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Pharmaceutical Technology Transfer Best Practices

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Pharmaceutical Technology Transfer Practices into Design Control Systems for Combination/Convergent Products Roy Fennimore Research Fellow Product & Process Scientific Solutions (P 2 S 2 ) Johnson & Johnson INTERPHEX New York City, NY 24 April 2013 1
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Page 1: Pharmaceutical Technology Transfer Best Practices

Pharmaceutical Technology Transfer Practices into Design Control Systems for Combination/Convergent Products

Roy FennimoreResearch Fellow

Product & Process Scientific Solutions (P2S2)Johnson & Johnson

INTERPHEX New York City, NY 24 April 2013

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Page 2: Pharmaceutical Technology Transfer Best Practices

“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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Page 3: Pharmaceutical Technology Transfer Best Practices

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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Page 5: Pharmaceutical Technology Transfer Best Practices

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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Page 6: Pharmaceutical Technology Transfer Best Practices

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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Page 7: Pharmaceutical Technology Transfer Best Practices

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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Page 8: Pharmaceutical Technology Transfer Best Practices

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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Page 9: Pharmaceutical Technology Transfer Best Practices

Benchmarking – Some BestPractices & 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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Page 10: Pharmaceutical Technology Transfer Best Practices

Integration Strategy for Pharmaceutical TT Delivera blesResources, Organization, Stage Gates, Dashboards, B usiness 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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Page 11: Pharmaceutical Technology Transfer Best Practices

Example of Pharma Integration Management &Team Approach1. 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

Page 12: Pharmaceutical Technology Transfer Best Practices

Linking Pharmaceutical Development to Design Control Pharmaceutical Product Development can be Viewed as Two Separate but Integrated Proces ses

“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

“Claims” Development

“Process” Development

Pharmaceutical Product Development

Discovery Commercialization

“Claims” Development

“Process” Development

Pharmaceutical Product Development

Discovery Commercialization

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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

Page 14: Pharmaceutical Technology Transfer Best Practices

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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Page 15: Pharmaceutical Technology Transfer Best Practices

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 ReportLocks 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 ReportsThe 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

Page 16: Pharmaceutical Technology Transfer Best Practices

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

Page 17: Pharmaceutical Technology Transfer Best Practices

1

Technology Transfer (TT) Pharmaceutical Overview

Filing and Launch

Product and Process EvaluationProduct and Process

Development

Commercial Concept

Evaluation

Initiation StartingGate

Product DefinedGate

Product EvaluatedGate Closing

Registration Batches

TT Start(Sourcing Decision)

File PAI

•Technology Transfer Strategy and Checklist

•Pharmaceutical Development

Summary

•Analytical Development

Summary

•Product Transfer

Report

•Analytical Development Report

•Pharmaceutical Development Report

Product Development File

Define & Measure Analyze Design Verify and Validate

•API Characterization,

•Pre-formulation, Formulation, Early Process Dev

•Route of Administration

•Early Analytical Dev

•Early Stability

Monitor

ManufacturingOperations

File

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Page 18: Pharmaceutical Technology Transfer Best Practices

Linking Pharmaceutical Product Development to Desig n Control(Example of a Roadmap)

Stage 0Proof of Concept

Stage 1Product & Process De f

Stage 2Dose & Scale Def

Stage 3Efficacy & M FG

Stage 4Lice nsure & Launch

Stage 5Li fe Cycle M anagement

Discovery

Design Input - Product SpecificationDefine Produc t Specific ations

Pre-Formulation Formulation Development Production Support

API Process Development & Scale up

Process Development and Validation

Concept Phase Feasibility Phase Development PhaseImplementation

PhaseBase Bu siness

Phase

Chronic Toxicology Animal Studies .

In Vitro Toxicology

Acute Toxicology Animal Studies

Facili ty Start-up & Validation Commercial ProductionPAI

PAI Preparation

Assay Validation

Process Validation

Phase IIT rials Phase IV T rialsPhase I T rials Phas e III T rials

Design Validation (P roduct) – Safety and EfficacyRegulatory Fi ling Preparation and Submission

IND Subm iss ion

FIH Pivotal Tr ial Starts

NDA Subm iss ion Re gulatory Approval

Des ign Freeze

Phase Review Phase Review Phase Review Phase ReviewPhase Review Phase Review

GM P Starts

Design T ransfer/ Design ChangeT echnology T ransfer

Plan (TT P)TTP

UpdateTTP

Update T echnology T ransfer

Technolog y Transfer Strateg y

Product Stabil i ty Studies

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

Risk Management – Animal Studies

Expiration Date Es tablished

• Product Dev . Plan (Clinical, R egulator y, CMC, etc.)

• PDP Updates • PDP Updates• Launch Strateg y

T arget Produc t Profi le

Planning/Review 17

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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 levelcommercialization 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 ProductDevelopment to Commercialization

• 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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Page 22: Pharmaceutical Technology Transfer Best Practices

Design Control Waterfall Diagram vs. Pharmaceutical Deliverables for Integration

User Requirements

Technical Design Input

Design Output

Design Verification

Design Validation

Design & Development

Planning

Medical Product

Design Process

Process Validation

Analytical Development Summary

Pharmaceutical Dev Summary

Final Documentation for Product & Process Specifications

Validations Including:

Cleaning, Facility, Analytical Method

Technology Transfer Strategy and Checklist

Product Transfer Report

Pharmaceutical Dev

Report

Analytical Dev Reports

Analytical Method

Transfer

Technology Transfer of Knowledge from R+D to Commercial Operations

Technical

Requirements

Design Input – Output

Product/Process Development ReportsDesign Characterization and Design Summaries

Design and Development Planning

Verification and Validation Summaries

Facility Validation Cleaning Validation

Test Method Validation

Validations Including:

Cleaning, Facility, Analytical Method, Equipment

Product/ Process Transfer Report

Pharmaceutical Dev

Report

Analytical Dev Report

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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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Page 24: Pharmaceutical Technology Transfer Best Practices

Technology Transfer General ChecklistDetailed List could have 10 more Items per Subject Bullet

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

General Product InformationDrug 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

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.• SpecificationsDrug 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 assessmentPackaging:• 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 batchesCritical parameters:• Discussion of critical parameters identified

from lab and pilot scale.• Process Capability Report/ResultsReferences: 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 OutlinePharmaceutical 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 Outlineafter Transfer

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:• Manufacturing process from pilot

scale to full scale history (including biobatch).

• Process flow diagram• Batch overview table with:

Batch number, size and purposeAPI lot number, location and dateof 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

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Analytical Development ReportOutline 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 29

Page 31: Pharmaceutical Technology Transfer Best Practices

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 todaySpecial 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-learnedDon’t forget to complete the evaluation forms !

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