Transcript 36pt Trebuchet MS Bold

Generic Drug Design, Development and Analytical Aspects
Julian Williams
Manager, EU Development Projects Actavis Group hf
To be discussed
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Project Approval
Preformulation considerations
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Formulations development
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Timeline & Product Requirements
Project team/meetings
Literature search
Patent review/reports
Reference samples
API selection
Lab
Trial
Pilot BE-study
Pilot production
Analytical method development and validation
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API
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Pharmacopieal status
Assay
Paricle size analysis
Bulk analysis
Impurities
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Residual solvents
Other impurities
Sulphated ash
To be discussed
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Analytical method development
Finished form
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Dissolution
Assay
Impurities
Content uniformity
Average weight
other tests
Breakability
Validation of analytical methods
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API
Finished form
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Stability studies
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Bioavailability Studies
1. Project Approval
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A development projects is approved through the evaluation of a Feasibility Plan.
The Feasibility Plan needs to include;
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Technical Feasibility (Ability to develop)
• Formulation Issues
• Patent & Exclusivities review which determine Launch Possibilities
• Biopharmaceutics
• API Sourcing
• Regulatory Requirements (Ability to Register)
Market analysis (Ability to sell)
Financial analysis (Future economic benefits)
Risk analysis
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1. Project Approval
• As part of the approval process a Marketing
Strategy for each project is generated;
• Dosage form and strengths to be developed
• Launch plan (market/territory orientated)
• Target Completion Date (First Dossier Submission Date)
2. Pre-formulation considerations
Project Definition
• After project approval a detailed
technical and patent evaluation needs to
be undertaken. Once these key
evaluations have been concluded a
Development Strategy is defined.
2. Pre-formulation considerations
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Development strategy/Marketing Strategy
It is important in the beginning of the development
To define a Development Strategy for each Project that complies, (if
possible), with the Marketing Strategy. This task provides the crucial
definition of the project and also includes a Risk Management Plan. The
information is recorded in the Development Plan. Areas to be covered
include;
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API Strategy
Formulation Strategy
Bioavailability/Clinical Efficacy Strategy
Patent Strategy
Registration Strategy
2. Pre-formulation considerations
It is important in the beginning of the development
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To review the Development Strategy for all
development projects on a regular (f.ex.
monthly) basis. The regular (monthly) meeting
of the group working on the projects focuses
primarily upon the issues/risks and
opportunities associated with each ongoing
development. The critical output of each
meeting is the action plan that is designed to
address and resolve these threats and
opportunities.
2. Pre-formulation considerations
The Development Plan
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The Development Plan includes;
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The evolving development strategy
An evolving risk management plan
2. Pre-formulation considerations
Project team
• In our case the project manager is responsible for setting up
regular meetings with the team to discuss the project.
• The first meeting is a startup meeting where the whole project
team is involved.
• The startup meeting is held as soon as possible after the project
has been approved.
• The responsibility of each team member is explained at that time
point. The Development Strategy is formulated from basis of the
Project Team strategy.
• The Project Team will focus on the specific details, plans and
timelines that need to be executed in support of this strategy..
2. Pre-formulation considerations
Project team
• The Project Team meets to discuss all critical issues, provide
solutions and make the necessary plans and strategic decisions to
drive individual developments to a successful conclusion.
• Discussions are based largely upon the development strategy i.e.
API (crystal form, salt, particle size), possible patent
infringement, formulation, bioequivalence studies etc….
2. Pre-formulation considerations
Literature search inital phase
• Information should be gathered from various sources at
the beginning of each project and made available to the
Project team.
• It is very important to gather as much information as
possible in the beginning before starting the project
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Pre-formulation considerations
Patent search and review
• Patent report for each development project
• The Purpose of the Patent-Report is to give guidance for:
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The Development-team to circumvent patents
Business Development for marketing
Management to oppose/invalidate patents
Management to estimate the patent risk.
• Patent strategy;
• Patent applications, oppositions.
• Patents are investigated in the countries where marketing is planned and
in the countries where development is going to take place. Consideration
should also be paid to development and production sites of API and
where bio-studies are performed.
2. Pre-formulation considerations
Patent reports
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Patent reports needs to be updated on regular basis.
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Patent report for each development project can be divided into the following
chapters
Summary
Strategy
Product Patent
SPC status
Patents in specific countries as Iceland/Malta/Turkey
Method of use patents
API patents
Formulation patents
Other patents
Trademarks
Pre-launch possibilities
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2. Pre-formulations considerations
Patent reports
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• Summary
Give overview of history and main patents
Marketing-, development- and management “should get the picture” by reading this
section
• Strategy
Suggest possible routes for development and marketing
Identify constraining patents and a strategy for circumventing
Invalidation and oppositions
2. Pre-formulation considerations
Patent reports
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Product patent
Totally blocks an entry into the market
For Early Market Entry:
• Identify countries with no product patents
• Identify countries which only have process-patents
• SPC
Supplementary Protective Certificate
First Marketing Approval in EU
Totally blocking for market entry.... if an extension from product patent
• Patents in Iceland, Malta, Turkey, Bulgaria….
Can influence where development is going to take place, e.g. formulation, bio-studies,
stock-piling etc.
• Method-of-Use Patents
Emphasize the patent situation of the indication used for the marketing purposes
Other indications
Summary of Product Characteristics (SmPC)
Patient Insert leaflets
2. Pre-formulation considerations
Patent reports
• Formulation patents
• Guidance for formulator
• Is the generic formulation infringing any patents
• Other patents
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Impurity profiles
Analytical methods
Trademarks
Color and shape of tablets
Own marketing – product names
Future Objectives
List all outstanding issues which need further attention, such as:
Potential opposition
Invalidations and
Vigilance over pending patent-applications
2. Pre-formulation considerations
API sourcing and qualification
• The API sourcing is a important part of the development process
it includes;
• The first contact with the API supplier.
• Sourcing and accepting samples and documentation from the suppliers –
• Reviewing and testing samples and giving feedback to the suppliers and
negotiate new specs with them to fit your purposes.• Handle samples and documentations and have the same reviewed/analyzed
(quality, specs, patents, regulatory compliance, inspection status, etc)
• Handle communication to suppliers for technical issues for products
in development
• Receiving the route of synthesis from the supplier and having the
same reviewed by the patent department.
• Signing the confidentiality agreement with the supplier and follows up
on the questionnaires that are sent to each supplier.
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Pre-formulation considerations
API selection
• Critical items;
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Specifications
Purity (Impurity, Residual Solvent)
Crystal habit (X-ray, DSC, TGA)
Solubility, (PH & surfactant)
Physical attributes (effect on mfg)
Particle size
Stability & storage requirement
DMF, Tech Package., Specifications
Non-infringing material
2. Pre-formulation considerations
Specifications for the API
• Specifications for the API
• If working with two or more API suppliers the
harmonization of the specifications is a critical factor. The
specifications sheet is discussed within the project team
and the member from the regulatory is giving huge input.
It is important to set the preliminary specifications early in
the product development and the ICH guidance is the Bible
when setting those specifications. Crystal form, particle
size, impurities, assay, LOD, sulfated ash …
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Pre-formulation considerations
Characterisation of the Reference
• Originator drug:
• USA requirements: 3 different lots, smallest/biggest pack
size for each strength?
• EU requirements: samples from different marketing areas
• Description - appearance
• Tablet shape/size, coating, packaging material/sizes,
desiccants
• Compressional parameters
• Weight, weight variation, thickness, hardness,
disintegration, LOD, friability, punch sizes, score and
markings
• Additional parameters:
• Qualitative and quantitative composition, dissolution
profiles, pharmacokinetic parameters, impurities
3. Formulation development
Preformulation – direct testing of active
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An investigation and data collection of
physical and chemical properties of the drug
substance alone or combined with excipients
is a critical part
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The objective of preformulation testing is to generate
information useful to the formulator in developing stable
and bioavailable dosage forms which can be mass
produced
3. Formulation development
Preformulation – direct testing of active
• Physical and chemical tests:
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Particle size distribution: Laser scattering
• PSD affects flowability, dissolution/bioavailability, content uniformity and stability
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Specific surface area: B.E.T testing, indirectly from PSD testing
• SA affects dissolution/bioavailability and stability (contact area, H2O
pockets)
Microscopic studies – electronic or optical
• Crystal shapes, agglomerates
Xray Diffraction (XRD) or Solid State NMR – polymorphism - ISOR
• Polymorphs solubility/stability differences – bioavailability – patent issues
Compressibility: Plastic/Fragmenting/Elastic
• Important especially for a high dose drug
• Chose excipients that match the compressional properties of the active
Chemical tests: Compendial tests, according to CoA or in-house tests
• Quality and purity of the active drug
3. Formulation development
Compatibility studies
• Compatibility testing
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Sample of active + excipient (1:1 to 1:10) powder samples
Kept for one month at 40°C/75% RH in open/closed HDPE container
Impurity testing by HPLC (DSC, XRD, Isothermal microcalorimetry)
• Manufacturing method: DC or Wet granulation
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Direct compression:
Dose: 2 – 100 mg (2 – 35% of
tablet mass).
Advantages: simple, economical (cost < 30%),
better stability
Disadvantage: segregation
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Wet granulation:
Advantages: good flowability and
compactability
Disadvantages: expensive, many steps, inferior
stability
Drying step: fluid bed drying, vacuum drying
• On the basis of preformulation and compatibility testing few
formulations are proposed made either by direct compression or
wet granulation
3. Formulation development
Lab/trial
• The first formulations are developed and produced at Lab
scale (1-3kgs). Few different formulations are tested and
the first choice is always direct compression.
• Dose proportionality is an important factor in the
formulations development. The stability of few lab scale
formulations are tested and the most stable and most
robust formulation is produced in trial scale (5-10kgs) if
needed.
• In trial scale the robustness is checked further and if
needed the stability is tested further.
• Draft Specifications for the finished form are set at this
time point
3. Formulation development
• Excipients
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Excipient type and grade (PS, η, d0dt, MC etc)
Availability (cost, lead time, quality, quantity)
Drug-Excipient compatibility
Impurities (peroxide, iodine value etc)
Physical attributes (manufacturability)
Specific requirements (MeO-, HPO- content etc)
IIG Limits (USA requirments)
3. Formulations development
Scale-Up Consideration
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Batch Size (Short & Long Term Demand)
Manufacturing Issues
Compliance Issues
Cost Analysis
Process evaluation protocols
Process parameter & range
Equipment capacity
Reproducibility
3. Formulation development
Scale-Up Consideration
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Compliance Issues:
Specification
IQ, OQ, PQ etc.
Training, SOP
Cleaning validation
Environmental requirements
Cost, Technology & Environment
Optimum Output & Reproducibility
Technology to be Versatile
Cost Effective
Environmental Friendly
Safety
Process Analytical Technology (PAT)
Packaging
3. Formulation development
Pilot scale production
• Tablet/capsules design, punches
• The product is produced in pilot scale and as a minimum if the product is
of 3 strengths and the formulations is dose proportional is to produce
2X100.000 units of each strengths from material from the first API
supplier for EU submission.
• If the product is of one or two strengths (dose proportional) a 3 batches
of each strengths needs to be produced (one batch of each strengths can
be smaller than 100.000).
• Those batches are used to evaluate the robustness of the formulation and
the manufacturing process. The blending time of the granulate is set
according to the C.U results of the mixture after a set mixing time
points. The hardness limits, speed of the tablet machine and other
parameters are set at this time of the development.
• Coating
• The breakability is tested and other tests are performed
3. Formulation development
Packaging
• Packaging for the stability study. Decision
of which packaging material to be used is
based upon market requirements. Which
packaging material is the innovvator
using. Can we use the same or similar
packaging material. Stability issues.
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Analytical Method Development
• Test Methods & specifications
• The main methods developed and validated for are:
• API
• Pharmacopieal status
• Assay
• Paricle size analysis
• Bulk analysis
• Impurities
• Residual solvents GC methods for determination of residual
solvents
• Other impurities
• Sulphated assh
• LOD
4. Analytical Method Development
• Test Methods & specifications
• The main methods developed and validated for are:
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Finished form
• Dissolution
• Discriminatory
• Quality Control
• Assay
• Impurities
• Content uniformity
• Average weight
• Breakability
• other tests
• Assay methods for cleaning validation studies.
• Upgrading old methods
• Automation of Testing
• Method Transfer (R&D to QC),
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Analytical Method validation
Validation of analytical methods are performed
according to relevant ICH guidance's.
• API
• Finished form
4. Analytical Method validation
• Documents produced during method development
and validation work are:
• analytical development report,
• validation protocols
• validation reports.
• Responsible person is approving the protocols
and the analytical validation reports.
• The validation report is the base for method
description in release masters used in the
QC release laboratory and are also included into
registration documents.
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Stability study
• Stability studies on both products in development and fully
developed products are important.
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Compiling the stability protocols
Starting stability studies,
Preparing analytical masters,
Analysis
Compiling stability reports and approving the results
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Stability study
• Before packaging the stability protocol needs to be compiled,
reviewed and signed.
• The stability program is set up according to the ICH guidance's
and if a special conditions are requests they are included in the
protocol.
• Accelerated 40°C/75% RH
• Intermediate 30°/65% RH
• Long term stability 25°/60% RH
• Matrixing and bracketing
• Requirements for different markets referring to temperature, RH
and packaging material.
Document; Stability report.
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Stability study
• Documents produced during stability work are
• P8 Stability
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8.1
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Stability Summary and Conclusion
Post-approval Stability Protocol
and Stability Commitment
• 8.3 Stability Data
6. Bioequivalence study
In vitro/in vivo correlation
• Comparison of dissolution profiles for the test and the
reference aimed for the bioequivalence study at different
pH. Minimum 3 pH and 12 tablets of the reference and the
test is tested at each conditions. Different methods tested
based on the physical-chemical properties of the drug.
• 1. Highly water soluble drug,
• 2. Slightly soluble drug
• 3. Insoluble drug
• 4. SR drug
6. Bioequivalence study
In vitro/in vivo correlation
• Which country in EU the reference in the Bio study is taken
from is important, this decisions needs to be taken early in
the development phase. The reference country is chosen
carefully based on which market is the most critical one,
which strength is marketed in most of the countries.
• Based on the results from in vitro correlation the decision
is taken which pilot batch is used for the bioequivalence
study. The batch that has the most similar profile in all
dissolution media is chosen as the bioequivalence batch.
This is critical to minimize the risk of failing.
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Compilation of the registration
dossier
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Each part of the development will end with a report. Those reports will come as a part of the
registrations dossiers
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Product Development Report (Formulations people)
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Preformulation Characterization
Formulation development info
Process selection & Critical steps
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Analytical Method development and validation report (analytical department)
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Process Evaluation report (QA/FD)
Scale-up and submission batch info
Cleaning validation & process Evaluation
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Stability report
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Bioequivalence study report
Key to Success
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Key to Success
Development Efficiency
Product selection
Speed & accuracy in development work
Communication (supportive groups)
Quality integration in the system
Communication with authorities/ FDA
Address legal issues in timely manner
Invest in technology and scinece
Partnership (development and marketing)
Long-term progress objective