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Highly PotentActive Pharmaceutical Ingredients


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APIs made by Heraeus Quality and Reliability since 1982

Heraeus is a globally active precious metals and techno-

logy Group with rm roots in Germany, headquartered

in Hanau near Frankurt. The company has been amily-

owned or more than 155 years. Precious metals, sensors,

dental products and biomaterials, quartz glass, and

specialty lighting sources are the ocus o our activities.

Heraeus is a world leader in industrial precious metals

and special metals. A global network o companies

in Europe, North America, Asia, and Arica includes

production acilities or all phases o precious metal

production and rening. In addition, Heraeus holds

a leading international position in industrial precious

metal trading based on decades o expertise.

Based on Heraeus know-how in the handling o

demanding materials and production processes, the

Business Unit Pharmaceutical Ingredients has become

a preerred supplier o highly potent APIs (hAPIs)

to the pharmaceutical industry around the globe.


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We specialize in high potency oncology molecules.

Today our product portolio consists o generics and

a growing number o exclusive co-operations on New

Chemical Entities. We oer contract development and

manuacturing services throughout all phases o a products

liecycle rom basic research to large-scale production.

State-o-the-art Research & Development and production

acilities provide technological access to a wide range

o chemical and unique ermentation processes. These

capabilities make us an ideal partner to clients rom

the generics sector as well as innovative pharmaceutical

companies.

Since the launch o the rst API at Heraeus Cisplatin

in 1982 we have continuously expanded and improved

our services to customers. Beyond sophisticated API

development and manuacture, experienced Regulatory

Aairs, Quality Assurance and Quality Control groups

assure compliance with current ICH guidelines as well as

a continuous enhancement o our quality standards.

A successul history o GMP certications by the U.S. FDA

and the German health authority dates back to 1988.

Our dedicated engineering team employs experts or the

plant layout, installation and commissioning o complex

manuacturing acilities.

Global Presence Focus on Regulated Markets


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Technology

We continue to expand our capabilities or manuacturing

APIs used in ghting cancer.

The traditional chemical production capacities o Heraeus

refect the requirements or dealing with highly potent,

cytotoxic compounds:

Dedicated and multi-purpose installations

Product batch sizes between 100 g and 50 kg

Quantities produced per product between 100 g and

1000 kg per year (synthesis dependent)

Reactor volumes between 100 litres and 2000 litres

Complete encapsulation or multi-stage syntheses

Isolators to work in and handle highly active,

cytotoxic compounds

Entirely isolated production lines (up to 70 litres

volume), incl. distillation and ltration units

Explosion-prooed installations

Reaction temperatures ranging between

25 and +140 C

Condensers within a working range o 25 to +60 C

OELs up to < 100 ng/m

Strict control o emissions, installations and personnelto undercut OELs < 0.1 g/m and exclude the possibility

o cross-contamination

Lock system to avoid emissions and cross-contamination

or all production acilities

Production in clean room areas Class D is possible

Handling o highly toxic exhaust air as well as toxic fuids

and solid residues

Use o sterile, pyrogen-ree highly-puried water

(in conormity with EP) in all production stages

Electronic data recording in Research & Development

as well as in production

Proessional handling o precious metal containing

materials


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Having complemented our technical capabilities with

the commission o unique ermentation equipment, we

can oer our clients cutting-edge capabilities as regards

product purity and synthesis eciency.

The ermentation o active or initial-stage substances

is proving to be a very attractive economic alternative

to chemical synthesis on account o the ever-growing

complexity o the target molecules. In act ermentation

oten proves to be the sole economically justiable course.

Heraeus is one o the very ew service providers on

the market that can oer the combined possibility o

ermenting highly active, cytotoxic substances (upstream

processing), with the option o purication (downstream

processing) and also urther chemical modication.

Our current biotechnological production capabilities

embrace:

Fermenter volumes o 10 litres to 3000 litres

Total ermentation volume > 6000 litres

Handling o genetically modied organisms

up to Risk Class S2

Clean room areas Class C and D

Unique ermentation technology using absorber resins

Sterile work under microbiological saety work benches

(clean room Class A)

Separate development and testing laboratory

up to Risk Class S2

Long-term controlled storage o microbial cell banks

at -70 C at several locations (back-up emergency plan)

Sluice system to avoid emissions

and cross-contamination or all production acilities

Handling o highly toxic exhaust air as well as

toxic fuids and solid residues


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From Platinum Chemistryto Fermentation

Innovation plays a key role in the pharmaceutical market.

For more than 25 years, Heraeus has been closely

ollowing technological and regulatory trends and

developments, setting standards or the production o

highly active APIs.

hAPIs manuactured by Heraeus 25 years o high quality

products and services or the pharmaceutical industry.

Until today the Business Unit Pharmaceutical Ingredients

has experienced a straight, continuous development.

2009 Launch o our new multi-purpose production

plant and commercial ermentation acilityor hAPIs

2007 Successul FDA audit or various products

2003 New building or R&D and production under

operation

2003 FDA approval or Carboplatin

2000 General FDA approval as a manuacturer

o synthetic, non-sterile APIs

1996 Initial FDA approval or Cisplatin

1988 First FDA inspection confrming cGMP status

o Heraeus API production

1987 Beginning o Carboplatin production

1982 Start o commercial Cisplatin production

or pharmaceutical application

1970s Point o origin: Technical Cisplatin as homo-

geneous catalyst or polysiloxane production

History


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Idarubicin

Dacarbazine

Cisplatin

Epirubicin

Oxaliplatin

Carboplatin

Thiotepa

Generics

The basis o our API activities has traditionally been

precious metal chemistry. Over the last more than

25 years we have become a market leader in platinum

APIs products that play an elementary role in modern

cancer treatment.

Today our commercial product portolio and development

pipeline contain a variety o high-quality substancesproduced by chemical synthesis or ermentation.


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5000

10000

New drug development and marketing lie cycle

250 4.7 3.3 1.5 1.2

Research

Preclinical

Studies

Phase1

Phase2

Phase3

New

Drug

Application

Clinical Studies

2 4 6 8 10

Services of Heraeus Business Unit Pharmaceutical Ingre

Typical drug development and marketing lie cycle

Contract Services

Beyond a continuous expansion o our generics portolio

we oer our clients contract development and subsequent

commercial contract manuacturing o New Chemical

Entities.

Development o chemical and biotechnological processes

Development o analytical methods

Scaling-up

Internal engineering group supporting the development

and production acilities

Production o active substance batches or R&D, clinical

studies and commercial demand under cGMP conditions

Comprehensive regulatory support

cGMP and DIN EN ISO 9001:2000 conorm quality

management system backed by experience in clinical

phase I-III and commercial products

As a partner or API development and synthesis on the

basis o commissioned orders, Heraeus is characterized by

short response times and great fexibility, combined with

utmost reliability in terms o quality and on-time delivery.

Our customized services cover integrated project manage-

ment and partnership project work ranging rom all initialclinical active agent development activities right up to

commercial production.

The know-how o our teams o highly qualied chemists,

chemical engineers and bio-technologists orm a sound

basis or the ecient development o our pharmaceutical

active agents.

Development and commercial production acilities meet

the highest requirements that allow us to ulll, in every

respect, our clients specic expectations in all areas

o process development work and the scale-up o highly

potent APIs.

Chemical and biotechnological process R&D

All operations involving highly active substances are

handled in project-specic isolator units.

The development o biotechnological processes can

be commenced at Heraeus with a micro-organism strain

supplied by the client. It is a matter o course that we

guarantee strictest condentiality regarding client know-

how and intellectual property rights.

Laboratories specically designed to handle highly

active substances

Laboratories extensively equipped with the necessary

acilities or process development in the areas o

synthesis, cleaning, isolation and drying

Electronically controlled parallel reaction equipment or

highly ecient examination o critical process parameters

Synthesis optimization and parameter investigations

controlled by statistical programs (DoE)

Capabilities to synthesize highly active

substances on a scale o up to 70 litres under controlled

room conditions

Production o clinical or pilot-registration batches

under cGMP conditions

Testing and optimization o microbial ermentation

processes (upstream) on laboratory scale

Testing and optimization o subsequent product

preparation and extraction (downstream)


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.0

New Drug Approved

Marketing Innovator Drug

GenericDrug

Development

16 18 20 22 24 26 28

s and Analytical R & D; API Manufacture

years

Regulatory Affairs

All activities are supported by a strong Regulatory Aairs

group. Depending on customer requirements, we compile

high-quality registration dossiers in CTD ormat o

our APIs to be used or national procedures, European

procedures or ANDAs.

Preparation o registration dossiers:

Compilation o registration documents according FDA

und CTD Standards

Preparation o chemical-pharmaceutical dossiers

(CMC, Part II), basing on raw data.

Active Substance Master File: Handling o ASMF

or Europe, USA, Japan

Provision o CEPs or all APIs having a pharmacopoeial

monograph

Preparation o Technical Inormation Packages

Handling o Letter o Access and urther regulatory

statements

Management o registration procedures:

Registration procedures consistent with current

guidelines and predetermined time-rames

Handling o deciencies in technical matters

as well as in orm and content

Competent personal contact during all stages

o validation and registration

Lie Cycle Management o existing products:

Regulatory support or marketed products

Continuous improvement o documentation

Update service and handling o variations

Long-term management o stability testing

or APIs and Finished Dosage Form acc. to

ICH guidelines

Generic Drug

Approved Marketing


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Quality Assurance

Our dedicated Quality Assurance group secures the

out-standing and constantly high quality o our APIs.

Top priority is always given to compliance with legal

regulations, occupational saety and the protection o

the environment. Products and processes are developed

according to current ICH guidelines, corresponding to the

necessary U.S. FDA and EU requirements. At the same

time our quality standards as well as the Heraeus Environ-

mental, Health and Saety (EHS) Policy are permanently

adapted to the continuously increasing and diverse

requirements on both national and international level.

The operational and organizational structure o our

department is in accordance with the requirements dened

in DIN EN ISO 9001:2000. Our vision to continuously

improve the quality system is encouraged by regular

inspections through competent authorities (or instance

the local authority Regierungsprsidium Damstadt or the

U.S. FDA), our customers and relevant certiying bodies.

In addition we have implemented a continuous sel

inspection system.

As a reliable, long-term partner o our customers we oer

high quality products and services which are developed

according to especially adapted processes. The Quality

Assurance system as well the cGMP conorm translation

o instructions and processes are in accordance with valid

standards and can be adapted, within legal rames, to

customer demands. Our biotechnologically produced APIs

are certied by a Qualied Person according to 15 o the

German Medicines Law.

Highly qualied personnel with a wide experience in the

pharmaceutical sector together with continuous training

represent a central element in the saekeeping o our high

level quality standards.


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Quality Control

Extensive analytical capabilities and reliability are o

great importance in the pharmaceutical world. With more

than 155 years o history in quantitative precious metal

analysis to the highest degree o accuracy and over

25 years o experience in the Quality Control o APIs,

Heraeus is enormously experienced in perorming a wide

range o modern analytical techniques.

The dedicated Quality Control department acts indepen-

dently rom the Business Unit Pharmaceutical Ingredients

which ensures objective services and data. All work

on in-process control, raw material, intermediate and API

release testing is being conducted in accordance with

cGMP and ICH guidelines.

Our Quality Control services include

Stability testing programs or APIs

and Finished Dosage Form

Fully characterized reerence standards available

or all APIs at Heraeus

Analytical and technical support during development

and routine production at our customers sites

Identication and in-house synthesis

o unknown impurities / degradation products

Availability o all standard equipment or modern phar-

maceutical analysis: HPLC, GC, IC, FTIR, NMR,

UV, ICP, DSC, TGA, KF, AAS, XRF, XRD

Analytical method development and validation


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W. C. Heraeus GmbH

Chemicals Division

Business Unit Pharmaceutical Ingredients

Heraeusstr. 12 14

63450 Hanau, Germany

Phone +49 (0) 6181.35-5446

Fax +49 (0) 6181.35-4302

[email protected]

www.heraeus-pharma.com

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