GMP-SERVICES & KNOW-HOW IN DEVELOPMENT - GUIDED BY ... · Page 7 | 25.05.2016 State-of-the-art...

GMP-SERVICES & KNOW-HOW IN DEVELOPMENT

- GUIDED BY INNOVATION AND EFFICIENCY

Overview of companies

Quasaar & MJR PharmJet

May / June 2016

| 25.05.2016 Joint Know-how

Service partner for Life Sciences

Quasaar GmbH

Outsourcing Partner for the Life Science

Industry

Scalable and efficient solutions for the lab

Stability testing in all dimensions

Product control / quality management

Efficient and proven GMP-systems

Choice between GMP or development stage

State-of-the-art analytics and lab works

Experienced in GMP processes – being

embedded into a development environment

ensures transfer of technologies

MJR PharmJet GmbH

Specialist for the development of product

or system applications

Formulations on active ingredients & excipients

Applications and barrier testing models

Specialist for challenging compounds

Critical, sensitive molecules

Hardly soluble compounds, etc.

Pharma, medtech und cross-over

Focus on application system

Scaling-up and process qualification

Method development and validation

Specialists for all kind of required analytical

technologies and pharmaceutical formulations

(added value: particle technologies)

In more detailed on pages 3 – 19 & 42 - 48

Specialists for all kind of particles and how to

manufacture them

Generating particles in a very precise way,

analyzing them in a competent way and

understanding how they interact and work

In more detail on pages 20 – 41 & 42 - 48

The GMP and the development

area are separated in two legally and organization-

wise independent companies

| 25.05.2016 Intro Quasaar

Your outsourcing partner

| 25.05.2016 Intro Quasaar

Innovation and efficiency – Added Value Quasaar

SERVICE OFFER QUASAAR

Attractive pricing model

Comprehensive, state-of-the-art

analytical techniques

Large volume capacity, versatile

stability center

Certified cooperation, all systems

and processes under GMP

Project stage / R&D to GMP -

interface to be defined by each

customer project

Fast track from GMP to R&D

Special expertise in all types of

particulate systems

Quality control and analytical support

Batch release analysis (release by QP on demand / EU – Retest)

Analytical support

Stability studies – storage (analytical investigations on demand)

Stress – and compatibility testing

Formulation screening

QC for API, raw material and excipients

Technology transfer

Method optimization (incl. robustness investigations)

Method transfer – concepts for GMP

Validation & qualification, design & performance

Cleaning validation, transport validation

Design & Performance of risk analysis

Method development & implementation into regulatory environment

Special techniques / methods (among more)

Added Value Quasaar: characterization of all kinds of particulate systems

Material Science – physical-chemical methods

Microbiology, Synthesis, Process optimization in cooperation with partners

Further services (among more)

GMP-Archiving, storage of retention samples, transport logistic

QP Services, preparation/execution of audits

Consulting and training concerning quality management, quality assurance, etc.

| 25.05.2016 Benefits Quasaar

Pricing differentiated by customer needs – Quasaar

solutions quite often more efficientPRICING

Hourly rates vary by

- Involvement of personnel

- Involvement of installed technical base

- Technical complexity

- Additional training & consulting

Examples of typical hourly rates

- € 95 base lab staff (pure documentation)

- € 100–125 (depending on equipment class)

- € 150 – 200 technical / academic experts

Quotations react on

- Individual project needs

- Individual customer needs

Pricing in the stability center

- Cost go by volume in units of 10 l

- Initial registration costs by time and effort

Attractive relation volume to cost

- due to large-volume climate chambers

- Suitable for high volume sku’s (incl. bulk)

- RFID-technology currently build-up

Prices for samples in the stability chambers

- € 0,80 – 1,0.- per l per month in standard

ICH-climate conditions

Quotations react on

- Individual project needs / customer needs

Analytical Laboratory Stability Center

Project performance based on KPITaylor-made pricing quotations on request

| 25.05.2016

All customer requests realizable

ANALYTICAL TECHNIQUES

Benefits Quasaar

• Several redundant HPLC/UPLC stations

• All common methods realizable

• Technical upgrades and additional capacity on

demand

• Detectors: UV-VIS, PDA, refractive index

• Drug Release / Kinetics

• Paddle & Basket & special devices

• SUPAC studies

• Automated systems

• IVIVC

• Special dosage forms

• Biopharmaceutical characterization

• GC, GC-HS (residual solvent)

• (GC-MS / ICP-MS)

• Spectroscopy (UV, IR, fluorescence)

• Compendium methods (USP, EP, CHP

etc.)

• Water determination (Karl-Fischer etc.)

• volumetric/coulometric

• Oven method

• Pharmaceutical-technical methods• disintegration

• resistance to crushing

• friability

• appearance, opalescence, turbidity

• density, pH-value, osmolality

• leakage tests

• Special analytical methods for

investigation and characterization of

particles

Established base techniques in the analytical lab

Further techniques on request – can be realized based on a smooth internal GMP supply

yet within the still initial project activities

| 25.05.2016

State-of-the-art outlay

Technical operations

efficient in design

All relevant climates

Capacity for small to big

units incl. as bulk ware or

on palettes

Easy scaling-up

500 m3 to be enlarged to

2000 m3

Extra warehouse for

retain samples

Up-coming:

500 m3 GMP-archive

Large and state-of-the-art capacity for stability

studiesSTABILITY CENTER

Available conditionsStandard / ICH climatic conditions

25°C/60% r.h. 280 m3

30°C/75% r.h. 180 m3

40°C/75% r.h. 50 m3

Refrigerator and freezer storage

-20°C ± 5 °C

5°C ± 3 °C

-80°C for special deep freeze samples

Available special conditions

25°C/40 % r.h.

30°C/65 % r.h

30°C/35 % r.h.

Cyclic conditions or transport validation

- 20 °C to 150°C

Benefits ÜberherrnTechnical characteristics

Redundant control systems for

temperature and humidity

Storage capabilities for palettes, barrels

or bulk ware

Protected against excess temperature

and humidity

Monitoring system Yokogawa

Alert system includes SMS & E-Mail

Benefits Quasaar

| 25.05.2016

How we collaborate with you

WORKING FOR OUR CUSTOMERS - I

GMP-Zertifikat

Quasaar

Built-up of collaboration

1. Agreed definition of basic concept for outsourcing cooperation

2. Ratification of secrecy agreement, exchange of relevant

documents

3. Quotation built on feasibility evaluation and compilation of

techniques and equipment to be used

4. Integration of all relevant GMP documents, ratification QAA /

service agreement

5. Audit

6. Definition of project team & time schedule plus capacity check

On-going collaboration

7. Installation of methods (if needed optimization & validation)

8. Sample logistic & storage of samples for stability tests

9. On-going work on tests and analysis

10. Certificates and stability reports, reporting of results to the

customers

11. Performance monitoring by KPI

12. Regular Jour Fixe with the customer team

Benefits Quasaar

| 25.05.2016

IT safety and data communication within a project

WORKING FOR OUR CUSTOMERS - II

Benefits Quasaar

Data back-up

What will be backed up?

Analytical raw data and documents

Separate, Quasaar-exclusive server established

Commercial data and documents on separate ERP server

Where and when will be backed up?

Backup files: 2 times a day (12:00 / 16:00) to back-up server

Backup VMs: 1 times per day back-up server

Backup: analytical raw data and documents 1 times per week

on Blue-ray Disc

RawdataServer

FileServer

ERPServer

Back-upServer

Data transfer / communication

Technical data connection fiber optic network / internet

Up / Down synchronous lines 100-300 Mbit

Redundant connections to the fiber optic network

Direct entry of data into customer systems (LIMS, SAP)

Establishing local clients (IT) at Überherrn site

Archiving of relevant hardcopies in Quasaar system

Telecommunication: 8-24 parallel trunks (fiber optic)

| 25.05.2016

Efficient Quality System guarantees GMP-compliant

workflows & proceedingsQA ELEMENTS QUASAAR - I

Benefits Quasaar

Quality Manual (QSH)

SMF, VMP, SOPs

Raw data, protocols, templates

Documentation

Change Management

Training

RiskManagement

Qualification

Validation

Deviation

Self inspection

Audits and inspections

Complaints

CAPA-Management

Lab evaluation,

Root cause analysis

OOX

(OOS, OOE, OOT, OOC)

Q

A

| 25.05.2016

Quality Assurance, the basis for customer

satisfactionQA ELEMENTS QUASAAR - II

Benefits Quasaar

Elements QM - System

Document management

• All computerized systems are validated

acc. GAMP5

• Redundant data archiving

• Document system

• Quality Manual, SMF, VMP

• SOPs, testing specifications

• Raw data, protocols, templates

Deviation management established

• Traceability

• Central management by QA

GMP-compliant training & documentation

• Internal training

• External training

• Advanced training & education

• Surveillance

Risk management

• FMEA / FTA / Ishikawa

Qualification

Supplier & subcontractors

Equipment

Validation

• Methods

• Processes

• Computerized systems

Compliance with

regulatory requirements

Customer

satisfaction

Patient safety

Continuous

improvement

Product quality

Data integrity

Document management

Compilation

Steering

Distribution

Archiving

Sample monitoring

Registration

Storage

Stability

Qualification monitoring

Training

Supplier & subcontractors

CS and equipment

Regulatory guides

Audits und inspections

Deviation

Lab evaluation (root cause analysis)

OOX

Audits and self inspections

Customer complaints

CAPA-Management

| 25.05.2016

Each project deserves specific attention

Project management

Customer orientation in outsourcing by Quasaar

Quasaar project management – embedded into the

customers project management

Long-standing experience with outsourcing

situations – gathered at both sides

Own management systems for continuous process

optimization

Highly qualified staff – including an own training

High dedication to deliver on time

Trusted relationships to authorities and customers

Interface development to GMP

Quasaar operates an established interface between

the GMP lab and the development lab

The Quasaar lab works within an environment for

pharma development

Well defined separation between development stage

and GMP

According to the customer needs

Development domain and GMP domain maintain

separate QM systems

Quasaar management highly experienced in GMP

Campus Überherrn provides further competencies to

lean on by a prolific network of partners

Highly flexible in the set-up of the desired test

design and the required documentation

Direct transfer of data into the customers IT systems

CHOICE BETWEEN GMP OR DEVELOPMENT STAGE

Benefits Quasaar

| 25.05.2016

Characterization of particulate systems

SPECIAL KNOW-HOW ON PARTICLES

Bild S. 29 oben

Business Plan 24.03.2016

MJR PharmJet GmbH

Benefits Quasaar

*) EFSA: European Food Safety Authority

Methods for analyzing the particulate structure

Particle size (laser diffraction, Sympatec)

Zeta-Potential (Malvern)

Electron microscopy SEM / TEM (on request)

Particle counting, sieve analysis, Micro-Flow Imaging

and many more

Typical topics with particles

Particle size

Particle contamination, - count

Particle-based formulations

Particle size distribution

EFSA* threshold 100 nm

Agglomeration or disintegration, leakage

effects

Specific drug release profiles

Residual solvent in particulate systems,

elemental impurities

Encapsulation efficiency

Customized HPLC methods

Surface properties

and many more

| 25.05.2016 Know-how Quasaar

Particles impose specific challenges

WHY UNDERSTANDING PARTICLES IS IMPORTANT

Particle range defined in regulatory guidelines (>100 nm, absence of particles >10 μm) does not

cover state-of the-art particle technology (100 nm – 1000 nm)

Not all relevant methods / equipment for characterization of nanoparticles are established in GMP

and other quality systems to be applied

Thorough characterization of particles important, because of great impact of particle

characteristics on product performance, bioavailability, efficacy and other properties

Need for own validation and qualification concepts and development of dedicated equipment

Long-term stability effects of particles must be evaluated (agglomeration, disintegration, leakage

effects…)

Toxicological effects of need to be investigated and an uncritical particle size range defined


Topics for our customers - I

TYPICAL CUSTOMER PROJECTS

Maintenance and variations support, GMP and analytical support

Life Cycle Management "old methods" because of new regulatory requirements, check validation

documents - concept to update the validation (including robustness)

Comparative studies SUPAC for relevant changes in production/formulation (validation of the

relevant methods)

Scientific assessment concerning monograph methods (e.g. Chinese Pharmacopeia), planning

and implementation of relevant validation or verification activities

Compatibility tests drug / excipients, generic methods for evaluating, implementing studies with

small batches of the final dosage form (production of batches MJR-PharmJet)

Development of concepts for qualification, implementation and compilation of GMP-compliant

documentation

Stability and analytical support in development projects - project team consisting of R&D of the

customer, MJR PharmJet for formulation (particulate systems, small batch sizes) and Quasaar to

develop the relevant criteria (e.g. encapsulation efficiency, residual solvents, drug release etc.. )

and many more


Topics for our customers - II

TYPICAL CUSTOMER PROJECTS

Quality Control

Batch release analysis for finished products, active ingredients and excipients (full analysis,

reporting, certificate)

QC of raw materials incl. method optimization and validation of methods according to current

GMP requirements and transfer back to the customer (protocol & report, laboratory training)

Biopharmaceutical characterization and comparison of finished product (pH solubility profiles,

release profiles)

Qualification and auditing of suppliers

GMP-compliant quality control of excipients, risk-based approach validation of analytical methods

Stability

Storage of large-volume batches at ICH conditions (parenteral products, veterinary drugs, bulk),

creation of the GMP documentation stability (storage plans, cumulative stability reports)

Performing of stress tests to proof stability-indicating properties of analytical methods

Determination of shelf life for standard substances and reagents, qualification of standard

substances

and many more


Scientific projects and a very competent network

ensure continuous innovationCOMPETENCE

Additional partner within a scientific

network – additional competence and

techniques

Mecadi GmbH

APV Arbeitsgemeinschaft, FG

Qualitätssicherung und Analytik

Technische Universität

Braunschweig

HTW Saarbrücken (Ibo-Institut,

Ri-Comet)

Helmholtz Institut (HIPS)

IBMT Fraunhofer, BioCryo

Synnovating GmbH

NanoBioNet

…

Recent Publications Quasaar-Team

The Transfer of Analytical Procedures

Influence of X-ray as PAT-Method on Drug Products

GMP-Berater, Kapitel 14G Ergebnisse außerhalb der Spezifikation

(OOX-Ergebnisse)

GMP-Berater, Kapitel 14B Substanzen im Labor

In-situ Drug Release Monitoring with a Fiber Optic System

Partikelmessung von F&E bis GMP

GMP-Berater, Kapitel 14H Dokumentation im Labor

GMP-Berater, Kapitel Geräte im Labor (in Erstellung)

Recent scientific projects – often with competent partners

Development of new methods and techniques for determining and

predicting stability data (IBMT Fraunhofer)

Use of RFID technology in the pharmaceutical environment (Ibo Institute,

Ri-Comet)

Nano-formulations in the context of biological barriers (MJR-PharmJet)

Development of analytical instruments to test innovative dosage forms

Increasing efficiency in the laboratory environment (Synnovating AG)

Permeation and new methods for leakage testing for packaging materials

(Mecadi)

| 25.05.2016

Dr. Christoph Jacobs

Study of chemistry, PhD in pharmaceutical and medical

chemistry

> 15 years GMP expertise in an industrial environment

Head of the API expert team with a provider of analytical

services (Across Barriers GmbH)

Head of QC with set-up and expansion of the QC lab

(PHAST GmbH)

Highly experienced with audits by FDA, European or local

authorities

Expert in dissolution studies and many other QC -

methods

Regular expert speaker about analytical methods under

GMP requirements

Know-how Quasaar

Management team with expertise and competence

MANAGEMENT

Dr. Markus Limberger

Study of chemistry, PhD in pharmaceutical and medical

chemistry

> 15 years GMP expertise in an industrial environment

Focus on drug QA

Many fold project experiences from collaborations with

almost all renown research driven pharma companies

> 10 years Head of Technical Management of a GMP service

provider (PHAST GmbH), installation of GMP and QM

systems

Regular expert speaker about QA and pharma analytics,

member of the respective committee within APV (an industry

association)

Author of several related publications (GMP Berater Verlag)

| 25.05.2016 Innovation & Efficiency

Benefits Quasaar

Combination of flexibility and expertise in a regulated environment

Project team with many fold management experiences in outsourcing

GMP trained team

Well sufficient capacity in laboratory and stability center – further scaling-up possible

Definition of the interface between development stage and GMP according to customers

requirements

Seamless transfer of R&D results into the GMP domain

Analytical lab embedded into an environment for research and product development

Flow of samples and data in continuously optimized processes – and very efficiently

Sustainable quality ensured by integrated staff management and own training efforts

Handling of CTM (Clinical Trial Material), specific qualification/validation projects or teaming-up

within larger programs - as examples - available as service as well.

SUMMARY

| 25.05.2016 Intro MJR PharmJet

Partner for your development projects in pharma or

medtech

Winner 2014Best Innovation

in Formulation

| 25.05.2016 Intro MJR PharmJet

CRO for challenging compounds

SERVICE SPECTRUM OF MJR PHARMJET FOR PHARMA

MJR PharmJet offers

Development partner in R&D projects

based on milestone payments

Specialty – formulation of challenging

API’s

Wide range of conventional methods for

the production of drug products (solid,

semi-solid and liquid)

Production and development of

particulate systems (micro /

nanoparticles)

Solutions with different micro channel

reactors including Micro Jet Reactor

Combination of micro channel reactors

with conventional methods

Optimization of existing formulations

Formulation optimization with Quality by Design methods (QbD)

Improvement of stability and production, excipient replacement due to

regulatory or QA issues- also with nanoparticle alternatives

Improvement of pharmacokinetics – if required

Novel formulations

Pharmaceutical end formulations - especially of challenging API’s

Formulation of Orphan Drugs

Micro channel reactor technology for chemical synthesis

Development of whole particulate systems

R&D services

Development of test systems for:

Detection of impurities

End formulation evaluation

Nanoparticle screening studies for NCE’s

Solubility studies (i.e. for new API’s) and dissolution

Solubility and dissolution studies for micro and nano particulate systems

IVIVC

Further offers

Patent screening for development feasibility

Lab services for clinical trials and CTM preparation

Production of small scale batches for stress and compatibility testing

| 25.05.2016

Contributions by MJR PharmJet can be decisive to

start many development stepsVALUE CHAIN PHARMA DEVELOPMENT

Pharma

MJRparticle-

based

screening

of

NCE’s

MJRparticles

for

in-vitro tests

MJR(particle based)

formulation

of the final

galenic formMJR

production

clinical

trial samples

MJRtechnology -

transfer and

design of

production process MJRset-up of

micro channel reactor

production plant

Lead

discovery

Pre-clinical

evaluationFormulation

development

Clinical

phases

Registration

processProductionScaling-up

| 25.05.2016

Micro reactors and other innovative methods for the

formulation of challenging API’sTECHNOLOGIES MJR PHARMJET

Pharma

Solutions by MJR PharmJet

MJR PharmJet offers almost every

type of innovative methods for the

pharmaceutical development

MJR PharmJet finds for almost all of

the challenging API’s (with low

solubility, unstable, toxic in high doses,

…) a solution

MJR PharmJet offers symbiosis

between modern micro reactor

technologies and other pharmaceutical

processes

MJR PharmJet has huge experience in

transfer of the methods and processes

to its customers - in case of micro

reactor applications with an usually

uncomplicated scaling-up

Innovative methods for pharmaceutical development

For low soluble substances

Wet granulation

Hot Melt Extrusion (HME)

Nano and micro particle development in micro reactors

Nanoparticle development in micro reactors

Complexation

Spray drying / lyophilization

For unstable substances

Encapsulation

Integration in matrix particles

Conventional technologies for scale-up

High pressure homogenization

Batch processes

Further innovative methods – uncomplicated scale-up possible

Micro reactors

Micro mixer

Continuous mixer

| 25.05.2016

Exceptional results with nano and micro particles

Oral Formulations

Improved bioavailability

No “Fed / Fasted” variability

Taste masking

Improved stability for sensitive substances

Controlled or delayed release

Parenteral formulations

No need for solubilizers

No need for surfactants

Immediate dissolution after injection

Increased stability

Low volume applications possible

Pulmonary formulations

Controlled drug delivery to lung

Increased activity

Improved absorption

Nanoparticle in suspension

Ready to use after filtration

Through lyophilization further stabilized and showing

very good redispersibility

PHARMA APPLICATIONS

Pharma

Realization of all steps

Step 1: Development of particle

Step 2: Development of end formulation

Step 3: Transfer to scale-up and production at

Customer/Partner

Manufacturing method selected

specifically (via micro reactor or other

methods)

Later a very efficient integration to

existing production processes

CTM production / early GMP production

for scaling-up possible

Competence for next steps is

established on the campus - early

integration of Quasaar as GMP-Partner

possible

Development of «Drug Delivery Systems»

with micro or nano particles

Technology licenses for finished drugs manufactured by using the special equipment of the micro jet reactor via leon nanodrugs GmbH

| 25.05.2016 Micro Reactor

How micro reactors work

REACTION PRINCIPLE

Optimized mixing

Minimal mixing time

Jet velocity 100 m/sec

Mixing time < 0.1ms

Reactant 1 Reactant 2

3 cm

Example here: Special type Mikro Jet Reaktor; diameter nozzle Ø 50-1000 μm

1. Continuous precipitation

Carrier Gas

inert / reactive

Stable particles (+ gas + liquid)

in suspension or emulsions

2. One-step reaction

3. Parallelization and serialization

4. Optimization by control of process parameters like temperature,

pressure, flow rates, solvent composition etc.

| 25.05.2016

Application of micro reactors – highly beneficial in

formulation development

Batch size independent results

Volume can be reduced

Good control of processes

Mixing velocity optimized

Chemical synthesis by stoichiometric feeding of reactants very well controllable

Production run as a continuous process – and via parallelization with high through-put

Scaling-up in further development steps well enabled

Also two step synthesis via the gas possible

Also for sensitive reactions, the micro reactor offers a highly suitable environment.

Several types of micro reactors are available today.

For each application, the best suitable type of reactor can be selected.

The Micro Jet Reactor was the first of this kind and MJR PharmJet has lots of expertise with it.

ADVANTAGES MICRO REACTORS

Micro Reactor

| 25.05.2016

From simple particles to complex shell systems

CASCADING THE PROCESSES

„naked“(nano) particles

Core/shell particles

Multilayered(nano) particles

Nano emulsions

Coatednano-emulsions

Specific advantages compared to

the Wet Nano Mill:

- Less harsh to sensitive

compounds

- Very narrow particle size

distribution

- Faster processes

- Lower production costs

Micro Reactor

Micro reactor processes in the

generation of particles provide:

- Continuous production

- Controlled reaction

- High quality particles

- Tight control over particle size

| 25.05.2016

Many types of micro - and nanoparticles can be

made in the micro reactor

Emulsions

Liposomes

(Nano) particles with a lipid-solid composition

Inorganic nanoparticles

(Nano) particles of active ingredients – w/o shell

(Nano) particles built-up by a polymer matrix

Particles used in modified release of API

TYPES OF PARTICLES

Nano- / micro particles – w/o shellBiocides

Insoluble metal oxides / specifically generated

Poorly soluble API

EmulsionsParticles made of lipophilic or oleic compounds will be

improved in

Uniformity / homogeneity, composition and color, and

their processing; applicable to

flavor additives, fragrances, or in general oils & waxes

Encapsulated nano / micro particles

- improved stability of sensitive compounds

- taste masking

- improved handling in production processes p.ex. by

higher dispersibility

Applicable to

- pigments / colorants

- food additives like vitamins, Omega-3 fatty acids, etc.

- fragrances

- agro-chemicals

Micro Reactor

| 25.05.2016

Also for medtech and cross-over products new

types of solutions are available

Potential application areas

In-vitro diagnostics

In-vivo diagnostics

Concepts within theragnostics or

companion diagnostics

Ready-to-use (RTU) parenteral

products

Particles as carrier systems (as

examples) for

Active ingredients

Tracer

Compounds for imaging

Applications within or by help of

medical devices

Cross-over applications

Plus more

APPLICATIONS MEDTECH/PHARMA

Medtech

Current projects MJR PharmJet

Drug targeting with iron oxide

particles

Pulmonary drug targeting with

extended release nanoparticles

Transdermal therapy with

nanoparticles

Drug targeting through blood brain

barrier

| 25.05.2016

Medtech profits from MJR PharmJet’s competence

in the design of whole systems

First examples from the medtech arena

Ready-to-use (RTU) parenteral drug formulations

Particle as carrier system for API’s

Integration of surface technologies from chemical

nanotechnology (for stents p.ex.)

Contrast agent

Specialized surfaces

Implants

Antimicrobial

Biocidal copper derivatives to be used in patients

(also as silver replacement)

Particles to release an API in wound healing

With antibiotics – applied to skin wounds

To fight a bacterial biofilm in the oral cavity

Nano-hydroxyapatite for dental care

Transfer of know-how and expertise from the

pharmaceutical development field

TRANSFER OF PARTICLE TECHNOLGIES INTO MEDTECH

Medtech

Highly controlled manufacturing of SPION’s with the

MJR technology

(= Super Paramagnetic Iron Oxide Nanoparticles)

Manufacturing of SPION’s in micro reactor

Construction of encapsulation (LbL – Layer by Layer) in

micro reactor

Magnetic nanoparticle (specially SPION’s)

Adapted to the physiologic environment with outer shells

Super para-magnetic for use in MRI etc. and stable

Bi-functional SPION‘s for optical imaging and MRI

Tracer conjugated SPION‘s as MRI – nano props with

different tracers (antibodies, carbohydrate chains,

aptamers and other oligonucleotides, peptides,

polymers, etc.)

Nano particles as carrier for radio nuclides for

diagnostics or therapy

Bi-functional nanoparticle for PET + MRI

| 25.05.2016

State-of-the-art test systems and technologies

available at MJR PharmJet

CaCo - 2

Skin models

Barrier models

Dissolution of API’s from nanoparticles

Magnetic mobility of nano particles

ELISA-methods

Cytotoxicity evaluations

Migration evaluations

Microbiological evaluations

Biofilm models

Mucus models

SOME SPECIFIC MEDTECH TECHNOLOGIES

Medtech

| 25.05.2016

High-through-put screening of poorly soluble lead

compounds – enabled by nano particlesAPPLICATION EXAMPLE

Application Examples MJR PharmJet

•Application route

•Definition of project objective

•Desired properties

Selectionof excipients

•Physical-chemical characteristics of target substances

•Application route

Definition of particle type •High throughput

screening with low amount of API

•> 500 trials in few weeks

Particle-based screening

•Diafiltration

•Lyophilization

•Wet granulation

End formulation studies

Advantages

Ideally suitable for R&D-labs

working with innovative and thus

not yet characterized substances

und lead structures

Very small amounts of the lead

compound or NCE / API sufficient

Initial and seminal results quite

early and fast available for further

orientation of the research project

Result

Early (wrong) bias against poorly

soluble, but otherwise promising

lead substances avoided

| 25.05.2016

Improved dissolution of an otherwise poorly soluble

API

Problem

Low solubility dependent low bioavailability

Dissolution kinetics should be improved

API dose should be decreased

Task

Screening for the best possible formulation to improve the

bioavailability

Solution

3 different formulation

Wet granulation

Hot melt extrusion

Nanoparticle

Best dissolution profile using nano particle formulation

0

20

40

60

80

100

0 10 20 30 40

Dis

so

lution

/ %

Time/ min

Dissolution with 1% SDS in water, 50 rpm

Crude API Wet granulation

Hot melt extrusion Nanoparticle formulation

APPLICATION EXAMPLE


| 25.05.2016

Extended release of a well soluble API – avoiding the

initial «burst» release after injection

Problem

API for a ready to use suspension

«Burst» effect should be prevented – good soluble API

Extended Release of the system

Task

Ready to use ER suspension of a good soluble API

Solution

With Micro Reactor in following steps

PLGA micro particles (in polymer matrix)

Lyophilisation

ER Formulation

Dissolution rate adjustable with different polymers (F1, F2, F3)

Stable formulation

0102030405060708090

100110

0 50 100

Dru

g re

leas

e/

%

Days

F1

F2

F3

APPLICATION EXAMPLE


| 25.05.2016

Drug eluting stents with nanoparticles

Out of the development platform for combined

products

Advantage of polymeric nanoparticles

Homogenous coating of stents

Extended release of API

Controlled application of API

Optimal API dosing

Enhanced stability

Advantage of micro reactor

High API loading into polymeric systems

Homogenous release through homogenous particle

size

APPLICATION EXAMPLE


| 25.05.2016

Antibiotics in wound treatment – good penetration in

nano particle formAPPLICATION EXAMPLE

Problem

Biocides and antibiotics are only moderately effective in plaster matrix

In the beginning to much API

Biofilm caused by the wound bacteria inhibit the penetration of

antibiotics

Task

Antibiotics should be integrated in a particle matrix– The particles

should penetrate into the wounds and realize the long term release of

the API

Solution

Matrix nanoparticle optimized for

Penetration into the wounds

Does not interfere with the wound healing and non-toxic

Release of antibiotics

Trials

Favorable matrix

Appropriate antibiotics

Barrier models

Wound model

Combination with plaster

(Center for Biofilm Engineering©

Cooperation with divers Institutes

Robert Koch Institute

Charité Berlin

Freie Universität Berlin


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In-vitro diagnostics with magnetic nanoparticles

Versatile system for Diagnostics

Advantage of magnetic nanoparticles

Easy visualization by MRT or EM

Moving of particles in magnetic field (lab on a chip)

Easy separation of particles by magnetic field

Easy quantification of bound substrate by magnet-

relaxometry

Advantage of micro reactor

High volume production of controlled particle size

Coating with various surface agents possible

Functionalization of surface with various molecules

possible

SPION’S - I


Ferrofluid

Nanoferrit

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SPIONS – can perfectly manufactured in the micro

reactorSPION’S - II

SPION’s = Super Paramagnetic Iron Oxide Nanoparticles

Task

Manufacturing of γ-iron oxide and at the same time coupling of

physiologically active / relevant substances

Solution

Production of complex structure in micro reactor using several

steps

Step 1: Synthesis of γ-iron oxide

Particle size: 20 – 30 nm

Homogeneity: PDI < 0,2

Concentration in water: 2% - 20% adjustable

Step 2: Coating of SPION

Polyanions or rather polycations or various silans

Molecular imprinting

Biopolymers

Step 3: Functionalization / activation agent integration

Step 4: Coupling of tracer for the desired diagnostics

TEM / picture of SPION

nanoparticles

Particle size distribution

of SPION 30 nm

with a PDI of 0.197


| 25.05.2016

SPIONS – coupled to a tracer for innovative imaging

and other medtech – pharma applicationsSPION’S - III

SPION’s = Super Paramagnetic Iron Oxide Nanoparticles

Use in medtech & pharma

For Imaging, p.ex. MRI diagnostics, where NMR seeks to

replace the radio nucleotide, but the signal of usual NMR is

limited

Imaging in combination with fluorescence dyes (see picture)

As drug delivery vehicle - moved by magnetic forces

Control of particles at tumor side

For Hyperthermia therapy

For various combinations of therapies

Tracer can be

Antibodies

Aptamers / Oligonucleotides

Peptides

Specific carbohydrate structures

Simple polymers


Polymeric

cover

Drug

Fluorescence

dye

Polycations

SPION

| 25.05.2016

Dr. Akif Emre Türeli

CSO MJR PharmJet GmbH

Studies of pharmaceutical sciences in Turkey

10 years experience in international nano technology

industry

Drug formulation specialist

Developer of many fold innovative applications of the

Micro Jet Reactor for the formulation of drugs

Co-founder and shareholder of Instillo Group

Know-how MJR PharmJet

Management team with expertise and competence

MANAGEMENT

Dr. Bernd Baumstümmler

CEO MJR PharmJet GmbH

25 years of experience in pharma and biotech

Product Manager with Abbott

Technology Advisor in biotechnology for Hessische

Technologiestiftung

Project Manager Mediport Venture Capital, Berlin

Several positions in Biotech and pharma start-ups, usually as

COO/CEO

Founder of the Instillo Group

| 25.05.2016

Benefits MJR PharmJet

Upon involvement at early stages in the development process, MJR PharmJet can find solutions

also for poorly soluble or sensitive substances

MJR PharmJet can ensure a seamless transfer of results into the highly regulated GMP regime

via Quasaar

MJR PharmJet is proud to think of issues in application systems instead of sole compounds – be

it in pharma, be it in medical technology

Deep understanding of the special challenges in medical technologies

Embedded into a network of research and development – working at the very recent topics in

medical technology

Several model systems to test particulate systems available

Optimization of formulations, QbD (Quality by Design), reformulations of products to bring-up the

product to actual standards or for life cycle management

All suitable and state-of-the-art formulation techniques available

Strong expertise in the development and application of particulate systems

SUMMARY

Know-how MJR PharmJet

| 25.05.2016 Joint Know-how

The campus in Überherrn

The commonly shared campus

at Überherrn is provided and

managed by Instillo GmbH.

| 25.05.2016

Combined competencies – highly beneficial for the

customer QUASAAR – MJR PHARMJET

Outsourcing partner

for the Life Science industry

Partner for the development of

product & system solutions

Method development &

validation

Efficient and proven GMP

system

Experts for the application

of all kind of analytical

methods – with all kind of

formulations

Also experts in handling of

all kind of particles

Experts in the handling of all

kind of particles and their

generation, i.e.

Precise manufacturing of

particles, specific analytics,

understanding the efficacy

Partner for early stage

development works

Very high quality level in

R&D

Synergies

Common development of methods, where

suitable

Seamless transfer from R&D into the regulated

GMP regime for production and control

Fast and easy transfer of know-how and

technologies from R&D into GMP

Synergies lead to faster projects and lower

costs

Commonly shared overhead services via the

“Shared Service Center” by Instillo GmbH

Joint Know-how

| 25.05.2016

State-of-the-art labs on the campus

CAMPUS ÜBERHERRN

GMP area of labs Quasaar

Development lab nanoSaar

Joint Know-how

Access to GMP area only via chip card control

Development lab MJR PharmJet

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GMP area - clearly separated

CAMPUS ÜBERHERRN

Access control

- Chip system

- Restricted key list

Monitoring system to control room temperature

- Sensor system

- Fully closed rooms

Pest control at critical points

Stability Center

Office building

Reception

GMP lab QuasaarDevelopment lab nanoSaar

Utilities

GMP resp. Quasaar-domain

Joint Know-how

Development lab MJR PharmJet

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Combined know-how on the campus and beyond

NETWORK OF COMPETENCIES

Including many fold external partner via the network of all companies on the campus

Joint Know-how

MJR PharmJet GmbH

CRO for pharma

Formulation development

for exacting substances –

with all suitable methods

Cooperation partner to

medtech companies

Application of the MJR

patents & technologies

in medtech

Quasaar GmbH

Outsourcing partner

QC & product control

Stability studies

Analytics & methods

Technology transfer

GMP-support

nanoSaar AG

Applications: Consumer,

non-Pharma and

cosmetics and other

Promotion of the

technology in specialty

chemicals & technical

applications

License models as well

as product supply on

choiceCompetence Center on the Campus Überherrn

Cost synergies

via the combined

group of

companies

Transfer of know-

how and

competencies

across the group

Fast track from

R&D to GMP

BEST OF 2016MIKROSYSTEMTECHNIK

MJR PharmJet also received the Gips-Schüle Award 2015 in Research: “Nano particles in the environment friendly production of solar cells”

nanoSaar also was a finalist (one of 4) with «Innovationspreis der Deutschen Wirtschaft 2016»

CPhI Pharma Awards

Winner 2014Best Innovation in Formulation

| 25.05.2016

The Überherrn premises

LOCATION / CAPABILITIES

Well located for logistics

D, F, Benelux within easy reach

5 min to motorway A 620, 10 min to A32/A4

(F)

40 min to Luxemburg airport

25 min to TGV/ICE

Paris – Saarbrücken - Frankfurt

Characteristics for the campus

12’000 m² total premises

5000 m² buildings

350 m² office space

1000 m² laboratory area –

further expandable

500 m3 stability center –

further expandable

Very modern energy concept

- photovoltaic arrays

- Batteries (also for safety reasons)

- Block heat and power plant

based on existing industrial premises.

Campus is operated by instillo GmbH.

Industrial area „Im Häsfeld“

Comotorstr. 2

Visitors: Industriestr. 1B

66802 Überherrn

Joint Know-how

| 25.05.2016

Contact

MJR PharmJet GmbH

Dr. Bernd Baumstümmler

T +49 (6836) 9691 100

M +49 (176) 32205115

[email protected]

Industriestraße 1B

66802 Überherrn

www.instillo.de

Quasaar GmbH

Dr. Markus Limberger

T +49 (6836) 9691 212

M +49 (162) 9677500

[email protected]

Comotorstr. 2

66802 Überherrn

www.quasaar.de

Your Partner in Outsourcing & Product Development

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