Title: The Value of Applying Quality by Design - Not Just Monoclonals, But Across Products and Systems
1The Value of Applying Quality by Design - Not
Just Monoclonals, But Across Products and Systems
- Tony Mire-Sluis, Executive Director, Global
Product Quality and Quality Sciences
2There Are Four Basic Principals for QbD
- Design
- Develop
- Monitor
- Improve
3There Are Four Basic Principals for Developing
Quality Systems
- Plan
- Execute
- Monitor
- Improve
4The Principles of QbD Are Not Unique to a Product
or Process!
5We Dont Need to Invent Something New Dr.
Deming Figured It Out In 1950
6The Principles of QbD are not a Regulatory
Strategy but Provide Business and Quality
Benefits
- QbD principles can provide
- Improved success rates for process and product
development through increased understanding - Reducing risks
- To patients, process failures, method invalids,
NCs etc. - Improving product quality
- More robust and consistent processes
- Less manufacturing failures
- Reduced complaints
- Continuous improvement
7How the Basic Principles Can Be Applied
Regardless of Product or Process
Post approval Lifecycle Management
Effective and Efficient Control Strategies
Establish Design Targets
Establish Design Targets
Develop Process to Meet Targets
Understand Process
- Integrated Controls
- Operational
- Testing
- Raw materials
- Continuous verification
Molecular Assessments And Engineering
Design space
Risk based control strategy
Fit for purpose processes
Efficient Continuous Improvement
Design
Develop and Execute
Monitor
Improve
8Molecular Design Can Be Applied Across Any
Product Class Our Understanding of CQAs goes
Beyond MAbs
- Sequence hot-spot analysis
- Engineering to impact CQAs
- Fit to FIH platform
- High productivity
- Optimal signal peptide usage
- Downstream process performance
- Compatibility with FIH platform formulation
- pH-jump study
- Serum based pH jump
- Particulation propensity
- Develop predictive particulation assays
- Degradation specific screens
- Develop degradation-rate database and Arrhenius
models to enable decisions based on predicted
rate at 2-8 ?C - Concentration viscosity screen
- Engineer in low-viscosity attributes by
incorporating principles of QbD
9Examples of Assays Used During Molecular Design
to Select Best Lead Candidates
t24h
pH jump study performed to eliminate candidates
with potential issues in vivo
Sequence binning used to identify antibodies with
diversity and desirable attributes
Expression Assessment to achieve high productivity
Viscosity testing for ease of SC delivery at high
concentration
10Design Principles and their Benefits do Not Just
Apply to Product or Process
- Product
- Manufacturing Process
- Equipment
- Facility
- Utilities
- Raw Materials
- Containers
- Transport
11Risk Assessment is a Critical Element of the
Development of Many Systems
- Risk Assessments can be applied across many
different programs - Critical Quality Attributes
- Equipment selection and maintenance
- Non conformances
- Facility design
- Packaging
- Supply
- Finance
12Appropriate Monitoring is Also Neither Product or
Process Dependant
- Monitoring and analysis of data should be applied
regardless of the product, process or system
being used - Incoming Inspections
- During the process
- Lot Release
- Stability
- Non conformances
- Complaints
- APR
- Frequent cross functional assessments
13Applying QbD Principles to Raw Materials A Case
Study of Vials
14Raw Materials are an Essential part of both
Product and Process
- Raw materials and their controls are vital at all
stages of manufacture - In fact, they can make up the product itself
beyond just the protein water, buffering
components, tonicity agents, polysorbate, primary
packaging etc. and QbD principles apply to RMs at
all stages of manufacture - Application of the principles is carried out on a
risk based approach depending where they are in
the manufacturing process (downstream or
upstream) or how much they impact the quality of
the product (e.g. media components are downstream
away from the final product but can have a
tremendous impact on protein CQAs during
fermentation)
15It is Essential to Understand a Raw Material -
Design
- Initial Characterization
- Raw material itself
- Design appropriate Analytical Methods
- Lot to lot variability
- Set Specifications
- Interaction with process
- Impact to Critical Process Parameters
- Affect on Product
- Impact on Critical Quality Attributes
- How much is required depends on where in the
process the RM is used - Managing Change over time
- Supplier need to communicate when changes are
proposed / made - The company needs to evaluate if changes matter
to their processes ideally before they are
implemented
16What do you Need to Characterize in a Raw
Material? What is There
- Relying on the manufacturers CoA is often not be
enough - One needs to understand all the components of the
raw material as the manufacturer may not even
measure the parameters you require control of - Product Heterogeneity
- Additives
- Preservatives
- Degradation products
- Contaminants
17What do you Need to Characterize in a Raw
Material? What Might Appear
- There must be a thorough understanding of the
degradation pathway of the raw material relying
on an expiration date from the manufacturer may
not be enough - The impact of degradants on the product or
process is needed - There needs to be an understanding of the use of
raw materials over time and the impact to the
expiration date of the product - The impact of handling the raw material over time
must be assessed (aliquoting, light, temperature,
oxygen etc.)
18Supplier Management is Necessary for Ensuring Raw
Material Quality
- Expectations must be clear
- We need to understand the manufacturing processes
for raw materials so we know how they could
impact product quality, allow us to set
appropriate specifications and help us during
investigations Design and Monitoring - Notification of change - Monitoring
- Thorough investigation of defects Continuous
Improvement - Supplier site visits are key
- Audit of Quality system - Plan
- Technical visits to understand processes, process
capability and identify indirect product contact
materials - Design - Technical visits to evaluate changes and ensure
that they are managed properly - Monitor
19One can Use a Risk-Based Approach to Segment the
Supplier Base
Material and Supplier Criticality Assessment
- Quality Assessment 40
- Technical Assessment 40
- Business Assessment 20
Low Medium High
Preferred Audits every 4 year Audits every 4 year Audits every 3 year
Standard Audits every 4 year Audits every 3 year Audits every 2 year
Marginal Audits every 3 year Audits every 2 year Annual Audits
Supplier Performance Rating
- Quality 50
- Delivery 30
- Service 20
CAPAs manage up or out plans for marginal
suppliers
20Vial FMEAs were conducted by a Global team -
Design
- Vials are an essential part of a product in which
they are filled, critical to product quality and
close to the patient - FMEAs were conducted at fill finish lines across
internal and contractor manufacturing sites - Risks were identified, mitigation plans
developed, and CAPAs documented completion - Identifying what were the
- important attributes for vials was
- essential to develop appropriate
- specifications
- Extractables/Leachables
- Interactions with equipment
- Handling and Storage
- Possible glass defects
21An Example of Specifications Required for Vials
Design/Monitor
- Finish Inner Diameter (ID)
- Finish Outer Diameter (OD)
- Lip/Flange Height
- H Dimension
- Vial Length (Height)
- Vial Outer Diameter
22Incoming Inspections of Raw Materials to Assure
Specifications are Met
IQA Receipt of Material
Evaluate Disposition
Sampling
Inspection
-
-
- IQA review received docs (CoA, Receiving
Inspection Report)
Sample as per SOP
IQA inspect samples as per SOP
-
-
- IQA perform batch evaluation and disposition of
material
23Inspection for Tubular Glass Vials Includes over
50 Criteria
- Defect Classification Critical Visual Examples
- Wrong component
- Split on vial interior with nonremovable, marked
deposit - Internal Airline Elongated gaseous inclusion
that appears as a vertical line. - Chipped (Broken Finish) (if the seal is
compromised) A finish that has actual piece of
glass broken out of it. - Contamination Foreign substance (particle,
stain, dirt) deposited on the internal surface - Crack Fracture that penetrates completely
through the glass wall - Malformed Finish is grossly distorted or
deformed, if seal is compromised (lip malformed).
24Automated Inspection of Vials Prior to Lot
Release - Monitor
Neck Inspection Camera C1/C6
Body Inspection Camera C2/C7
Cap Inspection Camera C4/C9
Base Inspection Camera C3/C8
25A Global Primary Container Team was established
to Monitor Vial Performance
- The Primary Container Team
- Comprises of all Amgen site, quality and
technical groups - Tracks key glass metrics from the glass process
monitoring, NCs, and Product Complaints - Identifies and implements Glass Handling best
practices - Alignment to new equipment requirements
- Identifies Quality/Process improvements and
container standardization
26Embedding the Quality System - Improve
- Primary packaging issues are monitored globally
and lessons learned applied - A governance body is covering vial platform
projects and tasks - A global team is ensures Amgen wide scope and
communication oftasks and work streams - The team monitors Amgen production and CMC
activities
The creation of a global team allows for
continuous monitoring and improvement
27In Summary
- The basic principals of QbD can (and should) be
applied across product types as well as multiple
processes and systems - We dont have to label it QbD and treat it like
something special, it just makes good business
sense and we have been doing it to a certain
extent anyway and it can be applied to all
products and across multiple systems/processes - Using the principals of QbD in many cases does
not require a great deal of cost mostly good
planning, increased understanding and more
successful execution - A risk based approach can be used to help
appropriately focus QbD efforts