1. Discuss the Strategies to Increase the Number of Excipients Labeled USP-NF October 10-11, 2006 DISCUSSION TOPIC D Closing Presentation Moderator:Barbara Ferguson Scribes:Catherine Sheehan Dr. Hong Wang

2. PQRI Workshop Discussion D 1.a. What are the barriers to labeling an excipient as USP-NF grade? Low demand, not main business, may charge premium for USP-NF grade, may be a by-product and not final excipientLow demand, not main business, may charge premium for USP-NF grade, may be a by-product and not final excipient GMP requirements are perceived to be too stringentGMP requirements are perceived to be too stringent Difficult for chemical supplier to come up to speed with GMPsDifficult for chemical supplier to come up to speed with GMPs Lack of excipient manufacturer’s understanding of what requirements, outside of the USP-NF monograph, need to be met, including GMP requirementsLack of excipient manufacturer’s understanding of what requirements, outside of the USP-NF monograph, need to be met, including GMP requirements Many monographs developed prior to establishment of GMP requirement for excipients Many monographs developed prior to establishment of GMP requirement for excipients

3. PQRI Workshop Discussion D 1.a. What are the barriers to labeling an excipient as USP-NF grade? Don’t want to put NF on the label because of the liability to meet other requirements in addition to monograph requirements.Don’t want to put NF on the label because of the liability to meet other requirements in addition to monograph requirements. The Act 501b does not distinguish between the drug and the excipient in the drug, so the requirement to comply with USP-NF exists if the excipient manufacture supplies the drug market. Need clarity on this point from FDA. The Act 501b does not distinguish between the drug and the excipient in the drug, so the requirement to comply with USP-NF exists if the excipient manufacture supplies the drug market. Need clarity on this point from FDA. User needs to understand why the vendor will not certify material as USP-NF to ensure that it will not impact quality of product User needs to understand why the vendor will not certify material as USP-NF to ensure that it will not impact quality of product

4. PQRI Workshop Discussion D 1.a. What are the barriers to labeling an excipient as USP-NF grade? Time/resources for auditsTime/resources for audits more than one audit by a firm more than one audit by a firm Pharmaceutical manufacturer auditorsPharmaceutical manufacturer auditors mistakenly apply drug GMPs to excipients mistakenly apply drug GMPs to excipients different requirements for each auditor/firm different requirements for each auditor/firm do not understand excipient process do not understand excipient process utilize audit check list mentality utilize audit check list mentality use terms for drug GMPs which are not pertinent to excipient control use terms for drug GMPs which are not pertinent to excipient control

5. PQRI Workshop Discussion D 1.a. What are the barriers to labeling an excipient as USP-NF grade? Lack of understanding of use of excipient in formulationLack of understanding of use of excipient in formulation Needs to be an understanding between maker and user regarding the necessary qualifications Needs to be an understanding between maker and user regarding the necessary qualifications Purchasing buys the material - gets you cheap excipients, not good science Purchasing buys the material - gets you cheap excipients, not good science Scientist/formulator should communicate with vendor for necessary qualities/use of excipient Scientist/formulator should communicate with vendor for necessary qualities/use of excipient Insurance/internal requirements to qualify two sources of excipientsInsurance/internal requirements to qualify two sources of excipients Excipient manufacturers vary (some will supply the pharmaceutical market, some won’t, some are fully dedicated to the drug/food industry, some are chemical manufacturers)Excipient manufacturers vary (some will supply the pharmaceutical market, some won’t, some are fully dedicated to the drug/food industry, some are chemical manufacturers) Monograph testing does not appear to be a contributing factorMonograph testing does not appear to be a contributing factor

6. PQRI Workshop Discussion D 1.b. How can the barriers be reduced? Foster better understanding by excipient manufacturers and drug product manufacturers regarding the appropriate GMPs for excipients – see #6 for recommendationsFoster better understanding by excipient manufacturers and drug product manufacturers regarding the appropriate GMPs for excipients – see #6 for recommendations Provide guidance to educate both parties as to what is needed/expected – see #6 for recommendationsProvide guidance to educate both parties as to what is needed/expected – see #6 for recommendations AuditsAudits focus on vendor’s control of excipient process focus on vendor’s control of excipient process coordinate audits from the drug product manufacturer coordinate audits from the drug product manufacturer utilize third party audits after initial qualification utilize third party audits after initial qualification May still come down to the bottom line: Is there enough of a market to supply this grade?May still come down to the bottom line: Is there enough of a market to supply this grade?

7. PQRI Workshop Discussion D 2. What excipients are no longer available as USP-NF grade, which were formerly available as USP-NF grade? If there is no USP-NF grade excipient commercially available, then there is no one to support the continuation of a monograph; USP monograph is deletedIf there is no USP-NF grade excipient commercially available, then there is no one to support the continuation of a monograph; USP monograph is deleted Recommend retaining monograph as minimum standard as long as there is no safety issueRecommend retaining monograph as minimum standard as long as there is no safety issue Monographs that have been omitted (deleted)Monographs that have been omitted (deleted) Dehydroacetic acid (proposal to be reinstated) Dehydroacetic acid (proposal to be reinstated) Propylene glycol diacetate Propylene glycol diacetate Gentisic acid ethanolamide Gentisic acid ethanolamide Can the deleted list be published?Can the deleted list be published? USP will reinstate monograph if supplier will support itUSP will reinstate monograph if supplier will support it Some examples provided for vendors no longer certifying material as USP-NF (e.g., methanol in tankers)Some examples provided for vendors no longer certifying material as USP-NF (e.g., methanol in tankers) Can Distributor assume liability and call it USP-NF if they perform final processing step under GMPs?Can Distributor assume liability and call it USP-NF if they perform final processing step under GMPs?

8. PQRI Workshop Discussion D 3. What are the implications when an excipient user moves from a compendial grade excipient to noncompendial grade (i.e., not designated through labeling suffix, namely USP-NF, Ph. Eur. or JP), when it was previously procured as compendial grade? Drug product manufacturer assumes liability if continues to use materialDrug product manufacturer assumes liability if continues to use material need to know why it is not USP-NF need to know why it is not USP-NF may be using same process, but are controls the same? may be using same process, but are controls the same? Need to change regulatory filing, if applicableNeed to change regulatory filing, if applicable Changes to regulatory filings could be costly (e.g., Europe) Changes to regulatory filings could be costly (e.g., Europe) Look for another supplierLook for another supplier

9. PQRI Workshop Discussion D 3. What are the implications when an excipient user moves from a compendial grade excipient to noncompendial grade (i.e., not designated through labeling suffix, namely USP-NF, Ph. Eur. or JP), when it was previously procured as compendial grade? Even if monograph is maintained, testing alone is insufficient – need greater assurance, possibly through auditsEven if monograph is maintained, testing alone is insufficient – need greater assurance, possibly through audits If fails when tested, drug product manufacturer assumes risk/loss If fails when tested, drug product manufacturer assumes risk/loss Justification to move from compendial to noncompendial gradeJustification to move from compendial to noncompendial grade If monograph is deleted, can reference last official version of USP-NF monograph in regulatory filingIf monograph is deleted, can reference last official version of USP-NF monograph in regulatory filing

10. PQRI Workshop Discussion D 4. What is industry’s burden in supplying analytical method validation data to regulatory agency for excipients no longer labeled USP-NF? If not using USP-NF method, then drug product manufacturer is required to provide this in filing, if applicableIf not using USP-NF method, then drug product manufacturer is required to provide this in filing, if applicable Method must still be capable of controlling quality of the excipientMethod must still be capable of controlling quality of the excipient Reference prior version of USP-NF, and if still appropriate for excipient, no additional validation needs to be suppliedReference prior version of USP-NF, and if still appropriate for excipient, no additional validation needs to be supplied Refer to Ph. Eur., JP, FCC, ACS Reagent Grade, or AOAC – no additional validation needs to be suppliedRefer to Ph. Eur., JP, FCC, ACS Reagent Grade, or AOAC – no additional validation needs to be supplied Refer to excipient manufacturer’s DMF, no additional validation needs to be suppliedRefer to excipient manufacturer’s DMF, no additional validation needs to be supplied Validation only required for other methods used to control excipientValidation only required for other methods used to control excipient

11. PQRI Workshop Discussion D 5. What test methods are used when an excipient user must replace a compendial grade excipient with noncompendial grade? ACS Reagent Grade, FCC, AOAC, JECFAACS Reagent Grade, FCC, AOAC, JECFA Excipient vendor methodExcipient vendor method Noncompendial excipient section of filingNoncompendial excipient section of filing May need to send supplement to FDAMay need to send supplement to FDA

12. PQRI Workshop Discussion D 6. What are the ongoing initiatives at the USP to address these problems? Monograph development guideline on USP website with excipient sectionMonograph development guideline on USP website with excipient section Provide more background/policies on tests – “technical guide” Provide more background/policies on tests – “technical guide” Outreach programs to industry – USP staff available to assist with development of monographsOutreach programs to industry – USP staff available to assist with development of monographs USP General Information Chapters for ExcipientsUSP General Information Chapters for Excipients GMPs (official but is being updated to reflect current IPEC) GMPs (official but is being updated to reflect current IPEC) CoA (coming soon) CoA (coming soon) Significant Change (coming soon) Significant Change (coming soon) Excipient qualification guidelines being developed by IPEC and will eventually be included in USP Excipient qualification guidelines being developed by IPEC and will eventually be included in USP I - Excipient manufacturer (new proposal soon)I - Excipient manufacturer (new proposal soon) II - Excipient user (being drafted by IPEC)II - Excipient user (being drafted by IPEC) III - Negotiation process (later)III - Negotiation process (later) USP lab may assist with revisions to monographs (e.g., glycerin)USP lab may assist with revisions to monographs (e.g., glycerin)

13. PQRI Workshop Discussion D 6. What are the ongoing initiatives at the USP to address these problems? Recommendations:Recommendations: Reach out to distributors and non traditional USP-NF suppliers. Reach out to distributors and non traditional USP-NF suppliers. Use USP Annual Science Meeting as a forum to reach out and educate the non traditional USP-NF users.Use USP Annual Science Meeting as a forum to reach out and educate the non traditional USP-NF users. The distributors, once educated, could assist in educating the excipient vendors.The distributors, once educated, could assist in educating the excipient vendors. Establish Excipient Stakeholder ForumEstablish Excipient Stakeholder Forum Utilize USP verification program to reduce the amount of audits. Utilize USP verification program to reduce the amount of audits. Establish a process for vendors to notify USP as to when the NF grade is no longer available. Establish a process for vendors to notify USP as to when the NF grade is no longer available. FAQs on USP website FAQs on USP website More transparency for PDG Harmonization updates – USP website link to EDQM’s PDG status reports More transparency for PDG Harmonization updates – USP website link to EDQM’s PDG status reports

14. Closing Questions / Comments Section 501b of the Act does not distinguish between the drug and the excipient in the drug, so the requirements to comply with USP-NF exists if the excipient manufacture supplies the drug market. This could cause excipient manufactures to remove “NF” from their label. This could cause excipient manufactures to remove “NF” from their label. Removing the “NF” designation from the label does not obviate the requirement to comply with the compendial standards if the excipient is tended for use in the manufacture of a drug product. That is because section 501 (b) of the FD&C Act applies if the excipient purports to be or is represented as a drug the name of which is recognized in the official compendium. Removing the “NF” designation from the label does not obviate the requirement to comply with the compendial standards if the excipient is tended for use in the manufacture of a drug product. That is because section 501 (b) of the FD&C Act applies if the excipient purports to be or is represented as a drug the name of which is recognized in the official compendium.

15. Closing Questions / Comments What is industry’s burden in supplying analytical method validation data to regulatory agency for excipients no longer labeled USP-NF? What is industry’s burden in supplying analytical method validation data to regulatory agency for excipients no longer labeled USP-NF? Refer to excipient manufacturer’s DMF, no additional validation needs to be supplied.Refer to excipient manufacturer’s DMF, no additional validation needs to be supplied. If the Drug Manufacturer uses the excipient manufacturers DMF does the Drug Manufacturer needs to supply the validation?If the Drug Manufacturer uses the excipient manufacturers DMF does the Drug Manufacturer needs to supply the validation? No additional analytical methods validation data need to be supplied in an (abbreviated, or) new drug application (NDA or ANDA), if FDA determines the DMF to be adequate in support of the NDA/ANDA.No additional analytical methods validation data need to be supplied in an (abbreviated, or) new drug application (NDA or ANDA), if FDA determines the DMF to be adequate in support of the NDA/ANDA.

16. Closing Questions / Comments Excipients no longer available as NF Grade Excipients no longer available as NF Grade USP list Corn Syrup Corn Syrup Diethyl phthalate Diethyl phthalate Edetate Calcium (Calcium EDTA powder) Edetate Calcium (Calcium EDTA powder) IPEC List Glycerin (synthetic) Glycerin (synthetic) Lecithin Lecithin Liquid Glucose Liquid Glucose Propylene Glycol Stearate Propylene Glycol Stearate Dehydroacetic acid Dehydroacetic acid Propylene glycol diacetate Propylene glycol diacetate Gentisic acid ethanolamide Gentisic acid ethanolamide

17. Closing Questions/ Comments Guideline for submission of a revision to the USP-NF http://www.usp.org/USPNF/submitMonograph/subGuide.html Guideline for submission of a revision to the USP-NF http://www.usp.org/USPNF/submitMonograph/subGuide.html http://www.usp.org/USPNF/submitMonograph/subGuide.html Chapter 3 Excipients and addendaChapter 3 Excipients and addenda