The Future of Excipient Auditing P2: Partnership for Supply Chain Management Monday, June 3, 2013, 3:30 p.m. – 5:30 p.m Dale Carter Director Global Quality, Huber Engineered Materials Silica Immediate Past Chair – IPEC Americas www.ipecamericas.org

IPEC Offers Excipient Stakeholders a Regional Voice with Global Influence IPEC Federation Established in 2009, based in Belgium / made up of regional IPECS IPEC-Americas North, South and Middle Americas Partnership with Sindusfarma (Brazil) and SaFybi (Argentina) IPEC-Europe Europe, North Africa, Middle East IPEC Japan IPEC China IPEC India (being formed)

IPEC Americas Provides Balance Maker members covering the diversity of excipients Distributor members User members This combination of members provides the full view of issues surrounding excipients, providing IPEC Americas the unique capability to develop science based guidance and position documents that work.

IPEC History & Guidance Documents Stability Program Guide Glossary for Excipients GDP IPEC /PQG GMP Safety Evaluation of New Excipient USP <1074> GMP Rev1 EQ 1 IPEC/PQG Audit CoA EIP Rev1 EQ 1, 2, 3 Pedigree Paper GMP Audit Dist. Cert. of Analysis USP <1080> Sig. Change USP <1195> EIP Sig Change R1 EIP Template Quality Agree. Composition Dist. Audit Guide 2011 Excipient GMP USP <1078> EMF GMP Audit Rev GMP Audit 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 Reg. Affairs Conf. Reg. Affairs Conf. Reg. Affairs Conf. IPEC Forms Reg. Affairs Confer. combines with Excipient Fest

The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients 2006 Basic Quality Management Systems principles plus key processes necessary to ensure production of safe consistent products Emphasizes communication between manufacture and user Significant Change Certificate of Analysis Stability International in scope Useful and acceptable to suppliers, users and regulators

Current State IPEC/PQG Guideline is the basis for most audits Individual company auditors in single or group audits. Quality of the audit varies with auditor background and experience. Excipient manufacturers essentially have the same audit multiple times. Numerous audits per year for each excipient manufacturer. Drives group audit practice “Check-box” type approach One day audit

Excipient GMP Certification Standards 2 standards from 1 GMP (2006 IPEC PQG) EXCiPACT – GMP/GDP certification as an Annex to ISO 9001:2008 Quality System Standard Joint effort of IPEC Europe, European Fine Chemicals Group, IPEC-Americas, Pharmaceutical Quality Group, and European Association of Chemical Distributors NSF/IPEC 363GMP – Good Manufacturing Practices for Pharmaceutical Excipients Forthcoming ANSI Standard for certification of effective implementation of excipient GMPs by a manufacturing facility For use by companies without ISO 9001 registration Team of Makers, Users, and Regulatory/Academic/public DRAFT Feb 8, 2013

Guidelines and Standards IPEC PQG GMP Guidelines No certification option IPEA Certification done through “SOP # 8” that converts the IPEC guide into a certification protocol EXCiPACT ISO Annex for GMP Certification Addition to existing ISO certifications NSF/IPEC 363 GMP Standard (4Q 2013) Stand alone QMS + GMP certification

Standards Development Process The IPEC/PQG GMP Guideline is the basis for both EXCiPACT and the ANSI/NSF 363 Standards. Both development processes had multiple stakeholders involved. NSF/IPEC 363 followed ANSI process for consensus standard Great care was taken to have the two standards have identical requirements. IPEC Americas and IPEC Europe were represented on both development committees.

Risk Assessment in Excipient GMPs Procedures and controls implemented in following the IPEC-PQG GMPs have always been the output of risk assessment exercises Now the justification and thought process to support these controls are documented. Documentation facilitates better understanding of GMP controls and helps prevent perpetuation of unfavorable consequence from changes made by the uninformed So what’s new?

Why is Risk Assessment in NSF 363? Challenge in defining a clear and auditable standard that can be applied across the vast diversity of excipient manufacturing processes… Attempts to define requirements for one excipient often absurd for another. Joint IPEC-PQG GMP Guide for Pharmaceutical Excipients 2006, a source document, addressed differences by presenting various options or points for consideration and in some sections also referred to risk assessment.

NSF/IPEC 363 GMP Documented Risk Assessment Required in sections: 4.3 Change Control 5.5.3 Internal Communication 6.2.3 Hygienic Practices 6.3.1 Buildings and Facilities 6.3.2.1 Equipment Construction 6.3.3 Utilities 6.4 Work Environment 7.4.1 Purchasing Process 7.5.5.2 Excipient Packaging Systems 8.3.2 Reworking DRAFT Feb 8, 2013

Risk Assessment Identification The sections of NSF/IPEC 363 requiring risk assessment preload the process by: defining the scope or “risk question(s)”, providing the nature of hazards to be considered, and pointing to risk controls that may be implemented

Risk Assessment for Excipients differ from that for Food Products People can chose other food and be nourished but have no choice in taking the medicine prescribed by their physician ICH Q9 definition of “harm” includes everything from Food Risk Assessment plus the additional “damage to health, including the damage that can occur from loss of product quality or availability” Failure of a drug batch as the result of an excipient also consumes a good API that is no longer available to the market

Documentation Allows an assessment of the results in terms of the risks to be controlled, the reasoning and facts leading to the conclusions, understanding the risks that were considered Provides evidence that competent people performed exercise adequate information was available a standard process was followed an appropriate assessment was conducted

Can a 3rd party audit do what a 1st party audit does? Assess compatibility of supplier with internal programs Indentify risk and validate controls Educate supplier Enhance communication Meet regulatory/policy requirements

Nothing in FDA regulations prevents using 3rd party auditors to evaluate suppliers Sec. 211.34 Consultants. Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained. Records shall be maintained stating the name, address, and qualifications of any consultants and the type of service they provide.

Why audit? Regulatory expectation / requirement Understand how well the risks from your suppliers are mitigated by your internal process/programs Confirm the reliability of your supply chain Collect objective evidence that supports your confidence in the supplier

Benefits of Audit Business intelligence to secure supply chain Process improvement Validate assumption Risk assessment Continuity of supply Communication with suppliers

Additional Considerations Audits help both supplier & customer understand Language differences exist between the chemical and pharma industries (e.g. process capability vs. validation) IPEC Guides help with translation Environmental health and safety systems address GMP principles.  In the chemical industry, consequence of system failure may be tragic to plant, workers and community Keeping product in pipes and out of environment may be same as the control of contamination to keep environment out of product in GMP

Third Party Certifications Standards build GMP from a universal QMS foundation whose processes connect well to other systems Preparation for certification educates suppliers and provides greater understanding of their own processes Using qualified auditors in an IPEA or EXCiPACT certification program provides confidence in the audit results (both regulatory and internal) Audit reports provide information from which to ask further questions Communication can proceed more effectively through other channels building on certification information Quality Agreements, shorter site visits, conference calls

Excipient GMP Certification Application Planning Audit Report Review Certification Review Board

IPEA Excipient GMP Certification Program Comprehensive Site Audit to Excipient GMPs Minimum 2-days, 2 auditors, single excipient Excipient manufacturer decides scope of site audit Identifies excipients within scope Annual surveillance audit Certification Board 4 Independent Qualified Experts Review Application, Audit Report, and CAPA plan to Certify Audit Sponsorship Excipient Maker, or Excipient User Audit sponsors are considered confidential and are not disclosed NOTE: IPEC-Americas has signed an agreement to sell IPEA auditing to NSF International

IPEA Certification ANSI Accredited to ISO/IEC Guide 65, General requirements for bodies operating product certification systems FDA requested IPEA become accredited Accredited since April 2010 E-mail :  valeria.stewart@ipecamericas.org www.ipeainc.com NOTE: IPEC-Americas has signed an agreement to sell IPEA auditing to NSF International

Cost of Certification & Reports First year certification - $20,000 IPEC members, $22,000 non- members for a single site & single excipient (often including multiple grades). Additional excipients or manufacture that includes contract operations are priced according to the additional time required for the on-site audit. Audits with extraordinary travel requirements and related costs may cost slightly higher. Annual fee for surveillance audit and recertification is half the price of certification. IPEC-Americas member companies receive a 10% discount from all prices unless otherwise posted. The Certification Audit Report is available for purchase $500 for IPEC-Americas member companies $750 for non-members Most of the proceeds from report sales are provided as a credit to the excipient supplier to reduce their annual surveillance cost

Benefits of IPEA Certification Security that you have opportunity to review report draft for any factual errors, omissions, and confidential information before report is finalized. Confidence that, if needed, any CAPA plans will be included as an addendum to an audit report before a final copy is sent to the Sponsor. Quality review of each audit report by IPEA review board who insure consistent and appropriate application of IPEC excipient GMP requirements. Opportunity to use audit reports to establish to customers your compliance to appropriate GMP requirements. Independent and impartial IPEA assessments help gain customer confidence in your quality system Confidential audit reports are never sold without notification and approval of the audited manufacturer . Affords you the opportunity to prevent the report from being sold to a competitor.

EXCiPACTTM Certification The process and relationship Legal Agreement with 3rd Party Audit Organisations Publish on website lists of Valid Certificates Qualified Auditors Agreement with supplier Provides audit reports and Certificate Supplier passes on audit report User can verify audit report and certificate with EXCiPACTTM Association Excipient user EXCiPACT Association 3RD Party Audit Organisation Excipient Supplier Excipient user EXCiPACTTM – minimize risks, maximize benefits 27

EXCiPACT™ Certification EXCiPACT™ Certification Current Status Two Agreements have been signed with Certifying Bodies blue inspection / mdc, Stuttgart SGS Pilot Audits have been completed Discussions are ongoing with other Certifying Bodies EXCiPACTTM - minimise risks, maximise benefits

Cost for EXCiPACT Audit EXCiPACTTM Certification Cost savings for stakeholders Cost for EXCiPACT Audit Pharmaceutical Company Excipient Supplier Audit fee ~ $13,000 Certificate fee ~ $7000 Surveillance ~ $7000 Internal cost ~ $8000 Total cash-out ~ $35,000 Reduction by one two-day audit a month, plus one day for preparation, at internal cost incl. of ~ $2500 each, plus ~ $6000 travel expenses per year ~ $37,000 savings per year Reduction by one two-day audit a month , plus three days for travel and preparation of the report , plus travel expenses, at total cost of ~$22,000 ~ $74,000 savings per year Total cost in 3 years ~ $35,000 Total Savings in 3 years ~ $110,000 Total Savings in 3 years ~ $225,000 Total Industry Benefit $75,000 $300,000 29

Audit Sharing Programs Other  programs have many challenges Use of Industry auditors The Quality of the audit is only as good as the auditor Legal complexity Many excipient manufacturers legal departments will not allow for sharing of audits. Excipient manufacturers fear loss of control of confidential or proprietary information. Unlike IPEA or EXCiPACT certified auditors, auditors are not  subject to qualification standards. These are not certification programs

Immediate Past Chair IPEC Americas dale.carter@huber.com William Dale Carter Immediate Past Chair IPEC Americas dale.carter@huber.com Director of Global Quality JM Huber, Engineered Materials – Silica 3100 Cumberland Blvd, Suit 600 Atlanta, GA 30339 Phone 678-247-2735 Acknowledgements: Kathie Ulman – Dow-Corning Ann Van Meter - Dow Wolff Cellulosics Irwin Silverstein – IPEA Priscilla S. Zawislak - Ashland Iain Moore - Croda