Excipient Certification: Schemes and Auditable Standards - the role in Supplier Qualification

Excipient Certification: Schemes and Auditable Standards - the role in Supplier Qualification European Compliance Academy Vienna, 20 th & 21 st October 2009 Dr Iain Moore Chair Certification Committee IPEC Europe

Excipient Certification Certified 1. Supplier Qualification 2. Role of 3 rd Party Audits and Certification 3. Limitations of existing Schemes 4. New scheme principles and design 5. New scheme implementation benefits

Excipient Supplier Qualification Drug product manufacturers (users) have to qualify their suppliers A comprehensive assessment of Excipient quality The manufacturing process to make the excipient The distribution controls used to deliver the excipient to the drug product manufacturer The latter 2 aspects require a detailed assessment of the suppliers systems and capability A physical audit is the ideal way to achieve this

Excipient Supplier Qualification The purpose of this qualification is to ensure that the safety of the drug product is not compromised by the excipient Both manufacturing (GMP) and distribution (GDP) aspects need to be covered Failures at any point in manufacture or in the supply chain may put patients at risk The modern Pharmaceutical Paradigm requires a Quality by Design (Qbd ICH Q8) and a Risk management approach (ICH Q9) to determine the details of that qualification Those excipients posing the greatest risks require the most thorough controls

Role of GMP and GDP in Assuring Patient Safety Patient Safety = Excipient Specification + GMP + GDP Excipient Specification The technical controls define the excipient E.g. particle size distribution in inhalation grade lactose The Excipient is what it is and has associated properties and functionality E.g. it acts as a solubiliser / it is a surfactant So GMP and GDP controls cannot assure these features are other than consistent from batch to batch Or enhanced GMP and GDP controls will not add much assurance of patient safety if the specification is wrong Assurance of patient safety is therefore a combination of the technical controls and the complimentary GMP and GDP measures

Excipient Certification So we need a physical audit. 1000s of excipients (1200 in IID) 1000s of suppliers globally? Could the Inspectorates or Regulators perform the basic Audits of all these manufacturers AND distributors? Do users have the resources? 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 1 person solely employed to deal with audits

Excipient Certification Some Suppliers are refusing audits on top of all of these Insufficient business justification Less than minimum order levels Complexities of purchasing through a distributor A few 100Kg per year with all this? Some suppliers are charging for audits Up to 10,000 per audit The chemical industry is traditionally reluctant to share intellectual property Restrictions to view batch records Can we find another way around these issues?

Excipient Certification What if excipients could be qualified 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

Excipient Certification Indeed, the FDA and EU have indicated very positively that: 3 rd Part Excipient Audits and Certification have a role to play The FDA has a system to approve 3 rd party auditing organizations For APIs, The December 2008 Pharmaceutical Package from the EU indicated that 3 rd party audits from accredited organisations would be acceptable The key components are in place then for the Excipient industry to implement a valuable Excipient Certification Programme

Who can Provide Auditors? With 1000s of excipient 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 3 rd Party Audit BUT FDA and EU have indicated this is viable if and only if the auditors are competent

Auditor Competency How can we be sure the auditor is competent? Do they have experience of the pharmaceutical industry? Do they have experience of the excipient industry? Do they understand GMP and GDP as a applied to excipients? And most importantly can they identify hazards that could pose a risk to patient safety? If yes then we can use 3 rd parties with confidence

Do we need another Excipient Certification Scheme? PQG PS 9100:2002 Audit runs concurrently and seamlessly with an ISO 9001 audit ISO 9001 audits are lengthened by around 50% So 2 audit days a year becomes 3 typically As based around ISO 9001 audit there is an audit every 6 months Costs are insignificant in comparison to the overall business costs www.pqg.org

Do we need another Excipient Certification Scheme? EFfCI GMP Guide for Cosmetic Ingredients Scheme launched November 2008 ISO 9001 type certification 3 ISO style 3 rd party audit bodies have signed up, one with global reach NB EFfCI GMP Guide is based on the IPEC-PQG GMP Guide and is 80% identical Interest in certification reported from outside Europe - Asia and US www.effci.org

Do we need another Excipient Certification Scheme? IPEA International Pharmaceutical Excipients Auditing Independent subsidiary of IPEC-Americas Contract to generate an audit report which is then offered to users to demonstrate GMP Compliance against USP <1078> Able to audit in 90 countries worldwide Higher investment costs, but overall similar over 3 year cycle to PS 9100, and much less than some expert audit options e.g. USP Verification Scheme www.ipeainc.org

Do we need another Excipient Certification Scheme? Why there has not been widespread uptake of these schemes? Is it because Users are uncertain of the value of these certificates to the regulatory authorities? Are they too expensive? Not enough transparency on auditor competency?

Excipient Certification Project Principles Evolve existing best practices Base on the IPEC-PQG GMP Guide 2006 Base on IPEC GDP Guide 2006 & SQAS Distributor ESAD Scheme 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 Project Principles Include as many Excipients as possible Classify excipients Set the standards in relation to the risk posed Set standards that are achievable Set standards that are auditable Address the definition of and policing of auditor competency Be accessible to existing 3 rd party audit organisations Consult with all Stakeholders throughout the project One session held in Europe in May 2009 One session held with FDA in July 2009

Excipient Certification Project Principles Include as many Excipients as possible IPEC Members Accidental excipient suppliers

Excipient Certification Preparation: Manufacturers Perform gap analysis on GMP Annex The GMP Audit guide is a useful aid Determine excipient classification Distributors, repackers etc Perform gap analysis on GDP Annex The GDP Audit guide is a useful aid

Excipient Classification Why classify Excipients? They 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 2 critical risk factors have been identified and verified as the most relevant in Classifying excipients 1. The route of Administration of the drug product (Dose) 2. The impact of the excipient manufacturing process variation on functionality (Function) These risk factors drive different GMP requirements

Excipient Classification It is critical that the Supplier and User of the excipient agree on the Classification in a 3 step process 1. Manufacturer classifies excipient, and assigns GMP Manufacturer to communicate result to Suppliers and Users (e.g. on CofA) 2. User to classifies excipient and requests GMP from supplier E.g. at contract review / Quality Agreement 3. User and Supplier to perform joint risk assessment Best option, but may not always be practical due to numbers of customers (1000s) and number of excipients (1000s) BUT an agreement at least on the GMP class must be part of contract review between the two parties as a minimum

Excipient Classification Classification Analysis Route of Administration If the route of administration is not known Apply the GMP that most accurately reflects you knowledge of the use of the excipient Examples when to apply the Dose Enhanced GMP: Unbroken skin Oral Compromised skin Mucus membranes Inhalation, intranasal Eye/ocular Parenteral Excipients GMP Excipients GMP Excipients GMP Excipients GMP Enhanced GMP (dosage) Enhanced GMP (dosage) Enhanced GMP (dosage)

Excipient Classification Classification Analysis Manufacturing impact on Functionality Where the functionality of the excipient is important to the bioavailability of the API and when that functionality is sensitive to small changes in the manufacturing process, then there can be an increased risk to the patient. And so need to apply Enhanced GMP (Function) Excipient does not remain in the dosage form Little or no impact on Active bioavailability Moderate impact on Active bioavailability Critical impact on Active bioavailability Excipients GMP Excipients GMP Enhanced GMP (function) Enhanced GMP (function)

Excipient Classification Expectation that the majority of excipients will match the existing IPEC-PQG GMP Guide and not require enhanced GMPs Proportion of Excipients by Classification IPEC-PQG GMP Guide Enhanced GMP

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 Two definitions of Excipient GMP containing the same requirements DOSE and FUNCTION additional requirements for GMP apply to both standards

Excipient GDP 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 This will be available in the scheme

Excipient GDP The GDP Standard will include key elements of existing best practices The NACD (National Association of Chemical Distributors) Responsible Distribution Process (SM) The European SQAS ESAD II assessment scheme Section F&G (www.sqas.org) is aligned to the IPEC GDP Guide subject to independent assessment has a defined auditor training programme These elements will be used as part of GDP certification

Excipient GDP Common GDP and GMP elements will be synchronised matrix of applicability Scheme will allow organisations to attain GMP certification alone or in combination with GDP

Excipient GMP & GDP Certification Scheme How will 3 rd Party Certification Work? i IPEC signs an agreement with 3 rd 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 These 3 rd party audit organisations should meet the criteria for a certification body as defined by the competent national authorities e.g. hold ISO Guide 65. ISO 17021 certification Which means the bodies will have a suitable and independently assessed quality management system in place

Excipient GMP & GDP Certification Scheme How will 3 rd Party Certification Work? ii Once an agreement is in place Auditor identification, training and assessment of competency can occur IPEC will publish a list of 3 rd party audit organisations that have met the criteria and signed an agreement Once auditors are assigned then audits can commence The 3 rd party certification body will indicate to IPEC the audit outcome (pass/fail) and IPEC will publish the result (Pass / Suspended / Failed / Withdrawn etc.) to allow Users to validate the certificate presented by the supplier

Excipient GMP & GDP Certification Scheme How will 3 rd Party Certification Work? iii Supplier selects 3 rd Party Audit organisation to provide certification User or group of users select 3 rd Party Audit organisation 3 rd party provides detailed audit report at successful conclusion of audit for access by Users IPEC publishes status of audited organisation on website

Excipient GMP & GDP Certification Scheme Certification Plans Supplier or User commissions 3 rd Party Who is accredited by national competent authority 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 USERS SUPPLIERS & MANUFACTURERS CERTIFICATION ASSURED EXCIPIENT USE AUDIT REGULATORS 3rd PARTY ACCREDITATION

Excipient GMP & GDP Certification Scheme Current Status Classification Risk analysis and factors defined GMP Annex to ISO 9001 Drafted Enhancements for higher risks drafted NSF/ANSI standard sub team being assembled GDP Annex to ISO 9001 drafted Auditor Competency Structure outlined detailed work in progress Certification Scheme Team being formed Certified

Excipient GMP GDP Certification None of this is realisable without the commitment and contribution of all the volunteers to the various working parties and the Steering Committee I thank them for all their efforts Thank you for your attention