Discuss the Strategies to Increase the Number of Excipients Labeled USP-NF October 10-11, 2006 DISCUSSION TOPIC D Closing Presentation

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Discuss the Strategies to Increase the Number of
Excipients Labeled USP-NF October 10-11,
2006DISCUSSION TOPIC DClosing Presentation

• Moderator Barbara FergusonScribes Catherine
  Sheehan
• Dr. Hong Wang

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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 excipient
• GMP requirements are perceived to be too
  stringent
• Difficult for chemical supplier to come up to
  speed with GMPs
• Lack of excipient manufacturers 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

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PQRI Workshop Discussion D

• 1.a. What are the barriers to labeling an
  excipient as USP-NF grade?
• Dont 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.
• User needs to understand why the vendor will not
  certify material as USP-NF to ensure that it will
  not impact quality of product

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PQRI Workshop Discussion D

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

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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
  formulation
• Needs to be an understanding between maker and
  user regarding the necessary qualifications
• Purchasing buys the material - gets you cheap
  excipients, not good science
• Scientist/formulator should communicate with
  vendor for necessary qualities/use of excipient
• Insurance/internal requirements to qualify two
  sources of excipients
• Excipient manufacturers vary (some will supply
  the pharmaceutical market, some wont, some are
  fully dedicated to the drug/food industry, some
  are chemical manufacturers)
• Monograph testing does not appear to be a
  contributing factor

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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 recommendations
• Provide guidance to educate both parties as to
  what is needed/expected see 6 for
  recommendations
• Audits
• focus on vendors control of excipient process
• coordinate audits from the drug product
  manufacturer
• 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?

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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 deleted
• Recommend retaining monograph as minimum standard
  as long as there is no safety issue
• Monographs that have been omitted (deleted)
• Dehydroacetic acid (proposal to be reinstated)
• Propylene glycol diacetate
• Gentisic acid ethanolamide
• Can the deleted list be published?
• USP 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)
• Can Distributor assume liability and call it
  USP-NF if they perform final processing step
  under GMPs?

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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 material
• need to know why it is not USP-NF
• may be using same process, but are controls the
  same?
• Need to change regulatory filing, if applicable
• Changes to regulatory filings could be costly
  (e.g., Europe)
• Look for another supplier

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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 audits
• If fails when tested, drug product manufacturer
  assumes risk/loss
• Justification to move from compendial to
  noncompendial grade
• If monograph is deleted, can reference last
  official version of USP-NF monograph in
  regulatory filing

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PQRI Workshop Discussion D

• 4. What is industrys 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 applicable
• Method 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 supplied
• Refer to Ph. Eur., JP, FCC, ACS Reagent Grade, or
  AOAC no additional validation needs to be
  supplied
• Refer to excipient manufacturers DMF, no
  additional validation needs to be supplied
• Validation only required for other methods used
  to control excipient

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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, JECFA
• Excipient vendor method
• Noncompendial excipient section of filing
• May need to send supplement to FDA

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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 section
• Provide more background/policies on tests
  technical guide
• Outreach programs to industry USP staff
  available to assist with development of
  monographs
• USP General Information Chapters for Excipients
• lt1078gt GMPs (official but is being updated to
  reflect current IPEC)
• lt1080gt CoA (coming soon)
• lt1195gt Significant Change (coming soon)
• Excipient qualification guidelines being
  developed by IPEC and will eventually be included
  in USP
• I - Excipient manufacturer (new proposal soon)
• II - Excipient user (being drafted by IPEC)
• III - Negotiation process (later)
• USP lab may assist with revisions to monographs
  (e.g., glycerin)

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PQRI Workshop Discussion D

• 6. What are the ongoing initiatives at the USP to
  address these problems?
• Recommendations
• 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.
• The distributors, once educated, could assist in
  educating the excipient vendors.
• Establish Excipient Stakeholder Forum
• 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.
• FAQs on USP website
• More transparency for PDG Harmonization updates
  USP website link to EDQMs PDG status reports

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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.
• 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 FDC Act
  applies if the excipient purports to be or is
  represented as a drug the name of which is
  recognized in the official compendium.

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Closing Questions / Comments

• What is industrys burden in supplying analytical
  method validation data to regulatory agency for
  excipients no longer labeled USP-NF?
• Refer to excipient manufacturers 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?
• 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.

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Closing Questions / Comments

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

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Closing Questions/ Comments

• Guideline for submission of a revision to the
  USP-NF http//www.usp.org/USPNF/submitMonograph/su
  bGuide.html
• Chapter 3 Excipients and addenda