk Product
Cell Bank
E-14
Inocculation Train
10. Typical Process Changes
10
Cell System
Expression System
Cell Banking System
Drug Product
Excipients
Specification
Test methods
Drug Substance
Specification
Test methods
Purification/Downstream
Processing
Changes to purification steps
Changes to Scale (increased titers)
Production Bioreactor
Cell Growth and Harvesting
Scale-up
Production Process Analytical/Formulation/Packaging
Packaging
Container/closure system
Administration method
Formulation
11. It walks like a duck
It quacks like a duck
It is a duck
……… but is it the same duck???
Did the product change?
identity strength quality purity
How did it change and is it relevant?
11
12. Effect of Process Changes
9
Process Change
(Cell line, fermentation,
downstream processing)
Drug Substance/Drug Product
Chemical/biochemical Properties In vivo properties
13. Product Attributes to Verify
• Chemical Biochemical Properties
• Impurities
• Clearance (DNA, viral, HCP)
• Molecular weight
• Folding/disulfide bonds
• Glycosylation
• Aggregation
• Activity/Bioassay
• Physical Characterization
• Stability
• Etc.
• In vivo Properties
• Pharmacokinetics
• Safety
• Efficacy
13
14. Evaluate Proposed Changes
Decision if the proposed change can/should
be implemented
• Teams in place to evaluate proposed changes
and impact on product
• Implemented Decision Tree
• Risk Management
• Communication critical
“That natural selection generally acts with extreme slowness I
fully admit.” (Charles Darwin)
14
15. Creating a Process for a Drug Substance
(DS) is an Interdisciplinary Approach
The same principle applies to the evaluation of a proposed process change
ProcessDevelopment
QualityAssurance
Facilities/Engineering
Analytical
Validation
Manufacturing
PROCESS
17. Implementing Change
• Change control in place
• Realistic timelines and resource allocation
• Know the agency and their expectations
• Communication
• Good science
“The degree of regulatory flexibility is predicated
on the level of relevant scientific knowledge
provided.”
(ICH 8 guidelines)
17
18. Basis for Success
• Crossfunctional team
• Project Management
• Alignment of
objectives
• Effective
communication
• Early involvement of
critical group members
• Clear process in place
for evaluating and
implementing a
proposed change
PROCESS
Manufacturing
Analytical
Process
Development
Quality
Assurance
Facilities
Engineering
Validation
20. How to reduce frequency for changes
• Invest time upfront
• Analytical methods early in place
• Realistic release specifications
• Scientific understanding of process
• Proper characterization of product
• Process development and scale-up driven by science and
engineering rather than deadlines
• Determine key points where implementation is sensible (e.g.
before Phase III start), and combine multiple changes into
one submission in order to reduce cost
• Carefully evaluate the necessity for change
• Clear PRODUCT specifications
• Dosage form and size
• Concentration
• Administration method
20
21. Available Tools
• Analytical Methods
• Risk analysis (part of QbD program)
• Process Analytical Technology (PAT)
21
22. Analytical Method Development
• On the critical path for process development
• Should be done early, however, is often
neglected
• Proper characterization essential for process
optimization, technology transfer, scale-up
• Some informal analytical methods may be
developed within PD
• Qualified method in terms of accuracy,
reproducibility, linearity important for successful
data analysis
23. A Quick Word on Specifications
• Specifications should be as wide as reasonably
possible given the stage of the development
• Scaled up process may need wider specifications
than bench scale
• Don’t pick best case product for preclinical safety
studies but “realistic case”
• Caution to set specifications too early and too
tight
• Continue to gather data FIO with the goal of
setting some specifications later in time
24. From the FDA Tool Box: QbD
Quality by Design (QbD)
“[…] The demonstration of greater
understanding of pharmaceutical and
manufacturing sciences can create a basis for
flexible regulatory approaches “
(from ICH Q8 (R2))
24
25. Risk Analysis
• Large component of QbD
• Goal: identify and prioritize weaknesses of
process in terms of process parameters
• Outcome:
• List of process parameters that are considered
high risk;
• Ability to improve process robustness;
• Reduction of OOS and associated corrective
actions
25
26. Risk Analysis
• FMEA (Failure Mode and Effect Analysis)
• Team Approach
• Performed at every unit operation step
• Critical analysis of operating parameters
• Evaluation of risk of failure/process upsets and
potential impact
• Detection (D)
• Occurrence (O)
• Severity (S)
• Based on historical data from small and large
scale if available (data mining)
27. Risk Analysis
Occurrence Detection Impact/Severity
Very high Remote Very high
High Unlikely High
Rare Moderate Moderate
Remote Likely Minor
High None
IncreasedRiskNumber
Assign qualitative values for each parameter (Scale 1-10):
28. Risk Analysis (cont’d)
Outcome:
A means to prioritize the level of risk
associated with a specific step or
process/material parameter
Risk Priority Number, RPN
RPN = D x O x S
(Detection x Occurrence x Severity)
29. FMEA - Example
Item
No. Process Step
Operating
Parameter
Potential
Failure Modes
OccurrenceRating
DetectionRating
SeverityRanking
Risk
Priority
Number
Additional Controls
and/or Comments or
Risk Remediation
1 Column Load
Product
concentration
Titer too high in
load 4 4 4 64
Expand design space for
load concentration
2 Elution pH
Failed pH probe
solution prep
error 6 6 6 216
3 Elution conductivity
Failed probe;
solution prep
error 2 5 7 70
Consider in-line
conductivity
sensor/alarm; expand
design space
4 Elution Temperature
Faulty temp
control
5 Equilibration
Equilibration
volume
Equil stopped too
early; operator
error, flow cell
error
6
31. Outcome of FMEA
• Increased understanding of process
• Critical quality attributes
• CPP (Critical process parameters)
• CMA (Critical material attributes)
• Safe operating ranges
• Partial understanding of design space
• Prioritized punch list of equipment/process
issues
• Prioritized list of operating parameters to
expand design space
32. Process Analytical Technology
“PAT is a system for designing, analyzing,
and controlling manufacturing through timely
measurements of critical quality and
performance attributes of raw and in-process
materials and processes with the goal of
ensuring final product quality.”
www.fda.gov/AboutFDA/CentersOffices/CDER/ucm088828.html
"real time“ quality assurance
32
33. PAT – Example 1
In-line buffer dilution with pH and conductivity control for
chromatography step (isocratic or gradient)
33
Conc. Acid
Salt solution
Recirc pump
WFI
cond pH
Waste
Chromatography
skid
35. PAT Example: chromatography
Gradient control for the separation of trypsinogen and ribonuclease A
using IEX chromatography using mass flow control versus PAT based
on pH and conductivity
Courtesy of: Michael Li, Asahi Kasei BioProcess
Chromatogram
using Mass
Flow
Chromatogram
using PAT
36. PAT – Example 2
• Continuous monitoring system for a protein
refolding step
• Goal: Consistency in product quality and
process performance across batches
• Protein: Recombinant human endothelial growth
factor (rhVEGF)
• Based on understanding of oxygen needs during
the reaction and its impact on quality
• Monitoring %DO maintaining constant oxygen
transfer KLa across scales 3L, 2,000L, 15,000L
37. Protein Refolding Using PAT
Courtesy of: Shelly Pizarro, Genentech
Experimental Setup:
Control of O2/N2 sparging based on DO profile in reactor at constant kLa
:
38. Protein Refolding Using PAT
Courtesy of: Shelly Pizarro, Genentech
Refold reaction:
• Reduction of monomers over time
• Creation of main peak (rhVEGF)
• After 3-6 hrs oxidized and misfolded
species appear
• Process Analytical Tool: DO
Stop reaction at specific point in DO
profile rather than just time to minimize
misfolds
39. PAT Summary
• PAT increases robustness of process
by controlling key parameters directly
• Reduced frequency of OOS
• Increased process understanding
• It comes at an increased cost
(development time, equipment cost,
validation)
39
41. 483s – Case Study I
AMAG Pharmaceuticals, Inc.
• Engineering modified wiring connections on
the same cooling relay which services the
Clean Room complex . This change caused
the relative humidity in the Clean Room
complex to exceed the established
specification […]. Therefore, Production and
Quality Control approved the relative humidity
specification change to XX %. A change
control was not executed to scientifically
evaluate how this specification change would
affect operations and quality of the Clean
Room […].
41
42. 483s – Case Study II
• Applied Laboratories Inc.
• Your change control procedure […] was found
to lack provisions for complete documentation
of the nature and approval of production and
process changes, (FDA-483 #14) as required by
21 CFR 820.70(b).
42
43. Case Study III
Nature Biotechnology 26, 592 (2008)
(by George Mack)
• FDA balks at Myozyme scale-up
• Genzyme ran into a snag in April [2008] when the
US Food and Drug Administration (FDA) rejected
its application to produce Myozyme
(alglucosidase alfa, rhGAA) in its 2,000–liter-scale
facility under the same approval authorization
given for its 160-liter-scale plant. The FDA says
the carbohydrate structure of the products
manufactured at each scale differs and thus the
2,000-liter product requires a new biologic license
application.
43
44. Myozyme becomes Lumizyme after
biologics scale-up
• In February 2009, Genzyme was scheduled to
launch the same biologic under two different
names in the US after the FDA decided the
drug produced at 2000L was considerably
different to the 160L version.
• Approval for Lumizyme was gained in May
2010 (after additional delays due to mfg
issues)
15 month delay
44
45. To Conclude
• Don’t be afraid of change, it is part of evolution
• Carefully evaluate and plan a process change
• Implement strategies for risk management
• Have procedures in place (documentation, validation,
additional preclinical or clinical studies, etc)
• Work with FDA
• Use scientific knowledge, historical data, experimental
design, and common sense
FDA and Industry have a common objective to ensure that high quality
pharmaceutical products continue to be available to the public.
(from: PAT workgroup presentation)
45
46. Thank you!
Special Thanks to:
• ISPE
• Michael Li (Asahi Kasei Bioprocess)
• Henriette Kuehne (Amylin)
• Mayank Patel (PAXVAX)
• Jörg Thömmes (Biogen IDEC)
• Shelley Pizarro (Genentech)
47. References
• ICH Q8R2 guidelines (2008) - http://www.ich.org/cache/compo/276-254-1.html
• ICH Q9 guidelines (2005) - http://www.ich.org/cache/compo/276-254-1.html
• Maximizing Uptime for Mission-Critical Manufacturing Units; By Gary
Shamshoian, P.E., Genentech, Inc., and Don Nurisso, P.E., EYP Mission Critical;
http://www.pharmamanufacturing.com/articles/2007/008.html;
• Change within design space is not a regulatory change: Genentech official.
http://www.thefreelibrary.com/Change+within+design+space+is+not+a+regulatory+
change%3a+Genentech+...-a0174973741
• Use PAT to Dilute Buer from Concentrate with a Linear pH Gradient for
Downstream Bioprocessing. Michael Li, Hiroyuki Yabe, Shree Jariwala, and
Tomo Miyabayashi Asahi Kasei Bioprocess; Poster Presentation at BPI conference
9/2010
• Biomanufacturing process analytical technology (PAT) application for
downstream processing: Using dissolved oxygen as an indicator of product
quality for a protein refolding reaction. Shelly A. Pizarro, Rachel Dinges, Rachel
Adams, Ailen Sanchez, Charles Winter Biotechnology and Bioengineering
Volume 104, Issue 2, pages 340–351, 1 October 2009
51. Design Space
51
Experimental Data
Design Space
Approved Process
Modeling used to support
Design Space Characterization
Looking at all critical process parameters and material attributes
52. PAT – Example 1
Courtesy of: Michael Li, Asahi Kasei BioProcess
53. Interrelation between Quality Attributes
and Process & Materials
Critical Quality
Attributes
Inputs Outputs
Material Attributes
Process
Parameters
MA1
MA2
CPP1
CPP2
CQA1
CQA3
CQA2
