Live from WBF 2008--Implementing ISA88 Across Life Science Development

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


ICH (INTERNATIONAL CONFERENCE ON HARMONIZATION) Q8 Pharmaceutical Development Q9 Risk Management Q10 Quality System Quality by Design (QbD) Pharmaceutical cGMP for 21st Century


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


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


Outlines Management responsibility for Quality Improvements for process performance and product quality Guidelines for overall pharmaceutical quality system


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)



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


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  • <p>Excellent stuff. Thanks for this amazing live blogging from the conference. </p> <p>I haven't been in the Batch world for a little while (I attended a WBF in 1999, I believe). I am wondering if there are any published examples where companies are using BatchML to exchange recipe information between applications. Or maybe something that I could use to validate the BatchML that I'm about to publish / consume. </p> <p>Pointers to websites or publications would be much appreciated.</p>


  • <p>[one more time. I keep being ham-fisted and losing comments] Thank you for this live reporting from WBF. It's very informative and reminds me of the one chance I had to attend when I was in Pharma, back in 1999. </p> <p>I am back in the Batch world and I would love to hear about examples where companies are doing what Conformia suggests (according to your notes). I'm particularly interested in whether they are using S88/S95 and BatchML to make the application-level communication happen across the whole development timeline. Each of those areas is using a different set of applications, usually requiring that they re-enter "recipe" information from one application into the other (and applications from several different vendors). BatchML seems like it could be a good fit. And if it isn't BatchML, why not? What is missing?</p> <p>Papers, articles, websites? What about a tool that does BatchML validation for the XML code that I'm about to consume/create?</p>


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