Pharmaceutical Technology Transfer
Practices into Design Control Systems
for Combination/Convergent Products
Roy Fennimore
Research Fellow
Product & Process Scientific Solutions (P2S2)
Johnson & Johnson
INTERPHEX New York City, NY 24 April 2013
1
“I don’t get it. We design one pill good for 240 maladies
and Marketing tells us there’s a design flaw.”
2
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.”
3
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 Process
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 Process (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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Benchmarking – Some Best
Practices & Applications
Product development roadmap and guidelines
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
Integrated Design/Process Excellence, Six Sigma
Practices
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Integration Strategy for Pharmaceutical TT Deliverables
Resources, Organization, Stage Gates, Dashboards, Business Practices
Design Input: Product Description (Profile and Specifications)
and Toxicology (including Toxicology Animal Studies)
Design Output: Product/Process/Packaging Documentation
Design Verification: Analytical, Assays, Stability Studies
including Packaging Stability Testing
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 pharma 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 generation
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.
6.
Coordinate with other teams in the reviewing process
Create internal guides
Draft/Review the ones that require the pharma deliverables
7.
Provide training after approval of method generation
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Linking Pharmaceutical Development to
Design Control Pharmaceutical Product Development
can be Viewed as Two Separate but Integrated Processes
Pharmaceutical Product Development
“Claims” Development
Discovery
Commercialization
“Process” Development
“Claims” development
– Integrates clinical, regulatory, and marketing strategies
– Optimizes claim structure, product positioning and promotional
messages
“Product/Process” development
– Integrates chemistry, formulation, and manufacturing
– Optimizes product/process specifications, cost and production
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Pharmaceutical Product Development and Device
Development Can Differ in Several Key Areas
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•
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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
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development
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
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CDA1
Definitions
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.
Analytical, Pharmaceutical Development Summaries and 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.
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.
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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
Technology Transfer (TT) Pharmaceutical Overview
Define & Measure
Initiation
Analyze
Starting
Gate
Commercial
Concept
Evaluation
Design
Verify and Validate
Product Defined
Gate
Product and Process
Development
Monitor
Product Evaluated
Gate
Closing
Filing and
Launch
Product and Process Evaluation
Registration Batches
•API Characterization,
•Pre-formulation,
Formulation, Early
Process Dev
TT Start
(Sourcing Decision)
•Route of Administration
•Early Analytical Dev
•Early Stability
•Technology Transfer
Strategy and Checklist
•Pharmaceutical
Development
Summary
•Analytical
Development
Summary
1
•Product
Transfer
Report
File PAI
•Pharmaceutical
Development Report
•Analytical
Development Report
Product Development File
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Manufacturing
Operations
File
I
Linking Pharmaceutical Product Development to Design Control
(Example of a Roadmap)
Conc ept Pha se
Fea sibility Ph a se
Stage 0
Pr oof of Conce pt
Di scover y
Im plem entation
Pha se
Dev elopm ent Pha se
Stage 2
Dose & Scale Def
Stage 1
Pr oduct & Pr ocess De f
Stage 3
Efficacy & M FG
Stage 4
Lice nsure & Launch
Ba se Bu sin e ss
Pha se
Stage 5
Li fe Cycl e M anagement
Design Inp ut - Product Specification
T arget P roduc t P rofile
Define P roduc t S pecific ations
Risk Manage ment – Animal Studies
In Vitro Toxicology
G LP Starts
A cute Toxicology Animal S tudies
Chronic Toxic ology Animal S tudies .
PA I Preparation
Process Devel opme nt and Valid ation
GM P Star ts
P re-Formulation
Facility S tart-up & Validation
Form ulation Development
API
PAI
A ss ay V alidation
De s ign
Fr eeze
P rocess Development & S cale up
Design O utput
Commercial P roduction
P roduc tion S upport
P rocess V alidation
Produc t/Proc ess/P ac kag ing Doc um ent atio n
•
•
•
•
• Pharma ceuti cal D ev elopment Summ ar y
• Anal yt ic al D ev elopm ent Summa r y
Product D ev elopment File (DH F)
Product Transfer Report
Pharma ceuti cal D ev elopment Report
Anal yt ic al Dev elopm ent Report
Design Ve rification – Test Meth ods & Stab ility Studies
A nalytic s Development
Develop & Qualify Charac terization & Releas e As says for RM, P roc ess , & P roduc t
T rans fer Ass ays
Anal yt ic al D ev elopm ent R eport
Anal yt ic al Dev elopm ent Summa r y
P roduc t S tability S tudies
P ac kaging S tability S tudies
S tability Study Updates
Start Final Stability Study
Design Valid ation (P rod uct) – Safety and Efficacy
Expir ation Date
Es tablis hed
Regulatory Filing P reparation and Submis si on
IND
Subm iss ion
NDA Subm iss ion
P has e II
T rials
P has e I T rials
Re gulator y Approval
P has e III T rials
FIH
P has e IV T rials
Pivotal Tr ial Starts
Design T ransfer/ Design Cha nge
T ec hnology T rans fer
P lan (TT P )
TTP
Update
TTP
Update
T ec hnology T rans fer
Technolog y
Transfer Strateg y
Planning/Review
Phase Review
• Product Dev . Plan
(Clinical, R egulator y,
CM C, etc.)
Phase Review
• PDP Updates
Phase Review
• PDP Updates
• Launch Strateg y
Phas e Review
Phase Review
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Phase Review
Generate a Roadmap for New Product
Commercialization Process
• 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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Develop Internal Guides for New Product
Development to Commercialization
• What is it…
• What are they used
– A guide for each step
for…
on the Roadmap, it
– Drive consistent and
could describe tasks,
repeatable project
inputs, outputs, bestplanning and
practices, etc.
management
– Linked to Quality
– Capture key
System requirements
planning
– Linked to applicable
assumptions and
Process DEX /Six
Company’s bestSigma Tools
practices
– Serve a primer and
training reference for
the NPD process
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Design Control Waterfall Diagram vs.
Pharmaceutical Deliverables for Integration
User
Requirements
Design Input – Output
Technical
Product/Process Development Reports
Design Characterization and Design Summaries
Requirements
Analytical Development
Summary
Technical
Design
Input
Pharmaceutical Dev Summary
Design Process
Final Documentation for Product &
Process Specifications
Design
Output
Design &
Development
Planning
Technology Transfer
Strategy and Checklist
Verification and Validation
Summaries
Design Verification
Design and Development
Planning
Design Validation
Medical Product
Validations Including:
Facility Validation
Cleaning Validation
Test Method Validation
Cleaning,
Facility, Analytical
Validations
Including:
Method, Equipment
Cleaning, Facility, Analytical Method
Product/
Process Transfer
Product
Report Transfer Report
Pharmaceutical
PharmaceuticalDev
Dev
Process Validation
Technology Transfer of Knowledge from R+D to Commercial Operations
Report
Report
Analytical
AnalyticalDev
DevReports
Report
Analytical Method
Transfer
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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
General Product Information
Drug Product
Active Pharmaceutical Ingredient
(API)
•
•
•
•
•
•
•
•
•
•
General API Information
Physical Description
Characterization and Proof of
Structure
API Manufacturer
Synthesis/Method of Manufacture
API Process Controls
Reference Standard
Specifications and Analytical Test
Methods
API Container Closure System
API Stability
•
•
•
•
•
•
•
•
•
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
Microbiology/Sterility
Drug Product Stability
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Pharmaceutical Development
Summary Outline
Executive Summary:
•
Comprehensive summary focusing on the
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.
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Analytical Development
Summary Outline
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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Product/Process Transfer Report Outline
Pharmaceutical development summary:
• 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:
• Process and cleaning validation
strategies and/or reports
• Sterilization validation strategy and/or
reports (if required)
Stability:
• Registration stability strategy and
stability protocol.
Conclusions:
• Conclusions concerning the scale-up
experiences.
• Development team and Operations team
approval signatures.
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Pharmaceutical Development Report Outline
after Transfer
Manufacturing process:
Purpose/Scope:
Product description:
• Short description about the product and
attributes.
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 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 inprocess 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:
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Analytical Development Report
Outline after Transfer
Purpose / Scope:
Product information:
• Short description about the
product.
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
justification.
Stability:
• 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.
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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
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Key Take-aways from the Technology Transfer Guidelines
• 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 bestpractices, experiences and lessons-learned
Don’t forget to complete the evaluation forms !
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