Transcript When is Excipient Reduced Testing Appropriate?

When is Excipient
Reduced Testing
Appropriate?
21 CFR 211.84(d) requirements (1)
“At least one test shall be conducted to
verify the identity of each component
of a drug product. Specific identity
tests, if they exist, shall be used.”
21 CFR 211.84(d) requirements (2)

“Each component shall be tested for conformity
with all appropriate written specifications for
purity, strength, and quality. In lieu of such
testing by the manufacturer, a report of analysis
may be accepted from the supplier of a
component, provided that at least one specific
identity test is conducted on such component by
the (drug product) manufacturer, and provided
that the (drug product) manufacturer establishes
the reliability of the supplier's analyses through
appropriate validation of the supplier's test
results at appropriate intervals.”
USP—NF General Notices
(section Tests and Assays under Procedures)

“Every compendial article in commerce shall be so
constituted that when examined in accordance with these
assay and test procedures, it meets all of the requirements
in the monograph defining it. However, it is not to be
inferred that application of every analytical procedure in the
monograph to samples from every production batch is
necessarily a prerequisite for assuring compliance with
Pharmacopeial standards before the batch is released for
distribution. Data derived from manufacturing process
validation studies and from in-process controls may provide
greater assurance that a batch meets a particular
monograph requirement than analytical data derived from
an examination of finished units drawn from that batch. On
the basis of such assurances, the analytical procedures in
the monograph may be omitted by the manufacturer in
judging compliance of the batch with the Pharmacopeial
standards.”
Survey Results
for Reduced Testing
Survey – Reduced Testing
Drug Product Manufacturers
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91% include COA qualification during
their vendor qualification
78% reduce frequency of complete
monograph testing based on COA
qualification
24% received FDA approval prior to
implementing reduced testing
Survey – Reduced Testing
Drug Product Manufacturers
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49% accept the excipient by ID test and COA
when an excipient manufacturer has been
audited, qualified, and has performed all
tests according to compendia, or as
approved in a drug product application

97% perform more than the ID test before
accepting an excipient
Survey – Reduced Testing
Drug Product Manufacturers
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Frequency of full testing
• 3rd lot by 3%
• 5th lot by 7%
• 10th lot by 29%
• Other frequency by 61%

The data suggest it is common to
fully test every 10th lot.
Survey – Reduced Testing
Drug Product Manufacturers
Vendor Certification Program
Reduced testing based on prior
approval?
C of A means reduced testing?
Include C of A qualification?
Have a vendor certification program?
0
10
20
30
40
50
60
Percent Yes
70
80
90 100
Survey – Reduced Testing
Distributor
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Distributor respondents stated that a
reduced testing program is applicable
to some, most, or all of the products
they distribute
Survey – Reduced Testing for Drug
Product and Excipient Manufacturers
Confirm Compliance with Multiple Compendia
Select most stringent method
Method
Test for method equivalence.
Test per harmonized monograph.
Accept on C of A only.
Conduct ID test with C of A from supplier
Test by one compendium and accept C of A
Test to all required compendia.
0
10
20
30
40
50
60
Percent
70
80
90 100
Excipient Reduced
Testing Issues
Excipient Reduced Testing Issues

How should industry resolve
problems with ICH Q4B
interchangeability?
Excipient Reduced Testing Issues

When can Industry start
implementing a new signed off
general chapter?
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Once it is published in USP-NF?
Wait until the delayed implementation
date?
When ICH Q4B has been completed?
Excipient Reduced Testing Issues

How many tests should be
performed to assure an excipients
quality for global drug products
when there are a number of nonharmonized tests in the global
(e.g., USP-NF, Ph.Eur., JP)
compendia?
Excipient Reduced Testing Issues

What are the regulatory approaches
when industry uses Ph.Eur. or JP
test results to meet the USP-NF
requirements?
Excipient Reduced Testing Issues

How is your company filing changes to USP-NF
excipient monographs and general chapters, to
your previous submission to the FDA?
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21 CFR 314.70 regulations apply, but FDA's
“Guidance to Industry, Changes to an Approved
NDA or ANDA; Specifications–Use of
Enforcement Discretion for Compendial
Changes” states discretionary enforcement, and
industry uncertainty remains.
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What are your company's policies/practices
based on FDA's 21 CFR 314.70 and the FDA’s
Guidance on Enforcement Discretion issued on
November 19, 2004?
Excipient Reduced Testing Issues

How should industry make effective
use of PDG harmonization in light of
the resulting changed excipient
monographs?