Challenges Facing the Excipients Supply Chain & “EXCIPACT” (Excipient Certification Scheme )

Supply Chain Risks 23rd February 2010

Challenges Facing the Excipients Supply Chain & “EXCIPACT” (Excipient Certification Scheme)

Supply Chain Risk Management Conference London, 23rd February 2010

Iain MooreChair Excipient Certification Project Committee IPEC

Europe

http://www.fecc.org/index.htm

http://www.pqg.org/


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


Excipients and Examples of Supply Chain Risk

• “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

• “New” risks from advances in scientific knowledge• BSE• Mesilates, (Di)Isetionates, Tosilates or Besilates

– Now recognised as a potential genotoxic risk factor


Excipients and Examples of Supply Chain risk

• 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

• So a mixture of traditional and emerging risks

• Can we still consider excipients as “low risk” because they are not pharmacologically active?


Excipients and Examples of Supply Chain risk

• 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

• 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 ?





3. Links to PQG Supply Chain Risk Management

Guide – Excipient Classification


Excipient Supplier Qualification

• 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

• The latter 2 aspects require a detailed assessment of the supplier’s systems and capability


Excipient Certification

• 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

• 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


Excipient Supplier Qualification

• 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

• Suppliers are at risk of “death by audit”– Some sites could receive 100 or more per year



• 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 – 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

• The many industries supplying excipients are reluctant to share intellectual property

• Can we find another way around these issues?



• 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



• 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)


Who can Provide Auditors?

• With 1000s of excipients and 1000s of audits where do we find all the auditors?

– 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


Certification

• The regulatory environment is changing and the signals are very clear

– It’s not a matter of what

– But of when

• 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

• And so EXCIPACT is being developed to address these issues


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


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


Excipient GMP

• 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

– Two definitions of Excipient GMP containing the same requirements

• Draft GMP Annex and Classification document has been undergoing membership review


Excipient GDP

• 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


Excipient GMP and GDP

• 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


Excipient GMP & GDP Certification Scheme

How will 3rd Party Certification Work? (i)

• “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)

• “IPEC” will publish a list of 3rd party audit organisations that have met the criteria and signed an agreement



How will 3rd Party Certification Work? (ii)

• 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



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

SUPPLIERS & MANUFACTURERS

REGULATORSUSERS

CERTIFICATION

CERTIFICATE OF GMP COMPLIANCE

ASSURED EXCIPIENT USE

AUDIT

ACCREDITATION

3rd PARTY





3. Links to PQG Supply Chain Risk Management Guide – Excipient Classification


Excipient Classification

• 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

• So can we use a classification system to identify “higher risk” excipients? – YES!



• 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:1. The origin of the excipient starting materials

2. The manufacturing process – non-dedicated equipment

3. The route of Administration of the drug product (Dose)

4. The impact of the excipient manufacturing process variation on functionality (Function)



1. The origin of the excipient starting materials• 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• 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)• 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)

• Small variations in manufacturing process which result in large changes in excipient performance require more thorough controls



• Classification Analysis – Route of Administration and Function Factors

• Examples when EXCIPACT would not be enoughUnbroken 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 dosage form

Little or no impact on Active bioavailability

IPEC-PQG GMP Controls suitable

Release Controlling Excipient IPEC-PQG GMP Controls with additional controls amplifying the GMP Principles in the GMP Guide



• 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

• 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



• 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

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The dedicated team

Excipient GMP GDPCertification

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!

Documents

Challenges Facing the Excipients Supply Chain & “EXCIPACT” (Excipient Certification Scheme )