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The Use of Critical Process Parameters and Quality By Design to Improve
Biopharmaceutical Product Quality
Howard L. Levine, Ph.D.BioProcess Technology Consultants, Inc.
Presented atBioProcess International Asia Pacific
Mumbai, IndiaOctober 21, 2008
and2008 PDA Development and Regulation of Clinical
Trial Supplies ConferenceCambridge, MA
November 11, 2008
From Clone to Commercial®
What is Quality by Design?
“Means that product and process performance characteristics are scientifically designed to meet specific objectives, not merely empirically derived from performance of test batches.”
The product is designed to meet patient needs and performance requirements
The process is designed to consistently meet product critical quality attributes
The impact of starting raw materials and process parameters on product quality is well understood
The process is continually monitored, evaluated and updated to allow for consistent quality throughout product life cycle
Critical sources of variability are identified and controlled through appropriate control strategies
Ref: H. Winkle, BPI Conference, Oct 1 – 4, 2007
From Clone to Commercial®
Defining Critical Quality Attributes (CQAs)
“…those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product…” (Q6B)
Can these attributes be properly defined for biologics?
• Often difficult due to complexity of biologic products
• Default is to look at many attributes
QbD focuses only on critical product attributes and the impact of those attributes across their ranges on safety and efficacy
• Product specifications based on mechanistic understanding of how formulation and process factors impact product performance
Need to develop a design space to be documented in application which is based on CQAs
From Clone to Commercial®
What are Critical Process Parameters (CPPs)
CPPs are independent process parameters most likely to affect the quality attributes of a product or intermediate
CPPS are determined by sound scientific judgment and based on research, scale‐up or manufacturing experience
CPPS are controlled and monitored to confirm that the impurity profile is comparable to or better than historical data from development and manufacturing
Quality attributes derived from CPPs include:
• Chemical purity
• Qualitative and quantitative impurities
• Physical characteristics
• Microbial quality
From Clone to Commercial®
QbD for Small Molecules vs. Biologics
Process control more difficult to define and implement
Process control readily defined and achieved
Characterization Complex Readily Characterized
Quality Attributes difficult to determine; defined late in product development
Quality Attributes determined early in product development
Variability derived from Drug Substance
Variability derived from formulated Drug Product
Biologic ProductsSmall Molecule Drugs
From Clone to Commercial®
The Application of QbD to Biologic Products
Quality by Design is an important element in achieving desired state, however, we’re not there yet
• Determining relationship between
Quality specifications and safety or efficacy results
Clinical Activity and Critical Quality Attributes
Product Attributes and Critical Process Parameters
Process Validation and the Design Space
• Insufficient Data on “Key” versus “Critical”
• Strong Conservatism on both sides
• “Traditional” development and validation approaches can be applied to QbD, especially in identifying CPP and defining the Design Space
From Clone to Commercial®Ref: B. Davis, FIP Conference 2007
Knowledge Space
From Clone to Commercial®
EstimatesBased on
Experience
Refined Based on Preclinical
and Safety Data
Refined Based on
Clinical and Process Data
Continually Reviewed and Refined Based on Increased
Clinical
Preclinical Phase 1 Phase 2 Phase 3 Post Approval
Defining CQAs Throughout a Product Life Cycle
Critical aspects throughout product life cycle define what is needed:To release productTo control the processFor post‐approval changes
From Clone to Commercial®
Linking Design Space and Control Strategies
Design space is based on our Knowledge Space
Control Strategy: Maintaining the process within the Design Space
Design Space is not intended to define critical attributes, rather these will follow from the “process flow”
The control strategy for a CQA is the selection and combination of different types of controls applied to the manufacturing process and associated systems to assure the right product quality at an acceptably low level of risk of manufacturing failure
From Clone to Commercial®
Defining Control Strategies
From Clone to Commercial®
Ran
ge o
f Raw
Mat
eria
lA
ndFa
cilit
y A
ttrib
utes
Process Designed toLimit Product Variability
Define API in terms of CQAs
Identify CPP that affect the CQAs
Determine range of each CPP that produces acceptable product to establish the Design Space
CPP Drive CQA to Create the Design Space
From Clone to Commercial®
Comparing CQAs and CPPs
Graphic adapted from Kozlowski and Swan (2006)
Process validation should provide “documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes…” (ICH Q7A)
Critical Quality Attributes derive from …… Critical Process Parameters
From Clone to Commercial®
Design Space: Identification of CPPs
Using data from development identify parameters that affect the defined product characteristics, for example• Level of key impurity• Desired glycoform content• Desired yield
Impurity 1
Gly
cofo
rm
Yield
Column Loading CapacityFl
ow R
ate
pH
From Clone to Commercial®
Design Space: Process Optimization
Use Factorial Analysis without interactions to map boundary conditionsUse Full Factorial to fully define response surfaces and examineinteractions
Column Loading Capacity
Flow
Rat
e
pH
Column Loading Capacity
Flow
Rat
e
pH
From Clone to Commercial®
Summarize results of multiple experiments to define response surface
Validate the process within the Design Space to demonstrate consistent production of product with desired characteristics
Design Space: Putting it All Together
Impurity 1
Gly
cofo
rm
Yield
[Fe] in Media
Agi
tatio
n R
ate
Final OD
Design Space
From Clone to Commercial®
Application of QbD to Cell Culture
Optimizing clone selection to achieve maximal product titer within a Design Space
Potential Critical Process Parameters in cell culture production…
• Temperature
• pH
• Agitation
• Dissolved oxygen
• Medium constituents
• Feed type and rate
From Clone to Commercial®
Optimization of Cell Culture
Many potential process parameters can impact the Critical Quality Attributes of the cell culture process, including:
• Cell viability and number
• Product titer
• Product Characteristics (e.g. glycosylation)
• Impurity profile
Identify those which are critical through process development evaluating impact of each parameter on the CQA
Create Design Space by optimization of these parameters through a two factorial design of experiment
From Clone to Commercial®
Optimization of Cell Culture Conditions
Optimization performed using SimCellTM technology from BioProcessors Corp.
50 conditions (10 T x 5 pH)n=9 (450 total chambers)
Two factorial design monitoring product titer (yield) as a function of pH and temperature
From Clone to Commercial®
Mapping Downstream Process Design Space
Critical Process Parameters in column chromatography…• Column bed height and packing efficiency• Media selectivity• Dynamic capacity for product and total protein• Buffer conditions (pH, conductivity)• Temperature• Flow rate ranges• Sample load ranges• Media particle size and size range
All impact product purity and yield
From Clone to Commercial®
Defining Ion Exchange Column Conditions
Purification of a natural protein by anion exchange chromatographyAnion exchange column equilibrated with 10 mM TRIS‐Phosphate bufferVariation of load solution pH will impact product yield and purity
From Clone to Commercial®
Anion Exchange Column Yield and Purity
Best yield at pH 7.0, however, additional contaminant present in pool not seen at higher pH’s
Can subsequent process steps remove this contaminant?
Product
Contaminant
From Clone to Commercial®
Final Product Purity
Subsequent purification of Anion Exchange Column pool removes process contaminant regardless of pH at which Anion Exchange column is run
A – Anion exchange column pool, pH 7.0B – Anion exchange column pool, pH 8.6
C – Column 2 pool following loading with “A”D – Column 2 pool following loading with “B”
From Clone to Commercial®
Summary and Conclusions
Application of QbD to biopharmaceutical products is often difficult reflecting the complexity of these products
Process development of biologics has always included some aspects of QbD, including science‐based decisions and the use of scale down process models
Once optimized, CPP ranges can be used to define the design space for biologic manufacturing processes
From Clone to Commercial®
Summary and Conclusions
Combining DOE with science‐based decisions can decrease the time required to optimize production, speed the development of robust processes, and reduce risk in biologics product development
Using QbD can facilitate the technology transfer by describing the design space for complex products and allowing process variability
From Clone to Commercial®
AcknowledgementsBioProcess Technology Consultants
• Sheila Magil, Ph.D.
• Susan Dana Jones, Ph.D.
• Alex Kanarek, Ph.D.
BioProcessors, Inc.
• Cell culture optimization
Neurobiological Technologies, Inc.
• Chromatography optimization
From Clone to Commercial®
THANK YOU!
For more information, contact
Howard L. Levine, Ph.D.
BioProcess Technology Consultants, Inc.
289 Great Road, Suite 303
Acton, MA 01720
978‐266‐9153
978‐266‐9152 (fax)
www.bioprocessconsultants.com
