Transcript No Slide Title

Challenges Facing the Excipients Supply Chain
& “EXCIPACT” (Excipient Certification Scheme)
Supply Chain Risk Management Conference
London, 23rd February 2010
Iain Moore
Chair Excipient Certification Project Committee IPEC
Europe
Supply Chain Risks 23rd February 2010
Excipients Supply Chain
1. Excipients and Examples of Supply Chain Risk
2. EXCIPACT - Excipients Certification Scheme
3. Links to PQG Supply Chain Risk Management
Guide – Excipient Classification
Supply Chain Risks 23rd February 2010
Excipients and Examples of Supply
Chain Risk
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“Traditional” risks such as:
Upgrading Technical Substances to Compendial grade simply
by testing them to the monograph
Repacking in the supply chain
Unsuitable controls in the manufacture of a material that is
going to be used for pharmaceutical use
– Failings of GMP and GDP
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“New” risks from advances in scientific knowledge
BSE
Mesilates, (Di)Isetionates, Tosilates or Besilates
– Now recognised as a potential genotoxic risk factor
Supply Chain Risks 23rd February 2010
Excipients and Examples of Supply
Chain risk
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And now significant and systematic Criminal Activity
Glycerine (Diethylene Glycol contamination)
In 2000 WHO reported “500 unnecessary deaths in the last 10 years
due to contaminated starting materials”,
How many more instances since then?
Melamine contamination of pet food and milk
Heparin
– All examples of Economically Motivated Adulteration
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So a mixture of traditional and emerging risks
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Can we still consider excipients as “low risk” because they are
not pharmacologically active?
Supply Chain Risks 23rd February 2010
Excipients and Examples of Supply
Chain risk
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One key control for these known and emerging risks:
Supplier Qualification
But additional burdens now placed on Supplier Qualification –
ever more information has to be obtained;
– Effective risk assessments require knowledge of the excipient,
how it is made and supplied
– Suppliers have to provide more and more information of
manufacturing processes, supply chains
– Users have to evaluate all this information and perform the risk
assessments
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How can we reduce that burden and allow both parties to focus
on the critical aspects?
How can we Minimise the Risks - Maximise the Benefits ?
Supply Chain Risks 23rd February 2010
Excipients Supply Chain
1. Excipients and Examples of Supply Chain Risk
2. EXCIPACT - Excipients Certification Scheme
3. Links to PQG Supply Chain Risk Management
Guide – Excipient Classification
Supply Chain Risks 23rd February 2010
Excipient Supplier Qualification
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Supplier Qualification - a comprehensive
assessment of
– Excipient quality
– The excipient manufacturing process
– The distribution controls used to deliver the
excipient to the drug product manufacturer
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The latter 2 aspects require a detailed
assessment of the supplier’s systems and
capability
Supply Chain Risks 23rd February 2010
Excipient Certification
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And now legislators intend to further enhance these
requirements in law on both sides of the Atlantic
– In the EU the Pharmaceutical Package as amended by
the European Parliament requires:
– GMP and GDP for Excipients
– Registration of excipient manufacturers and
distributors/traders/brokers
– Inspection of excipient manufacturing sites
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In the US the draft legislation would require similar
registration of excipient suppliers who export to the
USA
Overall an expectation of routine physical audits
from all users on all their suppliers
Supply Chain Risks 23rd February 2010
Excipient Supplier Qualification
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How many audits will be needed then?
1000s of excipients (1200 in the FDA Inactive Ingredient
Database)
1000s of suppliers globally?
Could the Inspectorates or Regulators perform the basic
Audits of all these suppliers?
Do users have the necessary resources?
– Currently only a fraction of suppliers are audited
– Standards are inconsistent from one User to another
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Suppliers are at risk of “death by audit”
– Some sites could receive 100 or more per year
Supply Chain Risks 23rd February 2010
Excipient Certification
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Even today it is common to find suppliers with staff solely
employed to deal with audits
So it is no surprise that some Suppliers are refusing audits
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Insufficient business justification
Less than minimum order levels
Legal complexities of purchasing through a distributor
A few 100Kg per year with all this?
Other suppliers are charging for audits
– Up to €10,000 per audit
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The many industries supplying excipients are reluctant to
share intellectual property
Can we find another way around these issues?
Supply Chain Risks 23rd February 2010
Excipient Certification
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What if excipients qualification could be
enhanced for all parties by another method?
What if there was an Internationally and
regulatory acceptable Excipient certification
system?
Covering the Quality Management Systems in
manufacture (GMP) and the supply chain (GDP)?
Users would then be able to focus qualification
resources on the technical aspects and higher
risk excipients
– Reducing the audit burden for for both parties
– Ensuring legal compliance without excessive
costs
Supply Chain Risks 23rd February 2010
Excipient Certification
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Indeed, the EU and FDA have indicated very
positively that:
– 3rd Party Excipient Audits and Certification have a
role to play
– The FDA has a system to approve 3rd party
auditing organizations
– In the EU the Pharmaceutical Package indicated
that 3rd party audits from accredited organisations
would be acceptable for starting materials (APIs
and Excipients)
Supply Chain Risks 23rd February 2010
Who can Provide Auditors?
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With 1000s of excipients and 1000s of audits
where do we find all the auditors?
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Could ISO auditors contribute?
Pharmaceutical Packaging (ISO 15378) ?
Medical Device (ISO 13485) ?
ISO 9001 – chemical / pharmaceutical sector?
Existing 3rd Party Audit organisations
BUT
FDA and EU have indicated this is only viable
if the auditors are competent
So if auditors are deemed competent then we
can use 3rd parties with confidence
Supply Chain Risks 23rd February 2010
Certification
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The regulatory environment is changing and
the signals are very clear
– It’s not a matter of what
– But of when
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The need for a viable and effective Excipient
Certification Scheme has never been greater if
assurance of excipient quality is to be
enhanced without disproportionate costs
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And so EXCIPACT is being developed to
address these issues
Supply Chain Risks 23rd February 2010
Excipient Certification
Scheme Principles
Evolve existing best practices
• Base on the IPEC-PQG GMP Guide 2006
• Base on IPEC GDP Guide 2006
• Align to ISO 9001
– Many excipient suppliers are already ISO
certified or familiar with this quality
management system standard
International in scope
Excipients are a worldwide commodity
Be valuable and acceptable to Suppliers, Users
and regulators
Supply Chain Risks 23rd February 2010
Excipient Certification
Scheme Principles
Include as many Excipients as possible
• Set standards that are achievable
• Set standards that are auditable
Address the definition of and policing of, auditor competency
Be accessible to existing 3rd party audit organisations
Consult with all Stakeholders throughout development of the
scheme
Supply Chain Risks 23rd February 2010
Excipient GMP
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Certification will be against the core
requirements in the IPEC-PQG GMP Guide 2006
– as converted to “ISO speak”
Suppliers with ISO 9001 will only require
additional audit time to cover GMP
Suppliers without ISO 9001 will require an audit
covering GMP and the Quality Management
System
A US National Standard is in Development to
cover the latter
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Two definitions of Excipient GMP containing the
same requirements
Draft GMP Annex and Classification document
has been undergoing membership review
Supply Chain Risks 23rd February 2010
Excipient GDP
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Certification will be against the core
requirements in the IPEC GDP Guide
2006 – as converted to an auditable
standard
IPEC GDP Guide 2006
Provides additional explanation to the
“Good Trade And Distribution Practices
For Pharmaceutical Starting Materials”
, World Health Organization, WHO
Technical Report Series, No. 917, 2003
Draft document undergoing first
membership review
Supply Chain Risks 23rd February 2010
Excipient GMP and GDP
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Both GMP and GDP can therefore be
certified
Common GMP and GDP elements have
been synchronised
Scheme allows organisations to attain GMP
certification alone or in combination with
GDP depending on their business model
Both GMP and GDP standards are in first
draft form and a public review is planned
for later this year
Supply Chain Risks 23rd February 2010
Excipient GMP & GDP
Certification Scheme
How will 3rd Party Certification Work? (i)
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“IPEC” signs an agreement with 3rd Party Organisations to
audit organisations which commits them to
– Utilise the auditor training and meet the auditor competency
criteria
– Perform audits using the scheme rules
– Meet the criteria for a certification body as defined by the
“competent national authorities”
– e.g. hold ISO Guide 65, ISO 17021 certification (so they have a
suitable and independently assessed quality management
system in place)
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“IPEC” will publish a list of 3rd party audit organisations that
have met the criteria and signed an agreement
Supply Chain Risks 23rd February 2010
Excipient GMP & GDP
Certification Scheme
How will 3rd Party Certification Work? (ii)
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Supplier selects 3rd Party Audit organisation to provide
certification or User(s) select 3rd Party Audit organisation to
qualify supplier
The 3rd party certification body will indicate to “IPEC” the
audit outcome (pass/fail) and IPEC will publish the result on
the website
3rd party provides detailed audit report at conclusion of audit
for access by Users
Once certified a user can access the audit report and then
use a risk assessment to determine if the certification is
suitable for their use of the excipient (supplier qualification)
Certificates used to advertise participation in the scheme
Supply Chain Risks 23rd February 2010
Excipient GMP & GDP
Certification Scheme
AUDIT
Certification Plans
• Supplier or User
commissions 3rd Party
• Who is accredited by
national competent
authority known to
regulatory body
• Supplier passes
evidence of GMP and
GDP to User
• User passes details to
regulators at
inspection or in
dossiers
• Virtuous circle
CERTIFICATE OF
GMP COMPLIANCE
SUPPLIERS &
MANUFACTURERS
3rd PARTY
ACCREDITATION
CERTIFICATION
REGULATORS
USERS
ASSURED EXCIPIENT USE
Supply Chain Risks 23rd February 2010
Excipients Supply Chain
1. Excipients and Examples of Supply Chain Risk
2. EXCIPACT - Excipients Certification Scheme
3. Links to PQG Supply Chain Risk Management
Guide – Excipient Classification
Supply Chain Risks 23rd February 2010
Excipient Classification
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When Excipient Certification (EXCIPACT) may
not be suitable as part of Excipient
qualification…
– Excipients have many diverse uses, functions,
manufacturing processes and origins
– The risks posed to the patient are also very
variable
– A one size fits all definition of GMP is not going
to be appropriate, as PS 9100 first defined in
2002
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So can we use a classification system to
identify “higher risk” excipients? – YES!
Supply Chain Risks 23rd February 2010
Excipient Classification
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The EXCIPACT development team used Risk Identification tools
to consider which factors would demand additional controls in
the manufacture and supply of excipients
They identified 4 factors:
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2.
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4.
The origin of the excipient starting materials
The manufacturing process – non-dedicated equipment
The route of Administration of the drug product (Dose)
The impact of the excipient manufacturing process variation on
functionality (Function)
Supply Chain Risks 23rd February 2010
Excipient Classification
1. The origin of the excipient starting materials
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A range of starting materials were considered and tested against the GMP
controls in the IPEC-PQG GMP Guide
No additional requirements were identified
Conclusion: the GMP Guide covers all raw material origins
2. The manufacturing process – non-dedicated equipment
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Multipurpose, continuous and dedicated processing was evaluated
Conclusion: the controls in the IPEC-PQG GMP Guide were suitable for all
scenarios
3. The route of Administration of the drug product (Dose)
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Parenteral, Inhalation routes required additional controls to those in the
IPEC-PQG GMP Guide to assure patient safety
4. The impact of the excipient manufacturing process variation on
functionality (Function)
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Small variations in manufacturing process which result in large changes
in excipient performance require more thorough controls
Supply Chain Risks 23rd February 2010
Excipient Classification
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Classification Analysis – Route of Administration and
Function Factors
Examples when EXCIPACT would not be enough
Unbroken skin
Oral
Compromised skin
Mucus membranes
IPEC-PQG GMP Controls suitable
Inhalation, intranasal
Eye/ocular
Parenteral
Haemodialysis
IPEC-PQG GMP Controls with
additional controls amplifying the
GMP Principles in the GMP Guide
Excipient does not remain in the IPEC-PQG GMP Controls suitable
dosage form
Little or no impact on Active
bioavailability
Release Controlling Excipient
IPEC-PQG GMP Controls with
additional controls amplifying the
GMP Principles in the GMP Guide
Supply Chain Risks 23rd February 2010
Excipient Classification
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So EXCIPACT is developing a Guide for Users to identify when
the Scheme would not be suitable as the only means of
Excipient Qualification
When these excipients are identified Users could still use
EXCIPACT as the base qualification but would then know
which areas and activities required additional knowledge
– Supplier aware of additional activities to address risks
– Focussed audits by user
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Equally true that some excipients could be supplied which do
not meet the IPEC-PQG GMP Guide requirements
In this case the User would need to use other methods to help
qualify the supplier
Supply Chain Risks 23rd February 2010
Excipient Classification
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Higher risk Excipients will not be adequately covered and
so need to be evaluated by other methods
Performing a risk assessment will help determine if
EXCIPACT is appropriate for you
GMP Distribution
35
30
25
Fraction
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Higher Risk
Lower Risk
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15
10
5
0
Supply Chain Risks 23rd February 2010
Higher Risk
Excipient GMP GDP
Certification
The dedicated team
Adrian Bone
Irwin Silverstein
Dave Schoneker
Beam Suffolk
Allan Whiston
Jayne Nichols
Felicitas Guth
Christiane Dzala
Alberto Galasco
Johanna Eisele
Frithjof Holz
Christophe Guechot
Alexandra Brand
Norman Randall
George Mansveld Jesus Rivas
Andreas Lekebusch Mathias Brenken
Hendrik Abma
Janeen Skutnik
Flavia Arce
Frank Milek
Ian Birch
Stephen Moss
Armand Janssen
Iain Moore
Ian McKeown
Steven Hewitt
Arnulf Heubner
Patricia Rafidison D Fermo
Kevin McGlue
Art Falk
Peter Jones
Dale Carter
Stephanie Messian
Ashley McCraight
Rainer Fendt
David Klug
Priscilla Zawislak
Damien Kerloch
Thank You!
Supply Chain Risks 23rd February 2010