Quality by Design: A Case Study on Why You
Should Care
Clinton Weber, NNE Pharmaplan
1
Summary of Industry QbD History
- From Regulators & Industry
FDA, New initiative about Science and Risk Based Approach, 2002 – 2004,
cGMP for the 21st Century
New paradigm of ICH Q8, Q9 & Q10
ISPE – To lead global innovation and change in pharmaceutical technology
and processes
GAMP®5: A Risk-Based Approach to Compliant GxP Computerized Systems
New ISPE Baseline Guide for Verification of Pharma Manufacturing Systems
Expected in 2010:
New Process Validation Guideline from FDA & EMEA
Case Study Background
•
•
Global Pharmaceutical Manufacturing company
Over 12 sites world wide
•
Product and Services portfolio:
• Generics, Biosimilars, APIs, Medical Devices, Crossover
products, CMO services
•
April, 2009 FDA Inspection of one site included
observations related to process validation and process
control
•
Subsequent October, 2009 Inspection of another site
yielded significant observations on process validation, and
lack of science and risk-based approaches
Case Study Warning Letter Language
“You have not provided a scientific rationale to justify that the mixing studies
conducted for Product X and Product Y are adequate and fully representative of the
mixing processes for the other (b)(4) products.
In addition, you have not identified the component attributes (e.g., solubility and
viscosity) and process parameters (e.g., speed, temperature, and pH)
that are important to produce a solution for all (b)(4) products. ”
“We note that your response is also inadequate because you have not provided the
statistically and scientifically sound rationale for the application of the solution tank
mixing validation matrix.”
“Different XYZ solutions contain different chemical ingredients, different excipients and
potentially different critical process parameters. The potential critical process
parameters like: pH, temperature, (b)(4) mixing time and mixing speed
have not been identified and evaluated. The "worst case" validation approach
utilized does not support the XYZ solutions manufacturing processes performed at your
facility.”
R&D Relationship to Manufacturing
Operations
R&D
Unnecessary cost and pain + lack of scientific knowledge
and understanding of products and processes
What’s the Plan?
• Focus on Process Validation approach
• Two pronged attack – at site and in Corporate Quality
Procedures
Corporate Quality
Site Validation
•Approach must address legacy products as well as new
products
Site Validation
• A Seven Step Approach:
1.
2.
3.
4.
5.
6.
7.
Product and Process Overview
Applying Knowledge
Product Understanding Overview Matrix
Product Assessment Summary Report
Improved Understanding
Validation
Continued Process Verification
Seven Steps for Legacy Products
Product &
Process
Overview
Product list
and
family
Process Flow
Diagram
Risk based
Prioritization
Improved
Process &
Product
Understanding
Experimentation
Data mining &
analysis
Use of scientific
expertise
Assessment of
Critical
Attributes and
Parameters
Specification
(CQA) to CPP
matrix scoring
Identify
priorities
Validation
Plan
& Execution
Scientific and
risk based
validation
Understanding
Overview
Matrix
Prior Knowledge
Historical data
Validation data
Forward data
Fundamental
knowledge
Unknowns
Continued
Process
Verification
Trending
Continuous
improvement
Product
Assessment
Summary
Report
Prior Knowledge
Historical data
Validation data
Fundamental
knowledge
Unknowns
Seven Steps: Product & Process Overview
Product &
Process
Overview
Assess
CQA’s and
CPP’s
Understan
ding
Overview
Matrix
Product
Assessment
Summary
Report
Improved
Process
Product
Understand
Step 1 – Product and Process Overview
Products should be prioritized:
• Rank risk to patient from a severity point of
view (this could be based on therapeutic effect
and mode of delivery)
• Rank the products in order of how important
they are to supply market
• Gain high level feel of validation concerns
• Group the products into product groups or
families based on formulation and presentation
• Gain conceptual understanding of facility
process steps to final product
• Use of Process Flow Diagrams to focus total
plant process understanding
• Walk down of process by those involved in
project
• Map the manufacturing process for each
product group
• Gain overview of existing process validation
per product group.
Validation
Plan
&
Execution
Continued
Process
Verification
Seven Steps: Assessment of CQA’s and
CPP’s
Product
and
Process
Overview
Assess
CQA’s and
CPP’s
Understan
ding
Overview
Matrix
Product
Assessment
Summary
Report
Improved
Process
Product
Understand
Validation
Plan
&
Execution
Continued
Process
Verification
Step 2 – Assessment of Critical Attributes and Parameters
• Initial data mine of capability
• Identify what is critical to the patient and how that is impacted by the process
• Identify CQAs for each product and variant
• Make a risk assessment of the impact of the different unit operations on the CQAs
• List for each product and variant potential CPPs
for each unit operations impacting CQAs
• Make a risk assessment of these potential CPPs
• All these risk assessments combined in one tool
• Tools such as Ishikawa and P-diagrams can be
used to quickly identify CQA and CPPs if not
already available.
• Exercise MUST include R&D, Process
Development or Product/Process SME!
Seven Steps: Understanding Overview
Matrix
Product
and
Process
Overview
Assess
CQA’s and
CPP’s
Understandi
ng
Overview
Matrix
Product
Assessment
Summary
Report
Step 3 – Understanding Overview
Matrix
• Gain overview of process understanding to
justify validation approach per product
variant
• Assess understanding in the following
categories
• Prior documented knowledge from R&D,
validation or manufacturing (including MBR)
• Referenced fundamental first principle
knowledge
• Historical data and statistical knowledge
• Forward looking data and statistics
• Identification of unknowns
•This matrix is used to pinpoint where data is.
• Step 3 is used to prioritize the future
process understanding, controls or validation
work to close the knowledge gaps.
Improved
Process
Product
Understand
Validation
Plan
&
Execution
Continued
Process
Verification
Seven Steps: Product Assessment
Summary Report
Product
and
Process
Overview
Assess
CQA’s and
CPP’s
Understand
Overview
Matrix
Product
Assessment
Summary
Report
Improved
Process
Product
Understand
Validation
Plan
&
Execution
Continued
Process
Verification
Step 4 – Product Assessment Summary Report
• Product specific CQA and CPP risk matrix (step 2)
• Product specific Understanding Overview Matrix (step 3)
• Validation performed and relevance
• Short summary and collation of information to demonstrate what knowledge supports
the conclusions
42 Lots
Seven Steps: Improved Process and
Product Understanding
Product
and
Process
Overview
Assess
CQA’s and
CPP’s
Understand
Overview
Matrix
Product
Assessment
Summary
Report
Improved
Process
Product
Understand
Validation
Plan
&
Execution
Continued
Process
Verification
Step 5 – Improved Process and Product Understanding
This step uses the following expertise, tools and methodologies to strengthen product or
validation understanding:
• Further historical data analysis
• Use of experts to gain additional fundamental understanding
• Use forward looking data analyses such as DoE and EVOP (Evolutionary Operations)
Process
Development
Process
improvements
based on science
and risk
Changes to
operating
procedures
Control
Strategy
Development
Use of increased
in process testing
for control
Data driven use
of
control and
sampling
Seven Steps: Validation Plan & Execution
Product
and
Process
Overview
Assess
CQA’s and
CPP’s
Understand
Overview
Matrix
Product
Assessment
Summary
Report
Improved
Process
Product
Understand
Validation
Plan
& Execution
Continued
Process
Verification
Step 6 – Validation Plan/Execution (Process Qualification)
This step builds on the science and risk based approaches to design a smart, science and risk
based validation plan which takes account of steps 1 to 5 in making decisions as to what should be
validated and how.
• Project Execution Plan for what should be Revalidated (missing pieces, lack of understanding)
• Revalidate using science and risk based approaches (use of traditional approaches, DoE,
science & risk and any other appropriate methods)
• It is essential that the validation plan and it’s execution should take account of steps 2 to 5 which
document product and process understanding. This should ensure only the gaps are validated to
strengthen position and not wholesale mass validation.
• Use the information from the revalidation to:
•
Update the Understanding Overview Matrix
•
Update the risk assessment (CQA / CPP)
•
Identify if further risk mitigation or risk control activities are needed
•
Update summary report
Seven Steps: Continued Process
Verification
Product
and
Process
Overview
Assess
CQA’s and
CPP’s
Understand
Overview
Matrix
Product
Assessment
Summary
Report
Improved
Process
Product
Understand
Validation
Plan
& Execution
Continued
Process
Verification
Step 7 – Continued Process Verification
Continuously verify data going forward for scientific justification of production of safe
and efficacious product for marketplace.
Trend relevant data and make needed continuous improvement or CAPA activities.
Relevant data is determined through Risk Assessment and knowledge gained during
the Validation/Qualification Execution phase.
Corporate Quality Procedures
Closing The Gap
1. Establish Understanding of FDA’s Draft
Process Validation Guidance
2. Develop Gap Analysis Tool for Comparison
of Existing Procedures
3. Create Prioritization Matrix of Procedures
4. Identify New Corporate Quality Procedure
Structure
5. Modify / Create New Procedures
6. Develop Execution Plan for Each Site
New FDA Process Validation Guidance Revisited
R&D / PD As Stakeholders
CQA’s / CPP’s Defined
Process
Design
1
Align with Risk
Assessments
Process
Qualification
2
Based upon Science
Not calendar year
Continued
Process
Verification
3
Gap Analysis Tool
• PV Guidance broken down
into consumable sections
• Top Priority Procedures
evaluated against Guidance
• Qualitative evaluation
performed
• Allowed for orthogonal
approach to understanding
gaps
Corporate Procedures Final “Look” at a Glance
INPUTS
Approvers:
R&D
Engineering
Manufacturing
Approvers:
Manufacturing
Validation
Manufacturing
Validation
R&D
Site Quality
Corp.Quality
Ø
Ø
Ø
Ø
Approvers:
Product List:
Grouping /
Families
Quality Target Product Profile defined
Process / Product Development Knowledge Ø
DOE’s documentation / review
Ø
Technology Transfer document approved
Ø
Ø
Defining CQAs, CPPs
Ø
Ø
Site Quality
Ø Risk Assessment:
Direct vs. Indirect
equipment
Ø
Ø
Control Strategy defined (equipment / unit
operations defined)
Process Flow Chart
Total # of parameters defined
Variation defined (ranges estimated)
Ø
Ø
Quality
Risk Assessment: PV
Enhance sampling strategy defined
per CPP
Product grouping strategy
Equipment bracketing strategy
Qualification Reports approved
Operational ranges defined
PQ
PQ
PQ
SIP
CIP
Mix
·
·
Continued process verification
Continuous improvement
Process Qualification Stage
PQ
Equipment, Facilities, Utilities Qualification
DQ/IQ/OQ
PV Report
Ongoing Verification RA
PQ
Ø
·
·
Approvers:
Risk Assessment: CQA’s / CPP’s
R&D
defined
Total product
parameters listed,
Manufacturing
evaluated - CPP’s identified
Validation
Unit Operations
defined
Site Quality
Corp. Quality
·
·
·
·
DQ
IQ
Qualification of equipment
OQ
End to end
PV Report approved
Ø
Non-product performance qualified
Functionality, control ranges verified
SOP’s approved, trained
Routine statistical analysis
Ties into Change Control
Ties into APQR
Approvers:
Ø
·
·
Risk Assessment:
Ongoing
R&D
verification / monitoring strategy
SamplingManufacturing
strategy defined per CPP
Product grouping
strategy confirmed
Validation
Quality
OUTPUTS
·
·
·
Corp. Quality
Periodic
Requal
or
Revalid.
The Payoff
1. Consistent Approach, specialized
focus
2. Elimination of unnecessary testing
3. Better alignment with other
proactive strategies (e.g., ASTM
E2500)
4. Allows for Reduction in Corp.
procedures
5. PROCESS IMPROVEMENT