mjr pharmjet - nano2clinic · 2019-04-13 · current state & future directions 12.04.2019...

MJR PharmJetChallenges of scale-up and GMP manufacturing of nanoparticles

Dr. Nazende Günday Türeli

Nano2Clinic: Cancer Nanomedicine - from the bench to the bedsideFIRST CA17140 TRAINING SCHOOL

Trieste April 8-11 2019

Member of Instillo Group

THE ECONOMIC DEVELOPMENT OF NANOTHERAPEUTICS

IN THE EU:CURRENT STATE AND FUTURE DIRECTIONS

12.04.2019 -confidential- 2

Nanotherapeutics


Liposomes

Polymeric Nanoparticles

Nanocrystals

Polymeric Therapeutics

Virosomes

Nanoemulsions

Polymeric micellesNanocomplexes

Nanotherapeutics with the pharmaceutical and commercial potential (Hafner A. et al., Dove Press, 2014)

Nanotherapeutics


Liposomes

Polymeric Nanoparticles

Nanocrystals

Polymeric Therapeutics

Virosomes

Nanoemulsions

Polymeric micellesNanocomplexes

Nanotherapeutics with the pharmaceutical and commercial potential (Hafner A. et al., Dove Press, 2014)

Nanomedicine for anticancer therapy(Biswas A. et al., Adv. Nat. Sci: Nanosci. Nanotechnol, 2014)

Successfully established Nano-formulations


Reference: A FDA Perspective on Nanomedicine Current Initiatives in the US, Carlos Pena, 2010

Nanotherapeutics

✓ According to data from 2005 nanomedicine industry in Europe;- 92 start-ups (44%)- 67 SMEs (32%)- 41 large pharmaceutical or medical device companies (21% )

✓ In the nanomedicine application, process development of nanomedicine is related to start-upsand SMEs

✓ 56% of nanomedicine companies have products related to drug delivery and therapy. Thenanomedicine publications in therapeutics have a wide coverage with 76% and the share ofproducts in overall nanomedicine market is about 80%.


Nano-Products


StatNano is a statistic bank dedicated to gather and analyses data in nanotechnology that includes lastest statistic.

(statnano.com, accessed on April, 2018)

Some Statistics…


The nanoarticle numbers in European countries (statnano.com, accessedon October)

The nanoarticle numbers in world (statnano.com, accessed on October)

✓ Leader of Europe in article numbers isGermany followed by France with 1071article in March, 2016

✓ Leader of world in article numbers10366, is China following by USA.

Some Statistics…


The nanotechnology patents (statnano.com, accessed on April, 2019)

The nanotechnology patents (statnano.com, accessed on April, 2019)

USA

Ger

man

y

Fran

ce

UK

Ch

ina

Taiw

an

✓ According to European Patent Office,patents on nanotechnology by years beforeand after USA joining to graph.

Some Statistics…


The ratio of nanotechnology patents to nano articles (statnano.com, accessedon April, 2019)

The ratio of nanotechnology patents to nano articles (statnano.com, accessed on April, 2019)

USA

Ger

man

y

Fran

ce

UK

Ch

ina

Taiw

an

24.04 article is related to nanotechnology for every 100 article published

In Germany:

World MarketNanotechnology in Healthcare

12.04.2019

Total Market 8 bio. US$ 119 bio. US$

Nanodrugs 6 bio. US$ 70 bio. US$(Antibodies, Drug-Delivery-Systems )

Implants 0.43 bio. US$ 39 bio. US$

Analytics & Diagnostics 1.9 bio. US$ 6 bio. US$

Reference: Ernst & Young 2007

2006 2021

11

Protection of Revenues

Life Cycle Management

12.04.2019 12

extentedproduct life cycle

reve

nu

es

time

revenuesgains

expiry of patent protection→ loss of exclusivity→ generic erosion

launch

typicalproduct life cycle

in January 01, 2007 issue of Drug Discovery

(Source: Cutting Edge Information “Defending brand revenue - Pharmaceutical life cycle management planning June 2005”)

Costs of Strategies

12.04.2019 13

Abbot LabsAlzaAmgenAstraZenecaAvanir PharmaceuticalsAxcan PharmaBayerBiogen IdecBristol-Myers SquibbEli LillyEndo PharmaceuticalGenentechGlaxoSmithKlineJanssen-CliagKing PharmaceuticalsKOS PharmaceuticalsMerck & Co.NovartisPfizerRocheSanofi-AventisSchering-PloughTerumo PenpolWyeth

Profiled companies:Life Cycle Management

Typical costs of strategy / millions US $

http://e-ditionsbyfry.com/Olive/ODE/RDDSupp/Default.aspx?href=RDD/2007/01/01&pageno=46&view=document

http://www.cuttingedgeinfo.com/research/portfolio-management/lcm-strategy/

ROI of Strategies

12.04.201914

130

29.92

13.30 11.33 10.80 10.00

0

20

40

60

80

100

120

140

$ e

arn

ed

pe

r 1

$ s

pe

nt

Report „Pharmaceutical Lifecycle Management (PH141)“ (2010).

Life Cycle Management

Blockbuster based on Nanoformulation

FenofibrateUS-Market / Abbott

12.04.2019 15

184 154

868

0

200

400

600

800

1000

1998 2000 2002 2004

Mio

. US

$ (

in Q

1)

LaunchCapsule / Abbott

Launch „Nano“ / Abbott

Launch ofseveral Genericswith “old“ technology

11

1999 2001 2003 2005

The launch of the Fenofibrate nanoformulation is a convincing example ofactive Life Cycle Management based on Nanotechnology.

Generics are not competitive and have no chance against Abbott‘s nano-Fenofibrate.

Dosing of Fenofibrate

1

0.67

0.530.48

0.45

0

0.2

0.4

0.6

0.8

1

0

50

100

150

200

250

300

1990 1995 2000 2005 2010

Year

Standard Micro Nano

Do

sis

/ m

g

Re

lati

ve D

osi

s

Reduction of Dosis by 55 % introducing Nanotechnology12.04.2019 16

No effect of foodEffect of food

300 mg

200 mg

145 mg135 mg

160 mg

par

en

tera

lo

ral

▪ Doxorubicin Essex Pharma, Cephalon Oncology

▪ Amphotericin Astellas, Gilead Anti fungal

▪ Sirolimus Wyeth Immunsuppressive

▪ Paclitaxel AstraZeneca/Abraxis BioScience Oncology

▪ Paliperidone Johnson & Johnson Schizophrenia

▪ Aprepitant Merck Sharp & Dome (MSD) Anti emetic

▪ Fenofibrate Abbott Dyslipidemia

▪ Megestrol Acetate Par Pharmaceutical Anti anorexic

Successfully established Nano-Reformulations

12.04.2019 17

Market Penetration

Approach & Company:• Liposomal

• Wet Milling

– Elan: “NanoCrystal”

• High Pressure Homogenisation

– SkyePharm: “DissoCubes”: no product marketed

– PharmSol: “Nanopure”

– Baxter: “NanoEdge”

• RESS

– No implementation in large scale production

5 out of 8 marketedproducts

2 out of 8

1

1990 1995 2000 2005 2010 2015

Year ofApproval

Evolution of Nanopharmaceuticals

1995 2000 2005 2010 2015

Liposomes

Year of FDA Approval

Wet Milling

What keeps us behind…


The production of innovative nanopharmaceuticalsin quantity and quality (GMP) required for them to enter clinical trials remains a challenge:

• Not easy implementation in existing manufacturing plants. • Lack of resources in small companies to scale-up and implement GMP manufacturing.

Nanotherapeutic Translation


The final aim of R&D activities in the field of the nanotherapeutics is successfultranslatable trends. In this direction some difficulties rises;

o Control deficiency;o Separation from undesired nanostructures;o Scale-up issues;o Increasing the production rate;o Reproducibility from batch to batch according to particle size distribution, charge, porosity, and mass;o High costs of fabrication;o Lack of nanosystem and living cell knowledge like biocompatibility and toxicity;o Venture funds;o Unwillingness pharmaceutical industries to nanotherapeuticso Media focus on the favorable aspects of nanomaterials often without proof

Europe holds a leader position for scientific research but has failed to turn powerinto commercially available products. It is expected to create new interest innanotechnology on patient benefit and EU economy.

Nanotherapeutic Research and Development


First generation nanotherapeutics with oral doses thathave attained marketing authorizations by EuropeanMedicines Agency (EMA).

✓ In 2010, first international workshop on medicine isorganized by EMA with more than 200 participantfrom all over world.

Another initiative is European Commission TechnologyPlatform on Medicine (ETPN) led by industry andpromoted by European Commission to achievebreakthroughs in health care and enhance innovationsin the nanotechnology.

✓ Nano-forum is a database financed by EuropeanCommission which focused on European countriesand show registrations. As an old butcomprehensive data, in 2005, overall number is1538 of organizations which were entire to databasefrom 33 countries and half of these registrationsfrom Germany.

✓ Framework Programme forResearch and TechnologicalDevelopment are the fundingprogramme created byEuropean Union/EuropeanCommission. During first fourinvitation of the SeventhFramework Programme theinvestments in nanomedicine ishigher than the investments innanomedicine projects duringwhole Sixth FrameworkProgramme.

✓ Nanomedicine will effectivelylend to the next programmeHorizon 2020.

Current State & Future Directions


The global market for nanotechnology products;✓ $22.9 billion in 2013 and increased to about $26 billion in 2014.

✓ This market is expected to reach about $64.2 billion by 2019, a compound annual growthrate CAGR of 19.8% from 2014 to 2019.

✓ The Global Nanotechnology Market Outlook 2025 is poised to grow at a CAGR of around18.1% over the next decade to reach approximately $173.95 billion by 2025.

A worldwide pharmaceutical market analyzing report has been published by BCC Research.In respect to BCC;

✓ Industry market values was US$214.2 billion in 2013 and US$248.3 billion in 2014.

✓ According to BCC report the total market is projected to grow at a compound annual growthrate (CAGR) of 16.3% from 2014 through 2019 and reach to US$528 billion by 2019.

Factors Driving the Development

• Market need for a product

• Real -> Cure for pancreatic cancer

• Perceived -> Nutritional supplements

• Potential

• Compounds with activity against target receptor

• Nascent technology

• New insights through basic research

• Defined target market characteristics enable

• Product to be promoted, distributed & sold

• Good return on investment

12.04.2019 24

Type of Products

12.04.2019 25

New Chemical Entities

New BiologicalsApproved Drugs

New Formulations

Approved Drugs

New IndicationsGenerics Biosimilars

DevicesDrugs&DevicesCombinations

Gene Therapies

Theranostics

Cell Therapies

BuccalSublingual

Across theSkin

Nasal

Inhalation

Oral

Parenteral

Route ofAdmin

Timeline for Development NCE

Basic research

Understand & identify target

Drug discovery

5000 compounds

Preclinical studies

250 compounds

Phase 1

5 compounds

1 approveddrug

− Discovery− Product Characterization− Formulation, Delivery, Packaging Development− Pharmacokinetics And Drug Disposition− Preclinical Toxicology Testing And IND Application− Bioanalytical Testing− Clinical Trials

12.04.201926

Pathway to Market

12.04.2019 27

Select candidate from preclinical studies & file IMPD/IND

Phase I: 20-100 candidates-Evaluate Safety & Dosage

Phase II: 100-300 patients-Evaluate Efficacy & Side Effects

Phase III: 100s-5000 patient-Against “Gold Standard“

File dossier & Obtain Regulatory Approval

Pricing, Reimbursement, Phase IV, Pharmacovigilance

6-7 years from beginningPhase I to End Phase III

0,5 to 2 years

Pharmaceutical R&D Requires the Highest Level of Investment in the World; A Measure of Risk

Source: PhRMA, 2001, Based on Data from PhRMA Annual Survey and Standard & Poor’s Compustat, a Division of McGraw-Hill

Industrial Sector Comparison:

10.5%

8.4%

7.8%

5.3%

4.7%

3.9%

1.2%

3.9%

0.73%

3.8%

Computer Software & Services

Office Equipment & Services

Automotive

Telecommunications

Leisure Time Products

Aerospace & Defense

Metals & Mining

Paper & Forest Products

All Industries

Electrical & Electronics

What is a Generic Drug?

A drug product that is comparable to a brand/reference listed drug product in dosageform, strength, route of administration, quality and performance characteristics, andintended use.

Generic drug can be marketed when;− After patent & exclusivity protection ends, or− Patent owner waives its rights, and− Regulatory requirements are met.

Basic requirements for generic drugs;− Same active ingredient(s)− Same route of administration− Same dosage form− Same strength− Same conditions of use− Inactive ingredients already approved in a similar

NDA

12.04.2019 29

Patent and generics

Patent Protection

− 17 years from the date the patent was issued or 20 years

from the date submitted to the Patent Office, not FDA

Approximately 12 years of marketing protection

− Exclusivity Award/reward of marketing protection of 3 to 5

years for innovative development to an existing product (i.e.

new uses, strengths)

− 6 months for pediatrics

12.04.2019 30

Why generics?

The Ultimate Endorsement for Generics;

− Reduce Drug Costs

− Increase Drug Use

− Prevent Drug Shortages

− Product rationalization

− Supply disruption

12.04.2019 31

Scale up

32

Scale up possibilities include…

➢ Conventional technologies

o High pressure homogenization

o Batch process e.g. Milling

➢ Innovative technologies

o Micro-channel reactors

o Micro mixers

o Continuous mixers

Wet Grinding with Perl Mill

Input• crude drug powder• stabilizers

– drug : stabilizer 20:1 till 2:1 w/w– cellulosics, pluronics, polysorbates,

povidones

• Water• Milling Media

polystyrene balls, Ø 200 µm or 500 µm

Output• suspension with particle size down to

100-400 nm• Particles coated with stabilizer

12.04.2019 33

http://upload.wikimedia.org/wikipedia/commons/c/c2/Ball_mill.gif

Lee, Development and Scale-Up of NanoCrystal Particles. In: Injectable Dispersed Systems (2005) 355-370.Merisko-Liversidge, European journal of pharmaceutical sciences 18 (2003) 113.

heat

Type of Nanoparticles

API

mixture of API & polymersolid solution

crystalline nanoparticleAPI + stabilizer

amorphous nanoparticleAPI + stabilizer

polymer

API coated with polymer

Need for Stabilizers

12.04.2019 35

Input for Production of TriCor• Fenofibrate ~ 30 %• Hypromellose ~ 6 %• Na docusate ~ 0.1 %• Water ~ 63.9 %

500 µm polystyrene balls as milling media90 min milling time to archive ~170 nm size

Manufacturing Hardware

12.04.2019 36Lee, Development and Scale-Up of NanoCrystal Particles. In: Injectable Dispersed Systems (2005) 355-370.

• Different batch size→ different manufacturing hardware• Different batch size→ different manufacturing process

• continous process for large scale• iterative for small size production

10 ml

100 ml

1 l

10 l

100 l

0.1 g

1 g

10 g

100 g

1 kg

10 kg

100 kg

1000 kg Ch

amb

er

Vo

lum

eB

atch

siz

e

Nan

oM

ill-0

01

Nan

oM

ill-2

Nan

oM

ill-6

0

Nan

oM

ill-1

0

Nan

oM

ill-0

1

Nan

oM

ill-1

recirculation

batch wise

NanoMill® Specifications

Manufacturing Hardware

12.04.2019 37Liversidge, G. G. Application of NanoCrystal ® Technology to Poorly Water Soluble Compounds (2009).

NanoMill-01

NanoMill-1

NanoMill-2

NanoMill-60

batch wiseprocess

recirculatingprocess

NanoMill®–2 Manufacturing Platform

12.04.2019 38

NanoMill® is a registered trademark of Elan Pharma International Limited.

Source: ELAN (2008)

Volume Milling Chamber 2 lBatch Size 1-10 kg

NanoMill™-60 Pilot Manufacturing Plant

12.04.2019 39Merisko-Liversidge, Liversidge, Advanced drug delivery reviews 63 (2011) 427.

100 - 500 kg API Batch Size

Milling chamber

Wet Milling & Particle Size Reduction

12.04.2019 40Merisko-Liversidge, Liversidge, Advanced drug delivery reviews 63 (2011) 427.

0

15

30

45

60

0.01 0.1 1 10 100 1000

Particle Size / µm

Mill

ing

Tim

e /

min

Wet-milling of naproxen stabilized with povidon

197 nm

328 nm

1 216 nm

89 882 nm

Snow, Size Reduction and Size Enlargement. In: Perry´s Chemical Engineers Handbook, Chapter 20 (1997).

Milling & Efficiency

(74µm Sieve Opening)

decreasing particle size

12.04.2019

with decreasing particle size• increase of processing time • decrease of capacity

• increase of energy consumption & cost

time consuming & costintensive,especially in nano range

41

Q C

Offices Gowning

Canteen

Incoming goods

Corridor

Corridor

Shipping

Corridor

Packaging Weighing Processing

Filling

Raw Materials

& Packaging

Storage

Washing

Machine

Shop

Finished

Products

Storage

Corridor Utilities and Services Waste Treatment

Premises

Example of Materials and People Flow

Arrival of goods Entrance for visitors Entrance for Workers Shipment of goods

Material Flow

People Flow

Zone: Clean

Zone: Packaging

Zone: Controlled

WHO, Training Workshop on Pharmaceutical Development with a focus on Paediatric Formulations, 2007

Existing guidance documents


Reference: A FDA Perspective on Nanomedicine Current Initiatives in the US, Carlos Pena, 2010

Existing guidance documents

ICH Quality Guidelines (http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html )

• Q1A - Q1F Stability• Q2 Analytical Validation• Q3A - Q3D Impurities• Q4 - Q4B Pharmacopoeias• Q6A- Q6B Specifications• Q7 Good Manufacturing Practice• Q8 Pharmaceutical Development• Q9 Quality Risk Management• Q10 Pharmaceutical Quality System• Q11 Development and Manufacture of Drug Substances• Q12 Lifecycle Management

FDA Guidelines• Bioanalytical Method Validation Guidance for Industry• Drug Products, Including Biological Products, that Contain Nanomaterials - Guidance for Industry• Regulatory Classification of Pharmaceutical Co-Crystals- Draft• Elemental Impurities in Drug Products• Good ANDA Submission Practices Guidance for Industry• Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms Containing Biopharmaceutics

Classification System Class 1 and 3 Drugs Guidance for Industry• Guidance for Industry Process Validation: General Principles and Practices• Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, guidance for industry• PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, guidance for industry, • Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, guidance for industry• Guidance for Industry. Container Closure Systems for Packaging. Human Drugs and Biologics.• Guidance for Industry. Sterile Drug Products. Produced by Aseptic Processing —. Current Good Manufacturing Practice• Guidance for Industry. Bioavailability and Bioequivalence. Studies Submitted in NDAs or INDs—. General Considerations

12.04.2019 -confidential-

http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

12.04.2019 45

Quality by Design in Development

Why QbD?

Generic industry business model: Regulator’s perspective

➢ File first, learn later

➢ Major amendments during review process

➢ Exhibit batch stability failure, formulation revision

➢ Longer time for generic product approval

➢ Approved product may not be marketed

➢ Post approval changes – prior approval supplements

What Does Drug Companies Do Wrong?

What is QbD?

➢ Systematic, holistic and proactive approach to pharmaceutical development.

➢ Begins with predefined objectives

➢ Emphasizes product and process understanding and process control

➢ Based on sound science and quality risk management

Ref.: ICH Q8 (R2)

What is needed?

How QbD Will Help Improve?

➢ Ensure higher level of assurance of product quality for patient

o Improved product and process design & understanding

o Monitoring, tracking & trending of product & process

➢ More efficient regulatory oversight

➢ Efficiency and cost saving for industry

o Increase efficiency of manufacturing process

o Minimize / eliminate potential compliance actions

12.04.2019

Overview of QbD

Quality Target

Product Profile

Product Design and

Understanding

Process Design

and Understanding

Control

Strategy

Continuous

Improvement

➢ Quality Target Product Profile (QTPP)

➢ Define Critical Quality Attributes (CQAs)

➢ Perform risk assessment

➢ Link raw material attributes and process parameters to CQAs

➢ Design and implement a control strategy

➢ Manage product lifecycle, including continuous improvement

Elements of QbDImportant Points of QbD

12.04.2019 50

Quality Target Product Profile-QTPP

What is QTPP?

– A set of elements that defines the drug product

– The target or goal set in advance

– A guide to Drug Product development

What forms the basis for QTPP?

– The RLD and its label

– Applicable regulatory guidelines

When to define QTPP?

– At the start of development

– Knowledge gained in development may change some elements

12.04.201951

Components of QTPP

Components related to safety, efficacy, identity, purity and potency

Critical and non-critical components, e.g.

– Critical: Assay, content uniformity

– Non-critical: Appearance

Fixed and variable components

– Fixed elements must be present

e.g. Dosage form, strength

– Variable elements may have a range of acceptable values

e.g. Tablet weight, assay

52

QTPP components for IR tablet-Example

Dosage Form

Route of administration

Strength

Weight

Pharmacokinetics

Appearance

Identity

Assay

Impurities

Content uniformity

Friability

Dissolution

Residual solvents

53

Specific requirements in QTPP

➢ Scored tablets

o Weight variation between two halves

o Dissolution of half tablet

➢ Orally Disintegrating tablets

o Hardness

o Disintegration time

o Container closure

➢ Extended Release products

o Alcohol induced dose dumping

12.04.201954

Critical Quality Attributes – CQAs

➢ CQAs are a subset of the QTPP

➢ Include critical parameters that are likely to change based upon variations in raw materials and processes

o Identity test for dosage form – Not a CQA

o Assay, Content uniformity – CQAs

➢ CQAs are monitored throughout the DP development.

➢ CQAs ensure that DP remains within safe and effective levels.

55

QTPP and CQAs

QTPP components

Dosage Form

Route of administration

Strength

Weight

Pharmacokinetics

Appearance

Identity

Assay

Impurities

Content uniformity

Friability

Dissolution

Residual solvents

CQAs

Assay (efficacy)

Impurities (safety)

C.U. (efficacy)

Dissolution (efficacy)

Residual solvents (safety)

12.04.2019 56

QTPP and Specifications

QTPP

• Desired target for developmental

work

• Components of QTPP may or may not

be in specification

- Not in spec – Dosage form, strength

- In spec – Assay, impurities

• Does not include acceptance criteria

SPECIFICATIONS

• Includes all of the CQAs

• Specification is a list of

- tests,

- references to analytical procedures

- acceptance criteria

• Establishes the set of criteria to

which DP should conform to be

considered acceptable for its

intended use

Defining a QTPP does not mean setting all acceptance criteria or the productspecifications before development work begins.

12.04.2019 57

QbD Tools – Risk Assessment

Why risk assessment in product development?

− To identify relative risk levels at the beginning of product development

− To prioritize limited development resources

− To document the decision making process throughout development

− To assess the needs of additional studies for scale up and technology transfer

− To identify appropriate specifications, critical process parameters and

manufacturing controls

− To decrease variability of critical quality attributes

12.04.201958

Risk Assessment

Risk assessment for;

− Formulation starting materialproperties, levels of components

− Manufacturing process

Steps for risk assessment;

− List out all components / processes

− Prepare the process flow chart

− Identify all potential failure modes foreach item with risk query (what mightgo wrong?)

− Risk analysis

− Risk evaluation

Various formal methodologies available forrisk assessment;

− Failure Mode Effects Analysis & FailureMode Effects & Criticality Analysis

− Hazard & Operability Analysis

− Supporting statistical tools

It is neither always appropriate nor always necessary to use a formal risk managementprocess….. The use of informal risk assessment processes can also be considered acceptable.

– ICH Q9

A risk-based justification based on experience and data is ALWAYS NECESSARY!

12.04.201959

CMAs, CPPs and CQAs

What factors affect drug product CQAs?

➢ Properties of Input Materials- Identify Critical Material Attributes (CMAs)➢ Properties of in-process materials- CQAs of one step become CMAs for a

downstream unit operation➢ Manufacturing process parameters- Identify Critical Process Parameters (CPPs)

Input Materials

CMAs1

Output Materials

PRODUCT

CQAs

CPPs1

Unit Operation 1

Unit Operation 2

CMAs2

CPPs2

12.04.201960

Critical Material Attributes (CMAs)

Drug Product CQAs

Drug Substance Attributes

Solid State Form

HygroscopicityParticle

SizeResidual Solvents

Process Impurities

Chemical Stability

Physical Attributes (size

and split ability)LOW LOW LOW LOW LOW LOW

Assay LOW LOW LOW LOW LOW LOW

Content Uniformity

LOW LOW LOW LOW LOW LOW

Drug Release HIGH LOW HIGH LOW LOW LOW

Risk Assessment of the drug substance attributes

➢ Solid state form and particle size of DS are CMAs

12.04.201961

CPPs

Risk assessment of manufacturing process

➢ Identify high risk steps (unit operation) that affect the CQAs of DP.

Drug Product CQAs

Process Steps

Pre-RC* Blending and Lubrication

Roller Compaction

MillingFinal

Blending and Lubrication

Compression

Assay MEDIUM LOW MEDIUM LOW MEDIUM

Content Uniformity HIGH HIGH HIGH LOW HIGH

Dissolution MEDIUM HIGH MEDIUM HIGH HIGH

Degradation Products LOW LOW LOW LOW LOW

12.04.201962

CPPs

CPPs DP CQAsRisk

AssessmentJustification and Strategy

Main compression force

Content Uniformity

LOWCU is dominated by BU and flowability and is

unrelated to main compression force.

Dissolution HIGHSuboptimal compression force may affect tablet

hardness and friability and, ultimately, dissolution.

Press speed (dwell time)

Content Uniformity

HIGH

A faster than optimal press speed may cause

inconsistent die filling and weight variability which

may then impact CU and dissolution. For efficiency,

the press speed will be set as fast as practically

possible without adversely impacting tablet quality.Dissolution HIGH

Process Step Compression

63

Control Strategy

“A planned set of controls, derived from current product andprocess understanding that ensures process performance andproduct quality…..”

ICH Q8 (R2) & Q10

Control Strategy includes following elements (but not limited to):

– Input material attributes (e.g. drug substance, excipients, container closure)

– Equipment operating conditions (process parameters)

– In-process controls

– Finished product specifications

– Controls for each unit operations

– Methods and frequency of monitoring and control.

12.04.201964

QbD Tools – DoE

Design of experiments (DoE)

– Useful for screening of variables with significant impact on DP CQAs

– Classical approach uses OFAT (One Factor At A Time)

– Limited number of experiments gives limited information.

– DoE helps study effects of interaction of multiple factors at a time

– Used in optimization studies, enables creation of “design space”

– “Design space” is proposed by the applicant and subject to regulatory assessment

and approval.

– “Design space” developed at lab or pilot scale can be proposed for commercial

scale, but needs to be verified at production scale for scale dependant parameters.

65

Process Analytical Technology (PAT)

➢ Timely measurements during processing

o Critical quality and performance attributes

o Raw and in-process materials

➢ At-line, on-line or in-line measurements

o Founded on “Process Understanding”

Opportunities for improvement;

− More reliable and consistent processes (& product)

o Less failures, less reworks, less recalls

− Flexibility w.r.t. scale and equipment

− Better / faster Quality Systems

− Process Enhancement Opportunities

66

PAT in Tablet Manufacturing

Stage Technique Measurement

Dispensing NIR / Raman Identification of raw materials

Wet Granulation NIR Moisture distribution

Drying NIR Moisture content

Blending NIR Blend Uniformity

CompressionStrain gauges Compression force

NIR Content Uniformity

67

PAT Examples

Spectral Probe NIR Analyzer installed onviewing window of Glatt® FBD without anydryer modification.

12.04.201968

Real-time Blend Uniformity by using TruProcess™

Analyzer

PAT Examples

12.04.201969

QbD: Required or Optional?

Required

− Quality target product profile (QTPP) including critical quality attributes (CQAs) of the drug product and including Product design and understanding

− Product design and understanding

o Critical material attributes (CMAs) of the drug substance and excipients

− Process design and understanding

o Critical process parameters (CPPs)

− Control strategy, including justification

Optional

− Design Space

− Process Analytical Technology

70

Business Case Example

Project Management

Many types of micro - and nanoparticles can be prepared

Extended release particles

Polymeric nanoparticles

Naked API nanoparticles

Emulsions

Liposomes

Inorganic nanoparticles

Solid lipid nanoparticles

TYPES OF PARTICLES

Micro Reactor

Oral

Parenteral

Pulmonary

Topical

Med. products

Diagnostics

Micro Reactor

Oral particulate systemsORAL FORMULATIONS

Production of oral nanoparticle formulations

(2) Galenic Formulation Process(1) Production

…Nano Suspension

Powder

No separation of nanoparticles

Wet granulation

Compound

Solid OralDosage Form

MJR : Formulation of WHOLE Suspension with Established Pharmaceutical Technologies

Intermediate 2Intermediate 1

APPLICATION EXAMPLE

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 formulation0

20

40

60

80

100

0 10 20 30 40

Dis

solu

tio

n/

%

Time/ min

Dissolution with 1% SDS in water, 50 rpm

Crude API Wet granulation

Hot melt extrusion Nanoparticle formulation

APPLICATION EXAMPLE

Application Examples MJR PharmJet


APPLICATION EXAMPLE


Formulation route % AUCNanoparticle po 53.7 %

iv 100.0 %Crude API po 6.4 %

0

0.2

0.4

0.6

0.8

1

0 60 120 180 240 300 360 420 480

time / min

ng

/ml p

lasm

am

ain

met

abo

lite

8 fold higher bioavailability fornanoparticle formualtion


APPLICATION EXAMPLE


0

10

20

30

40

50

60

70

80

90

100

110

0 20 40 60

% o

f m

ate

rial

dis

solv

ed

time / min

0 1 2 3 6

25 °C/60%

0

10

20

30

40

50

60

70

80

90

100

110

0 20 40 60

% o

f m

ate

rial

dis

solv

ed

time / min

0 1 2 3 6

Stability of nanoparticle/tablet formulations

Tablet formulations were stable for 6 months under accelerated conditions

40°C/75%

Technology transfer

• MJR PharmJet technology transfer services

• Production method optimization to increasethe GMP compliance and efficiency

• Scale up of production methods forparticulate systems from particle productionto end formulation

• Establishment of GMP compliant productionmethod for particulate systems

• Optmization of existing formulations for a smooth GMP transfer

• GMP compliant method establishment forproduction of nanoparticles andmicroparticles

• Innovative GMP compliant technologies tomeet required product specifications

Scale up from lab scale to pilotscale

Optimization of formulations forGMP compliance

Production method establishmentfor CTM

Production method optimization

Optimization of production methodfor GMP compliance

Scale up from pilot scale to large scale

EXISTING FORMULATIONS

EXIS

TIN

G F

OR

MU

LATI

ON

S

Technology transfer concept

ESTABLISHMENT OF PRODUCTION METHOD

Evaluation of existingformulation

Optimization ofproduction method forGMP compliance and

efficiency

Determination of criticalparameters and limits

Setting up in processcontrols

Production runs at pilotscale

Analyses of product

Evaluation of existingproduction method

Setting up productspecification

Setting up analytical methods

Sett

ing

up

and

op

tim

izat

ion

of

pro

du

ctio

nm

eth

od • Analytical methods and product specification transfer to ensure

the comparability of formulations before and after technologytransfer

• Evaluation of existing product and production parameters• Transfer and optimization of production method for GMP

compliance and smooth scale up• Determination of critical process parameters and limits• Establishment of in-processs controls for efficient process

control• Production of several pilot scale batches to determine the

robustness of method• Analyses of product samples and comparison with existing

production method

Production

API and excipientquality control

End formulationquality control

GMP documentation

Stability analyses

Batch release

Qualification

Establishment ofGMP compliant

production method

Validation ofproduction method

Establishment ofIPCs

Preparation of batchdocumentation

IMPD, CTD preparation

Production

• Production of trial batches• Production of CTM• Large scale production

• From concept development to GMP production complete service range

• Synergies of Überherrncampus shortening the time lines

• Seamless transfer from R&D into the regulated GMP regime for production and quality control

• Experts meeting for theoptimal project and processset up

Stability: Re-Suspension of driedNanoparticles

12.04.2019 81Data by E. A. Türeli, MJR-Pharmjet

Fenofibrate / Chitosan / HPMCP50

Stability: In-vitro Dissolution of driedNanoparticles

12.04.2019 82

50

60

70

80

90

100

110

0 20 40 60

% o

f m

ate

rial

dis

solv

ed

time / min

0 1 2 3 6

50

60

70

80

90

100

110

0 20 40 60

% o

f m

ate

rial

dis

solv

ed

time / min

0 1 2 3 6

Storage at 25°C / 60 % RH Storage at 40°C / 60 % RH

t_storage / months t_storage / months

• average of 6 replicates• dissolution medium:

SIF+1%TWEEN 20

• average of 6 replicates• dissolution medium:

SIF+1%TWEEN 20


Data by E. A. Türeli, MJR-Pharmjet

Stability: Particle Size & PDI of dried Nanoparticles

12.04.2019 83Data by E. A. Türeli, MJR-Pharmjet

monthsMean particle size

[nm]PDI

0 186.6 0.134

1 206.2 0.081

2 173.2 0.161

3 171.3 0.123

6 190.6 0.264

Storage at 25°C / 60 % RH


Requirements for GMP manufacturing of nanoparticles

Slide 84

Nanoparticles

• Particle size

• Homogeneity of particle population• Sterility• Particulate matter• Dilution properties• Compability

Microparticles

• Particle size

• Homogeneity of particle size distribution• Sterility• Particulate matter• Drug release• Viscosity• Concentration of particles• Dispersibility• Sedimentation

More specific requirementsdepends on:

• Particle type• Aim of formulation• Site of application• API• API concentration

Validation of nanoparticle manufacturing method

Slide 85

Determination of particle size limits for nanoparticles

Particle size has an effect on dissolution in

blood

In-vivo animalexperiments

Enzymatic metabolismin blood

Set particle size limits

Cross flow filtration

Slide 86

http://spectrumlabs.com/filtration/Edge.html

• Removal of organic solvent• Removal of dissolved API• Concentrating of nanoparticles

Purification

Concentration

EstablishedGMP process


− Cell harvesting

− Cell or lysate clarification

− Recover and purify antibodies or recombinant proteins from cell culture media

− Product fractionation

− Product concentration

− Purification

− Diafiltration


What can TFF do?

− Ultrafiltration CFF for concentration;

permeate volume ↑ retentate concentration ↑

− Ultrafiltration CFF for diafiltration;

target buffer ↑ original buffer ↓

No change in product concentration!


TFF Basics

How to choose the proper TFF System?

− Define the purpose of the TFF process

− Choose the membrane molecular cutoff

− Determine the required membrane area for application

𝑀𝑒𝑚𝑏𝑟𝑎𝑛𝑒 𝑎𝑟𝑒𝑎 𝑚2 =𝑓𝑖𝑙𝑡𝑟𝑎𝑡𝑒 𝑣𝑜𝑙𝑢𝑚𝑒 𝐿

𝐹𝑙𝑢𝑥 𝐿𝑀𝐻 𝑥 𝑝𝑟𝑜𝑐𝑒𝑠𝑠 𝑡𝑖𝑚𝑒 (ℎ)

TMP =𝐹𝑒𝑒𝑑 𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒+𝑅𝑒𝑡𝑒𝑛𝑡𝑎𝑡𝑒 𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒

2− 𝑃𝑒𝑟𝑚𝑒𝑎𝑡𝑒 𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒

Where ;

TMP : transmembrane pressure

Key Parameters to determine TFF processing;

− Crossflow (Retentate) Rate

− Transmembrane Pressure

− Filtrate (Permeate) Control

− Membrane Area

‼ To retain a product, select membrane with MWCO is;

3 to 6 times lower than the MW of target

product.

Cw > Cb

PF < PR


TFF Modules

Flat Plate Spiral-Wound Hollow Fiber

Non-uniform flow pathHigh packing densities

Hollow central core,filtrate passes through the

membrane and spiral tothe core.

Easy to set-up

Faster processing times

Membrane corners The separator screensincrease the turbulence in flowpath leading to higher

effiency

No build up and loss ofproduct

Scalable Not scalable Scalable


https://laboratory.pall.com/en/tangential-flow-filtration.html

http://microsite.sartorius.com/en/crossflow-solutions/cassettes.html

https://www.semanticscholar.org/paper/Protein-Concentration-and-Diafiltration-by-Flow/3f3af25bec5444fba79de31b5a52979648bb3772/figure/10


https://laboratory.pall.com/en/tangential-flow-filtration.html

http://microsite.sartorius.com/en/crossflow-solutions/cassettes.html

https://www.semanticscholar.org/paper/Protein-Concentration-and-Diafiltration-by-Flow/3f3af25bec5444fba79de31b5a52979648bb3772/figure/10

Modified

Polyethersulfone

(mPES)

Mixed Cellulose Ester

(ME)

Polysulfone

(PS)

Polyethersulfone

(PES)

− Hydrophilic membrane

− Low protein binding for

higher product yield

− Higher flux rate and faster

processing time


− Low protein binding

− Higher flux rate and faster

processing time

− Highly biocompatable for

filtration applications with

cells, cell and virus lysates



− More resistant to acid and

bases, and surfactants

− Nanoparticle processing

and diafiltration



− More resistant to acid and

bases, and surfactants


Membrane Types

Zhen-LiangXu et.al. Volume 233, Issues 1–2, 15 April 2004, Pages 101-111

Sterilization options - Nanoparticles

Slide 91

Moist heatsterilization

Ionizing radiation Filter sterilization Sterile processing

Nanoparticle sterilization options

1 2 43

The sterilization option for the nanoparticle formulations depends on:• Particle size of the formulations• Type of formulation• Structure of formulations• API used in the formulations

Filter sterilization


Slide 92

Particle size and PDI are of crucial importance

Filter type: PTFE membraneFilter rating: 0.2 µm

Moist steam sterilization


Slide 93

Change in Particle sizeafter sterilization

Assay and impurityAgglomeration

Contact:

Dr. Nazende Günday TüreliMJR PharmJet GmbH

[email protected]

Thank you…

mjr pharmjet - nano2clinic · 2019-04-13 · current state & future directions 12.04.2019...

Documents