Louis Ciabattoni is a CPIM from Conformia Software.
AGENDA:
Overview of Pharmaceutical Development Operations
Differences from Commercial Manufacturing
FDA Initiatives shaping Drug Development
New S88 Concepts for Development
Strategies for S88 Acceptance
Conclusions
Overview of Pharma Development Operations:
Research-->Drug Substance (API)-->Drug Product--->Commercial Manufacturing
Between Research and Commercial Manufacturing there is substantial clinical trialing.
Clinical trials constitute up to 30% of the cost
1 out of 10 drug candidates survive
New science and technology in product/process development and manufacturing are lagging
Improvements could save an additional $5 to $7 billion in drug development cost in the US alone each year.
Drug Development – 4.5 years
A $10M to $500M+ investment
How can S88 help?
Structure for Recipes
Structure for Technology Transfer
S88 Goals
good practices for the design and operation
improved control
can be applied regardless of the degree of automation.
OVERVIEW: Development Readiness
Historical Industry Practice
Three Reproducible Batches – Good to Go
FDA Observation
End Product Testing can not insure Product Safety
OVERVIEW: Recipe Structure
Structured Batch Record Repository*
Date referenced in FDA Submission
QbD Tenets
Critical Quality Attributes*
Design Space*
Continuous Process Validation
Process Understanding*
Real-Time Release
Risk Assessment
OVERVIEW: Technology Transfer
Transfer critical production recipe information
Development of product specifications
Flat and hierarchical recipes*
ANSI ISA S88 recipe standards*
Track and register product and process changes in multiple markets over product lifecycle
Collaboration with external vendors, suppliers, and distributors
Shifting focus to process and design space to identify critical to quality parameters
•
Differences from Commercial Manufacturing: Night and Day
(Never say "Never" in R&D)
Characteristic |
Development |
Commercial |
Operating |
Transitioning from non GMP to GMP |
Operating in full GMP Mode |
Traceability Lifecycle |
Need to be able to go back in time many years – find/search for data easily over time period |
Processes run for long time but generally no need to have long term traceability |
Traceability Direction |
Go back in Development and feed forward to Commercial Ops |
Feedback to Development Ops |
Process Flexibility |
Highly iterative business process, changes w/rev control. High degree of flexibility |
Fixed/Controlled operation |
Role of Batch Records |
Planning/analysis focus |
Execution |
Operating “Discontinuities" |
High – stop/go nature of campaigns is typical |
Low – Operations are continuous, no stopping |
Data Capture Definition |
Capture all data, don’t know what will be important until after the fact. |
Data to be captured during execution is well defined |
Analytical Methods Focus |
Develop and Execute Analytical Methods |
Execute Analytical Methods |
Process Understanding |
Create underlying foundation for Science “Process Understanding”, (prove “process understanding”) |
Improve Operations, Quality and demonstrate Compliance (execute against established SOPs, specification mgmt) |
Recipes constantly change
Even after FDA approval
Early Development
Non-GMP (Good Manufacturing Practice)
Late Development
GMP, but…
Recipes evolve
Early thru Clinical Trials
•
FDA GUIDELINES CHANGING DRUG DEVELOPMENT
ICH (INTERNATIONAL CONFERENCE ON HARMONIZATION)
Q8 Pharmaceutical Development
Q9 Risk Management
Q10 Quality System
Quality by Design (QbD)
Pharmaceutical cGMP for 21st Century
Q8 PHARMACEUTICAL DEVELOPMENT
Guideline for development of drug products
Quality cannot be tested into products
Manufacturing process understanding
within an approved design space without further regulatory review
“Real time” quality control
leading to a reduction of end-product release testing
Q9 QUALITY RISK MANAGEMENT
The evaluation of the risk to quality should
ultimately link back to the protection of the patient
The level of effort, formality and documentation of the quality risk management process
should be commensurate with the level of risk and be based on scientific knowledge
Q10 PHARMACEUTICAL QUALITY SYSTEM
Outlines Management responsibility for Quality
Improvements for
process performance and product quality
Guidelines for overall pharmaceutical quality system
PHARMACEUTICAL QUALITY ASSESSMENT SYSTEM (PQAS) IN THE 21ST CENTURY
Promotes
science and risk-based approach to regulation
Initiative
applies to new drugs, including biotech products
Established
to facilitate the implementation of Quality-by-Design
The FDA says that they want the current system migrated to the new desired state:
Empirical development -->Submission (Lack of PD and MS)-->Traditional CMC Review
needs to migrate to:
Development (QbD)-->Submission (Knowledge Rich in PD and MS)-->PQAS
The S88 Concepts for Development:
Flexibility
Mapping S88 Objects to
Laboratory Procedures
Batch Tickets
Unit Operations
S88 Commands
SKIP
COMPLETED
REDO
Conditionals (If, Then)
CONCEPTS: EXECUTION MODIFICATIONS
|
Drug Substance |
|
|
|
Drug Product |
|
|
|
Lab |
Early Dev |
Late |
GMP CT |
Pre-Form |
Formulation |
GMP CT |
Operator |
|
|
Exec |
Exec |
|
|
Exec |
Engineer |
|
Exec/ Edit |
Exec/ Edit |
Edit |
|
Exec/Edit |
Edit |
Scientist |
Exec/Edit |
Exec/ Edit |
Exec/ Edit |
Edit |
Analysis |
Exec/Edit |
Edit |
Adding Additional Results/Observations
Changing Equipment
New Raw Material Lots
Equipment Cleaning Required
Skip a recipe element
Insert a recipe element
Do Until
Repeat
If Then
STRATEGIES FOR S88 ACCEPTANCE
Mapping from Unit Operations
Reducing Process Steps
Process Optimization
Structured Recipe Repository
Enhancing Tech Transfer to Commercial
CONCLUSIONS-TECH TRANSFER:
"… and I’m sure none if you have been in the situation where R&D threw a half-developed process over the wall, and you were expected to begin high quality, high product immediately.”
Jim Dougherty, Clarkson Consulting, 2004
CONCLUSIONS - S88.01/IEC 61512-1 CENTRAL CONCEPT
The concept that the recipe that describes how the batch is to be made is separate from the equipment that is actually used to make the batch
Improves recipe transportability
Makes recipe more flexible
Simplifies recipe validation
Makes software reuse feasible
QbD IS AN ACCELERANT FOR S88 ACCEPTANCE!