1. 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

2. 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)

3. 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.

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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?

11. 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.

12. NSF/IPEC 363 GMP Documented Risk Assessment Required in sections:
4.3 Change Control
Internal Communication
Hygienic Practices
Buildings and Facilities
Equipment Construction
Utilities
6.4 Work Environment
Purchasing Process
Excipient Packaging Systems
Reworking
DRAFT Feb 8, 2013

13. 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

14. 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

15. 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

16. 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

17. Nothing in FDA regulations prevents using 3rd party auditors to evaluate suppliers
Sec 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.

18. 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

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

20. 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

21. 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

22. Excipient GMP Certification
Application
Planning
Audit
Report Review
Certification
Review Board

23. 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

24. 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
NOTE: IPEC-Americas has signed an agreement to sell IPEA auditing to NSF International

25. 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

26. 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.

27. 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

28. 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

29. 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, $300,000 29

30. 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

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