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Naiqi ya


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Naiqi ya

  1. 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 FDA1
  2. 2. Disclaimer Opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or policies of the FDA.2
  3. 3. Outline  Why compatibility study is needed?  Duloxetine Hydrochloride and formulation  Observations in submissions  Suggestions  Summary3
  4. 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.4
  5. 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. 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 amine6
  7. 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 copolymers7
  8. 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 CH38 * Jansen, P.T., Oren, P.L., Kemp, C.A., Maple, S.R., and Baertschi, S.W. J. Pharm. Sci. 1998, 87, 81-85
  9. 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, 81-859 2) US Patent No. 5,508,276 and US Patent Application No. US 2009/00171121
  10. 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 criteria10
  11. 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 patents11
  12. 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 uniformity12
  13. 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 polymers13
  14. 14. Suggestions For justifying impurities acceptance criteria (no USP monograph available): – ICH guidances – Comparison to reference listed drug (RLD) – Scientific literature – Pharm/Tox Study14
  15. 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 product15
  16. 16. Acknowledgment Gary Buehler, Office Director Lawrence Yu, Deputy Office Director for Science Florence Fang, Division Director Richard Adams, Deputy Division Director16