Traded Pharma Raw Materials

1
Traded Pharma Raw Materials Compliance and EU
Market Situation View from a Trading Company
with Q7 GMP focus

• Mr. Erol Thomas Isim, Pharma Action, Germany
• 3rd EFCG Congress, Lisbon, Portugal, 29. - 30.
  May 2008
• Strategies for Compliant Pharma Sourcing

2
Aim of todays Presentation

• This presentation is intended to provide
  information on how the implementation of current
  regulations affect the supply chain of traded
  APIs.
• Furthermore it will provide insight views on the
  compliance situation through an actual example.

3
Introduction (I)

• Implementation of EU guidelines into national
• law of EU member states
• "Basic requirements for active substances as
  starting materials" EU GMP Part II (curr. ed.)
  of the EU guidelines to good manufacturing
  practice for medicinal products for human and
  veterinary use (directive 2004/27/EC and
  2004/28/EC)
• in Germany via Arzneimittel- und
  Wirkstoffherstellungsverordnung/ decree for
  manufacturing of medicinal products and active
  ingredients AMWHV (in force since 10th Nov. 06,
  amended on 26.03.08, amendment in force since 4th
  April 08)
• Germany was the first state to implement the
  changes

4
Introduction (II)

• Implementation of a Quality Management
• System
• including
• clean room concept for sample taking, repacking
  and relabeling
• enterprise resource planning system (ERP)
• Establishment of a surveillance and
• information network
• in no. 1 and 2 API producing third countries
• India China
• market intelligence, auditing, pre-shipment
  inspections, registrations, screening of API and
  intermediate factories/ suppliers

5
Q7 GMP Target for Traders

• Traders must
• know and control the GMP relevant processes of
  the API supply chain
• increase level of trading part up to legal and
  industry GMP requirements in regulated markets

6
Differences in Q7 GMP Implementation (I)

• different interpretations
• of the EU directives in the different member
  states
• Germany implemented strict regulations
• (i.e. identification test, GMP certificates for
  transit material)
• Italy imposed almost prohibitive measures
• (compulsory third-country GMP inspections for
  all APIs / factories via Italian MoH, valid from
  01.01.09)

7
Differences in Q7 GMP Implementation (II)

• different speed
• of the implementation processes into national
  law
• different enforcement
• of national law by official bodies within member
  states

8
Current GMP Compliance Situation in Europe

• Costs and implementation necessities of different
  GMP compliant systems are prohibitive to small
  and medium sized trading companies.
• Q7 standards are not 100 suitable for trading
  activities (size, human resources).

9
Consequences

• only a few small and medium sized trading
  companies have invested into a QM-System
• most API trading activities do not comply with
  the EU GMP
• GMP compliant traders lack competitiveness due to
  higher process costs
• parallel imports loopholes remain open and are
  being used
• finished dosage form manufacturers accept non-GMP
  compliant processes and as a consequence non-GMP
  compliant API sourcing activities, f.e. old
  registrations

10
GMP Trading Review and Preview
before GMP after GMP (current state) outlook
many traders small, medium and big size traders many APIs and intermediates intransparent processes along the supply chain general consolidation of traders (survival of the fittest) only medium and big size traders have the opportunities to full fill GMP requirements elimination of small business movement towards transparent processes few big traders gain market shares and act as GMP compliance partners remaining small/ medium traders specialise on certain aspects of API supply chains or will be integrated by big traders transparent processes
11
Traditional API Supply Chain
12
Integrated TraderGMP Supply Chain
13
Excursion Heparin The B-Case (I)

• unknown impurities led to adverse reactions and
  possible deaths
• detection methods published on March, 6th 2008
• after starting of testing, product recalls in US
  and Germany, followed by further product recalls
  in CH, FR, DK, AUS, ... (regulated markets)

14
Excursion Heparin The B-Case (II)

• root cause according to official reading
  oversulfated chondroitin sulfate (OSCS) inside
  from China made Heparin (crude / purified
  Heparin)
• fractioned Heparin (low molecular weight) is
  affected too
• ongoing US-FDA investigation(s) in China
• insufficient inspection routines by industry and
  authorities
• most commonly the big players are being inspected
• intra-supply-chain trade, relabeling, commingling
  of batches remain un-inspected

15
Chinese Heparin Supply Chain (numbers)
crude Heparin workshops small purifiers medium
purifiers big purifiers
to EU authorities known Heparin sites
approx. 150 - 200 family owned/ small businesses
crude work shops, 2 big crude work shops, gt 5 big
crude Heparin traders, few medium sized purifiers
and 4 big sized purifiers
number of inspected crude workshops and purifiers
by EU-authorities ???
16
Chinese Heparin Supply Chain (compliance)
crude Heparin workshops small purifiers medium
purifiers big purifiers
non-GMP-compliant/ no production license
17
Chinese HeparinSupply Chain (linkages)
crude Heparin workshops small purifiers medium
purifiers big purifiers markets
eGMP
Chinese GMP
non-GMP-compliant/ no production license
regulated
un-regulated
18
Chinese Heparin Supply Chain (reality)
crude Heparin workshops small purifiers medium
purifiers big purifiers markets
Chinese Traders
non-GMP-compliant/ no production license
regulated
un-regulated
19
FDA 1H-NMR Spectroscopy
Source FDA
20
Heparin without Contamination
21
Heparin with Low Level of Contamination
22
Heparin with Medium Level of Contamination
23
Heparin with High Level of Contamination
24
Pharma ActionsIntegrated API Management System

• Pharma Action is specialised on GMP compliant API
  supply chain management.
• Benefit from our system, which
• releases bound capacities
• reduces costs and redundancies
• bundles suppliers and information
• creates transparency
• outsources threshold
• concentrates on core competence

25
Thank You!

• TRADE ACTION-PHARMA ACTION eK
• Kurfuerstendamm 133
• 10711 Berlin - Germany
• phone 0049 30 - 890 44 99 -0
• fax 0049 30 - 890 44 99 -99
• eMail office_at_pharma-action.com
• Internet www.pharma-action.com