1. Drug Excipient Compatibility:
What FDA Wants to Know
Case Study for Duloxetine HCl Delayed-Release Capsules
Naiqi Ya, Ph.D.
Division of Chemistry II
Office of Generic Drugs
FDA
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2. Disclaimer
Opinions expressed in this presentation
are those of the speaker and do not
necessarily reflect the views or policies
of the FDA.
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3. Outline
 Why compatibility study is needed?
 Duloxetine Hydrochloride and formulation
 Observations in submissions
 Suggestions
 Summary
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4. VERSED® Syrup Recall
Roche Laboratories is conducting a voluntary
Class I drug recall…, because of the potential
presence of a crystalline precipitate of an
insoluble complex of midazolam and
saccharin inside the bottle. The presence of
this precipitate causes a lack of uniformity in
the product and may result in the administration
of a super or sub-potent dose.
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5. Why compatibility study is needed?
 Required by ICH Q8R*:
“The compatibility of the drug substance with
excipients listed in 3.2.P.1 should be evaluated...”
 Achieve acceptable drug product stability
 Avoid to rely only on end-product testing,
which is considered high risk than using
quality by design (QbD)
5 * ICH Q8(R) Pharmaceutical Development, Section 2.1.1

6. Duloxetine Hydrochloride
(+)-(S)-N-methyl-3-(1-
naphthalenyloxy)-2-
O • HCl thiophenepropanami
S CH3 ne hydrochloride
N
H
• Acid labile compound that degrades to a highly toxic compound
1-naphthol
• Contain a secondary amine
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7. Delayed-Release Formulation
 Need an enteric polymer-coating to prevent the acid
degradation in the stomach
 Commonly used polymers in an enteric coated
formulation:
– Hydroxypropyl Methylcellulose Acetate Succinate
(HPMCAS) and Hydroxypropyl Methylcellulose Phthalate
(HPMCP)
– Methyl acrylate - methacrylic acid copolymers
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8. Issues with HPMCAS & HPMCP
 May accelerate degradation of duloxetine due to the free
acids contained in the polymers due to the free acids in
each polymer (allow up to 1% per USP).
 React with the polymer degradation products to form
succinamide (left) and phthalamide (right) impurities*:
O OH
O O O O
S OH S
N N
CH3 O CH3
8 * Jansen, P.T., Oren, P.L., Kemp, C.A., Maple, S.R., and Baertschi, S.W. J. Pharm. Sci. 1998, 87, 81-85

9. Subcoat Layer
A subcoat layer should be used to separate the
duloxetine-containing layer and the enteric
coating*.
Sugar Sphere Enteric Coating Layer
Subcoat Layer
Finishing Layer
(optional) Duloxetine-containing layer
* 1) Jansen, P.T., Oren, P.L., Kemp, C.A., Maple, S.R., and Baertschi, S.W. J. Pharm. Sci. 1998, 87, 81-85
9 2) US Patent No. 5,508,276 and US Patent Application No. US 2009/00171121

10. Observations in Submissions
 No discussion about the potential interaction of
duloxetine with the enteric coating polymers
 No study for thickness of subcoat layer
 No method developed or validated for the impurities
formed by the interaction of duloxetine with the
enteric coating polymers
 No justification for the impurities acceptance criteria
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11. Suggestions
For evaluating the potential interaction of
duloxetine with the enteric coating polymers:
– Analyzing excipients in formulation that:
 may react with a secondary amine
 may form free acid
– Analyzing aged and/or stressed drug product
– Searching scientific literature and patents
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12. Suggestions
For evaluating the thickness of subcoat layer:
– Provide rationale for polymer selection
– Establish a thickness range for the subcoat layer
with supporting data
– Establish a target value for the commercial drug
product manufacturing process
– Establish an in-process test for the coating
uniformity
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13. Suggestions
For developing or validating for impurity
method:
– Use known impurity/degradant standard or the
stressed samples
– Provide data to demonstrate a method is capable to
detect the impurities formed by the interaction of
duloxetine with the enteric coating polymers
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14. Suggestions
For justifying impurities acceptance criteria (no
USP monograph available):
– ICH guidances
– Comparison to reference listed drug (RLD)
– Scientific literature
– Pharm/Tox Study
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15. Summary
 Identify drug excipient compatibility issues (drug
– excipient – packaging materials)
 Justify drug product formulation design
 Establish appropriate manufacturing process
parameters
 Establish adequate quality controls (analytical
methods and acceptance criteria) for in-process
and finished product
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16. Acknowledgment
Gary Buehler, Office Director
Lawrence Yu, Deputy Office Director for Science
Florence Fang, Division Director
Richard Adams, Deputy Division Director
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