ispe 2011 presentation dagmar meissner - 13jan2011
TRANSCRIPT
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PROCESS CHANGES AS PART OF THE LIFECYCLE OF A PROCESS
Dagmar MeissnerJanuary 2011
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Outline
• Defining process change• Assessing and implementing proposed
process changes• Reducing the frequency of process
changes• What went wrong? (Case studies)• Conclusions
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(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.”
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DEFINING PROCESS CHANGE
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Drug Development LifecycleDiscovery
Process Transferand Design Process Scale-Up Process Scale-up #2
and prelim. optimization and Optimization
Preparation for Commercialization
Clinical TrialsPreClinical Studies CommercializationPhase IIIPhase IIPhase I
ResearchProcess Development
Manufacturing
Drug Development
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Willingness to change a process depends on the stage of the product
COST
PD/preclin. Phase I/II Phase III Commercial Scale
FlexibilityTo Change
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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
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ASSESSMENT AND IMPLEMENTATION
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Typical Protein Manufacturing Process
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FermentorCapture Column Purification 1 Purification 2
Clarification
UF
Sterile filtration
Bulk Product
Cell Bank
Inocculation Train
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Typical Process Changes
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Cell SystemExpression SystemCell Banking System
Drug ProductExcipientsSpecificationTest methods
Drug SubstanceSpecificationTest methods
Purification/Downstream ProcessingChanges to purification stepsChanges to Scale (increased titers)
Production BioreactorCell Growth and HarvestingScale-up
Production Process Analytical/Formulation/Packaging
PackagingContainer/closure systemAdministration methodFormulation
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It walks like a duckIt quacks like a duckIt 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?
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Effect of Process Changes
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Process Change (Cell line, fermentation, downstream
processing)
Drug Substance/Drug Product
Chemical/biochemical Properties In vivo properties
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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
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Evaluate Proposed ChangesDecision 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)
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Creating a Process for a Drug Substance (DS) is an Interdisciplinary Approach
The same principle applies to the evaluation of a proposed process change
Proc
ess D
evel
opm
ent
Qua
lity
Assu
ranc
e
Faci
lities
/Eng
inee
ring
Anal
ytica
l
Valid
ation
Man
ufac
turin
g
PROCESS
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Decision Process
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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)
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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
PROCESSManufacturing
Analytical
Process Development
Quality Assurance
FacilitiesEngineering
Validation
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REDUCING FREQUENCY OF CHANGES
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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
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Available Tools
• Analytical Methods• Risk analysis (part of QbD program)• Process Analytical Technology (PAT)
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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
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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
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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))
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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
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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)
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Risk Analysis
Occurrence Detection Impact/Severity
Very high Remote Very high
High Unlikely High
Rare Moderate Moderate
Remote Likely Minor
High None
Increased Risk N
umber
Assign qualitative values for each parameter (Scale 1-10):
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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)
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FMEA - Example
Item No.
Process Step
Operating Parameter
Potential Failure Modes
Occurrence
Rating
Detection
Rating
Severity
Ranking
Risk Priority Number
Additional Controls and/or
Comments or Risk Remediation
1 Column LoadProduct
concentrationTiter too high in
load 4 4 4 64Expand 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 TemperatureFaulty temp
control
5 EquilibrationEquilibration
volume
Equil stopped too early; operator error, flow cell
error 6
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FMEA: Prioritization of Parameters
0
50
100
150
200
250
300R
PN
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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
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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 assurance32
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PAT – Example 1In-line buffer dilution with pH and conductivity control for chromatography step (isocratic or gradient)
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Conc. Acid
Salt solution
Recirc pump
WFI
cond pH
Waste
Chromatography skid
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Buffer Composition Control by Mass Flow versus PAT
Courtesy of: Michael Li, Asahi Kasei BioProcess
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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
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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
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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 :
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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
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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)
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WHAT WENT WRONG?Case Studies (n=3)
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483s – Case Study IAMAG 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 […].
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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).
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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.
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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
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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)
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Thank you!
Special Thanks to:• ISPE• Michael Li (Asahi Kasei Bioprocess)• Henriette Kuehne (Amylin)• Mayank Patel (PAXVAX)• Jörg Thömmes (Biogen IDEC)• Shelley Pizarro (Genentech)
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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
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and prioritizand prioritiz
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Backup slides
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Defining Operating RangesFor a Single Operating Parameter
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Design Space
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Experimental Data
Design Space
Approved ProcessModeling used to support Design Space Characterization
Looking at all critical process parameters and material attributes
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PAT – Example 1
Courtesy of: Michael Li, Asahi Kasei BioProcess
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Interrelation between Quality Attributes and Process & Materials
Critical Quality Attributes
Inputs Outputs
Material Attributes
Process Parameters
MA1
MA2
CPP1
CPP2
CQA1
CQA3
CQA2