Transcript USP - NF - PQRI - PQRI: Product Quality Research Institute

Discuss the Strategies to Increase
the Number of Excipients Labeled
USP-NF
October 10-11, 2006
DISCUSSION TOPIC D
Closing Presentation
Moderator:
Scribes:
Barbara Ferguson
Catherine Sheehan
Dr. Hong Wang
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 manufacturer’s understanding of what
requirements, outside of the USP-NF monograph, need
to be met, including GMP requirements
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Many monographs developed prior to establishment of GMP
requirement for excipients
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.
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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
PQRI Workshop Discussion D
1.a. What are the barriers to labeling an
excipient as USP-NF grade?
• Time/resources for audits
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more than one audit by a firm
• Pharmaceutical manufacturer auditors
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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
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
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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 won’t, some are fully
dedicated to the drug/food industry, some are chemical
manufacturers)
• Monograph testing does not appear to be a contributing
factor
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
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focus on vendor’s 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?
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)
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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?
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
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need to know why it is not USP-NF
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may be using same process, but are controls the same?
• Need to change regulatory filing, if applicable
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Changes to regulatory filings could be costly (e.g., Europe)
• Look for another supplier
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
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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
PQRI Workshop Discussion D
4. What is industry’s burden in supplying analytical method validation
data to regulatory agency for excipients no longer labeled USPNF?
• 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 manufacturer’s DMF, no additional validation
needs to be supplied
• Validation only required for other methods used to control
excipient
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
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
 <1078> GMPs (official but is being updated to reflect current
IPEC)
 <1080> CoA (coming soon)
 <1195> 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)
PQRI Workshop Discussion D
6. What are the ongoing initiatives at the USP to
address these problems?
• Recommendations:
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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
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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 EDQM’s PDG status reports
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.
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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.
Closing Questions / Comments
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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.
• 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.
Closing Questions / Comments
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Excipients no longer available as NF Grade
USP list
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Corn Syrup
Diethyl phthalate
Edetate Calcium (Calcium EDTA powder)
IPEC List
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Glycerin (synthetic)
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Lecithin
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Liquid Glucose
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Propylene Glycol Stearate
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Dehydroacetic acid
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Propylene glycol diacetate
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Gentisic acid ethanolamide
Closing Questions/ Comments
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Guideline for submission of a revision
to the USP-NF
http://www.usp.org/USPNF/submitMonograph/subGuide.html
• Chapter 3 Excipients and addenda