Product Development - Roy R. Fennimore Jr.Roy Fennimore Research Fellow
INTERPHEX New York City, NY 24 April 2013
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“I don’t get it. We design one pill good for 240 maladies and Marketing tells us there’s a design flaw.”
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The 5th Wave By Rich Tennant “Oh sure, I’ve used historical data analysis in the past, but lately it’s been pretty much hysterical data analysis at work.”
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Agenda
Adapting Pharmaceutical Technology Transfer (TT) into a Design Control System
Integration Strategy Linking Pharmaceutical Development to the Design Control
System Technology Transfer Guideline: Key Concepts for Integration New Product Development Process – Roadmap and Guides Translation from Pharmaceutical to Design Control
Deliverables Design Control Waterfall Diagram vs. Pharmaceutical
Deliverables for Integration Review Report Outlines: Such as Product Development,
Analytical Test Methods and Process Transfer, if time permits
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Overview
A high level view where Technology Transfer integration aligns with Design Control (DC) and the New Product Development (NPD) Process
Review Report Outlines: Such as Product Development, Analytical Test Methods and Process Transfer, if time permits
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Purpose
Provide an overview of how pharmaceutical technology transfer deliverables and best practices can be integrated into the Design Control (DC) System and the New Product Development Process for Combination/Convergent Products
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Integrating Pharmaceutical Technology Transfer (TT) into Design Control (DC) for New Product Development Pro cess
Objective:
The New Design Control System should be compatible for device development and device/drug combination/convergent product development as well as compliant with QSR/FDA GLP/GMP/ISO regulations, standards and applicable international regulations etc.
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Adapting Pharmaceutical Technology Transfer into Design Control (DC) for New Product Development Pro cess (NPD)
Leveraging:
Literature search for “Technology Transfer (TT) Processes” and benchmarking can be used to identify relevant pharmaceutical development deliverables to include within NPD Process/Design Control System
Many of the general (TT) practices are applicable and can be adapted for both device and combination products, –e.g., characterization of product and process / summary reports
Must realize if your company has a different business model and development process from pharmaceutical companies
Could utilize Design Control terminology as the foundation for DC system – The development of any type of product is also similar to the Process
Design Excellence or Six Sigma Practices – Pharmaceutical requirements can be integrated throughout the design
control process Timing and ownership can be different in terms of Design Transfer Project Teams of NPD can own the design to sales launch
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Streamlined system with compliant, clear, concise documents
Program management and team structure
Support/maintenance for the product development system
Technology transfer requirements and procedures
Integrated drug-device requirements
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Design Input : Product Description (Profile and Specifications) and Toxicology (including Toxicology Animal Studies)
Design Output : Product/Process/Packaging Documentation
Design Validation : Assay Validation, Regulatory Requirements including filing and approvals, Clinical Trials
Product/Process Validation : Pre-formulation, Formulation Development, API, Process Development, Scale-up, Process Validation, Facility Start-up and Validation, Pre-Approval Inspection Preparation and PAI.
Technology Transfer : Technology Transfer Plan, Updates and Transfer
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Example of Pharma Integration Management & Team Approach 1. Develop communication strategy
Communicate the roles and responsibilities of pharma integration especially in the areas that overlap Generate a list of pharmaceutical deliverables for integration and reach agreement with the teams Communicate the timing of deliverables Regular updates to the management team
2. Identify pharma gaps and leverage best practice p harma deliverables from Literature and Benchmarking
Identify gaps - VOC, project lessons learn (e.g. On-going Device projects), mapping, internal audits or external observations
Identify leveragable material from literature – Pharmaceutical/Medical site visits, if possible (process, deliverables, guidelines, SOPs, etc.)
3. Generate pharma related requirements and provide these requirements to respective teams Develop a pharmaceutical deliverable integration matrix Partner with respective teams based on the pharma deliverable integration matrix
4. Coordinate with other teams in company method gen eration Provide content expertise Recommend what needs to be integrated and what could be stand-alone documents Draft/Review pharmaceutical specific sections for the integrated ones Draft/Review specific pharmaceutical methods for stand-alone documents if required
5. Coordinate with other teams in the reviewing proc ess
6. Create internal guides Draft/Review the ones that require the pharma deliverables
7. Provide training after approval of met hod generation 11
Linking Pharmaceutical Development to Design Control Pharmaceutical Product Development can be Viewed as Two Separate but Integrated Proces ses
“Claims” development
messages “Product/Process” development
“Claims” Development
“Process” Development
Pharmaceutical Product Development and Device Development Can Differ in Several Key Areas
• Product development cycle time – Pharma development can be as long as ten years – Device development is usually less than three years
• Product design and specification – Drug products are defined by the results of clinical trials
• Discovery-driven and little can be done to modify the drug substance to meet customer needs
• Process focuses on maximizing what is discovered to get best label for given indication • Development more like a legal process as in “claims” made
– Devices are specified to meet market needs • Products can usually be engineered to a much greater degree • Process focuses on optimizing commercial potential by focusing on trade-offs between
options • Development can be heavily customer-driven
• Magnitude of development effort – Since pharmaceutical drugs take so long to develop and typically require over $500M to bring to
market, a significant number of personnel are involved with a project (as many as several hundred)
– Device development can be tailored to the size of the project—from minor upgrades to significant technology implementations; however, their size is usually no where near that of drug development 13
Technology Transfer Guidelines – Key Concepts for Integration
Technology Transfer Strategy and General Checklist
Pharmaceutical Development (PD) Summary and PD Report after Transfer
Analytical Development (AD) Summary, AD Report after Transfer
Product/Process Transfer Report
Technology Transfer Strategy and General Checklist
The Strategy is a written document that outlines the agreements made between Development and Operations concerning the technology transfer. The “Checklist” is a detailed list of development requirements and corresponding documentation that guide the collection of technology transfer knowledge for a specific project.
Definitions
Product/Process Transfer Report Locks in the core product and process information prior to manufacture of the registration batches and to document comparability between the new product developed in R&D and the final to-be-marketed product.
Analytical, Pharmaceutical Development Summaries an d Reports The summaries are a compilation of technical product knowledge, according to the strategy established, takes place during the NPD phase. The activities performed during NPD phase are within the R&D environment and in accordance with Operations expectations. Reports document production scale development activities that occur after the actual transfer from Development to Operations has taken place.
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CDA1
Slide 15
CDA1 May want to consider making this into 3 slides (or have each definition fade in so that you focus the viewer on what you want him/her to see/read. CAllman1, 2/10/2009
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Filing and Launch
Development
•Pharmaceutical Development
•API Characterization,
•Route of Administration
•Early Analytical Dev
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Linking Pharmaceutical Product Development to Desig n Control (Example of a Roadmap)
Stage 0 Proof of Concept
Stage 1 Product & Process De f
Stage 2 Dose & Scale Def
Stage 3 Efficacy & M FG
Stage 4 Lice nsure & Launch
Stage 5 Li fe Cycle M anagement
Discovery
Pre-Formulation Formulation Development Production Support
API Process Development & Scale up
Process Development and Validation
Phase Base Bu siness
PAI Preparation
Assay Validation
Process Validation
Phase II T rials Phase IV T rialsPhase I T rials Phas e III T rials
Design Validation (P roduct) – Safety and Efficacy Regulatory Fi ling Preparation and Submission
IND Subm iss ion
NDA Subm iss ion Re gulatory Approval
Des ign Freeze
Phase Review Phase Review Phase Review Phase ReviewPhase Review Phase Review
GM P Starts
Plan (TT P) TTP
Packaging Stabil i ty Studies Stabili ty Study Updates
Design Verification – Test Methods & Stab ility Studies
Start Final Stability Study
T ransfer AssaysAnalytics Development
Analyt ical Developm ent Summar y Analyt ical Developm ent Report
Develop & Qualify Charac terization & Release As says for RM, Proc ess, & Product
GLP Starts
• Product Development File (DHF) • Product Transfer Report • Pharmaceuti cal D evelopment Report • Analyt ical Developm ent Report
Produc t/Proc ess/P ac kag ing Doc umentation
• Pharmaceuti cal D evelopment Summ ar y • Analyt ical Developm ent Summar y
Design Output
• PDP Updates • PDP Updates • Launch Strateg y
T arget Produc t Profi le
Planning/Review 17
• What it is…. – Could be a one-page
overview of New Product Development Process for Commercialization
– Captures steps, timing and sequence, phase deliverables, and roles and responsibilities
– Describes timing and sequence of Design and Business Reviews
– Can be aligned with Process Design Excellence / Six Sigma methodology
• What is it used for…
– Used by project teams as a template for repeatable and disciplined project planning and management
– Can serve as a reference to management oversight
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The Roadmap should illustrate a high level commercialization process, but also serve as a tool for project planning & execution.
Main Themes : Must be relative to your system today, the most unique aspects of this
process are the phases. The phases should be well defined and can be staged to promote technical excellence.
For example, the first phase may focus on defining the scope of the project, gathering user requirements, and translating these into technical requirements (specifications targets) prior to selecting a concept.
For example, the next phase could be mainly about project planning and concept selection.
The third phase could be about developing the concept and processes used to make that concept into a final design.
Business reviews could be separated from the technical design reviews to promote the Technical Design Reviewers focusing more on the technical aspects of the program. The Design Reviews and Project Management Reviews can be scaled for simpler programs.
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• What is it… – A guide for each step
on the Roadmap, it could describe tasks, inputs, outputs, best- practices, etc.
– Linked to Quality System requirements
– Linked to applicable Process DEX /Six Sigma Tools
• What are they used for… – Drive consistent and
repeatable project planning and management
– Capture key planning assumptions and Company’s best- practices
– Serve a primer and training reference for the NPD process
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User Requirements
Validations Including:
Product Transfer Report
Technology Transfer of Knowledge from R+D to Commercial Operations
Technical
Requirements
Design and Development Planning
Verification and Validation Summaries
Facility Validation Cleaning Validation
Product/ Process Transfer Report
Integration of Key Pharmaceutical Reports/Summaries Concepts
1. Summary of the development history and any changes since development.
2. Documents comparability of the product and process from development to commercialization. This is accomplished in the summaries by documenting that the impact of any relevant design changes does not affect the validity of the verification and validation activities.
3. Documents the critical links between the product and process from pivotal clinical activities, registration, and finally to commercialization. This can be documented through an equivalency assessment in the summary or report.
4. Justification and rationale to support the final commercial product and manufacturing process through an equivalency assessment in the summary or report.
5. Locks the critical product, process and analytical information prior to the manufacture of initial registration and ISS batches. This can be accomplished through the successful completion of validation and summarized in the process validation summary or report.
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Technology Transfer General Checklist Detailed List could have 10 more Items per Subject Bullet
Active Pharmaceutical Ingredient (API)
Methods • API Container Closure System • API Stability
General Product Information Drug Product
• Components • Composition • Specification and Test Methods for
Inactive Components • Manufacturer • Methods of Manufacturing and
Packaging • Specifications and Test Methods
for Drug Product • Drug Product Container Closure
System • Drug Product
development of the drug product and manufacturing process.
Introduction: Development Strategy: • Describe of the decision path and supporting rationale
and justifications taken in during the development of the drug product and manufacturing process. Include all issues and risks.
Information on the API: • Chemical Structure and molecular formula. • List special properties relevant for the product and/or
process development. • Specifications Drug product: • Formula rationale for excipients (include sensitivities
such as heat, light, etc.). • Formulation history. • Specifications/suppliers of excipient. • Product specifications. Manufacturing process: • Manufacturing process rationale. • Manufacturing history
Process Flow Diagram with process parameters and acceptable ranges.
• Manufacturing equipment requirements and principle of operation.
• In process controls. • Cleaning assessment Packaging: • Rationale for immediate container selection. • Immediate container
description/supplier/specification . Batch overview: • Development batches trending table to include: • Batch number and size • API lot number • Where and when batch was made • Purpose of the batch • Analytical result of the batches Critical parameters: • Discussion of critical parameters identified
from lab and pilot scale. • Process Capability Report/Results References: References to detailed reports that are
identified in your checklist.
Introduction: • General information on the API: chemical
structure, name and code number. Impurities and degradants: • Rationale for the selection of the specified
impurities and degradants (if applicable). • Provide historical data from explorative and
full product development. Analytical methods: • Rationale for the choice of the analytical
method for a particular specification and also provide in this section:
• Analytical method evaluation (ring test) and validation
• Analytical Method Development Report • Robustness testing • Drug Product stress degradation studies • Analytical Method transfer reports
Instrumentation: • Rationale for critical instrumentation
parameters, reagents, utilities and other relative instrumentation information.
Control of change: • Description and rationale for method
changes. Training: • Training requirements and support on all
methods used for the testing of raw materials, active ingredient(s) and finished drug product.
Conclusion: • Conclusions resulting from the available
method development data supporting the methods presented in the regulatory filing.
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• Brief description of the drug product development history.
Scale-up summary: • Brief description of the manufacturing
development history from pilot scale to full scale.
Product Composition: • Comparison of each separate ingredient in
the product and corresponding quantitative composition between the development site and manufacturing site.
• Explanation of any differences encountered between the development site and manufacturing site.
Raw Materials: • Comparison of each separate raw material
and corresponding code number, supplier, trademark and specification reference between the development site and manufacturing site.
• Explanation of any differences encountered between the development site and manufacturing site.
Immediate container: • Comparison of each immediate container
component, supplier and specification reference between the development site and manufacturing site and any differences encountered.
Product specifications and test methods: • A summary table identifying the test,
specification and corresponding analytical method.
Manufacturing process: • Comparison of the manufacturing
equipment, operating parameters and IPC limits for each step of the process between the development site and the manufacturing site.
• Explanation of any differences encountered between the development site and manufacturing site.
• Process flow diagram • Manufacturing instructions
Packaging: • Packaging description including
reference to specifications. Validation:
Stability: • Registration stability strategy and
stability protocol. Conclusions:
• Development team and Operations team approval signatures.
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Purpose/Scope: Product description :
Executive summary: • Clinical and commercial formulations
overview. • Manufacturing process scale-up overview.
Active pharmaceutical ingredient : • Include molecular structure, weight and
formula, relevant physico-chemical characteristic and specifications
Drug Product: • Formulation development history and
equivalency between clinical formula and commercial formula (if different).
• Purpose, rational and characteristics for each excipient with the corresponding supplier and specification references.
• Qualitative and quantitative descriptions for each formulation.
• Rationale for all product specifications.
Manufacturing process: • Manufacturing process from pilot
scale to full scale history (including biobatch).
• Process flow diagram • Batch overview table with:
Batch number, size and purpose API lot number, location and date of manufacture
• Identify equipment train and equivalency with pilot scale
• List critical parameters with operating ranges
• Provide acceptance criteria and in- process ranges
Cleaning validation: • Description of cleaning validation • Description of cleaning method and
relevant results and criteria. Conclusion:
• Conclusion on robustness and control of the final drug product and manufacturing process including stability summary and shelf-life statement. Provide equivalency with bio-batch and/or pivotal clinical batch(es).
References: 27
Purpose / Scope: Product information :
Executive summary: • Submitted methods overview. • Methods classification with regard
to their use for stability and/or release purposes.
• Transfer process status to the QC Operations sites with references to the transfer documents (your checklist).
Method development: • Selected methods rationale. • Experience summaries of the
stability development groups and the QC Operations sites when applying the methods.
Specifications: • Specifications with the
• Stability summary or report. Control of change:
• Applied control of change and of the communication with the regulatory bodies overview.
Conclusion: • Conclusions resulting from the
available method development and transfer data supporting the methods presented in the regulatory filing.
References: • Method descriptions, robustness
and validation report references.
Key Outputs/Documents for Technology Transfer (TT) of Knowledge for Combination/Convergent Products
• Process Overview and Process flows - Details of Process Description and format (Excel or Visio) for process flow diagrams
• SPC Strategy – Control Points, etc. • Characterization Strategies/Studies/Reports • CTQ Flow Down and Basic Process Science/Process
Principles • Critical Setup Parameters • Failure Modes; Probable Cause/Solution • Process - Specific Troubleshooting Guides and Technical
Manuals • Main Equipment Items and Function Detail • pFMEA – Risks, Mitigations, Impacts 29
Key Take-aways from the Technology Transfer Guideli nes
• Standardize checklist for transferring product development, process development and analytical method development knowledge – Describes the key requirements that must be completed or addressed
throughout the pharmaceutical development process • Requirements are summarized in key deliverables and reports such as:
– Technology Transfer Strategy, Technology Transfer Checklist, Pharmaceutical Development Summary, Analytical Development Summary, Product Transfer Report, Pharmaceutical Development Report, Analytical Development Report
• In developing a drug-device development model, must identify applicable requirements and integrate them into the development process – Product description to be updated to include inputs for active
pharmaceutical agent – New pharma-specific requirements such as dose, route of administration,
elution kinetics and metabolism of the drug substance
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Thank you for your participation today Special Thanks to the following individuals: • Angela Falzone • Saurabh Palkar • Theresa Scheuble • Diana Dai • Dave Blazek • Rich Tennant
If time allows, audience can share some of their best- practices, experiences and lessons-learned Don’t forget to complete the evaluation forms !
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