Extractables & Leachables

Extractables & Leachables. Analytical workflow. 1.

Definitions. 2. Extractables: Compounds that can be extracted from the container closure system when in the presence of a solvent. Leachables: Compounds that leach into the drug product formulation from the container closure as a result of direct contact with the formulation..

A Roadmap. Extractables screening (CCS / Component shortlist) CCS Selection (Exhibit batches) Leachables study in drug product (Stability samples) Routine QC Specification.

Extractables Goals. 4. To make an informed selection of materials To meet regulatory expectations To control Leachables To evaluate safety of materials To obtain a comprehensive extractable profile Compendial testing does not provide applicable data !.

Extractables Sources. 5. In-process single use systems Primary packaging components Secondary packaging Components Tertiary packaging Materials.

Suspected PRCA Cases Reported and EPREX Exposure Worldwide by Year as of April 30, 2002 Prior to 1999 1999 2000 2001 2002 # of Suspected PRCA Cases By Year of Onset 3 11 16 57 9.

7. 2010: More than 500 lots of Tylenol, Motrin, Benadryl and Zyrtec were recalled due to consumer complaints about a “musty” odor in the drug products. Cause: The cause of the musty odor was eventually determined to be caused by an antifungal chemical used to treat the shipping pallets, 2, 4, 6-tribromoanisole. Cost: Est. $900 million in lost sales..

LC-MS/MS or LC-QTOF. GC-MS/MS. Extractables Screening.

• Phthalates. • Metals (e.g., Zn, Fe, Ba, Ca, Al, Ni, etc.).

Image result for nitrosamines. ChemSpider 2D Image | 2-Mercaptobenzothiazole | C7H5NS2.

E&L Identification & Quantification. Image result for image+gas+chromatography.

Extractables Process. 12. Extraction Identification Quantification Potential Leachable?.

Extractables Process – Case Study. 13. Image result for sanitech tubing.

Extractables Process – Case Study. 14. Drug Product: Injectable (IV) pH Range: 3.5 – 4.5 Storage: 2-8 o C MDD: 2.304 grams/day Further information provided by sponsor: Composition of drug product.

Extractables Process – Case Study. 15. Study Design Project Kick-off meeting; Information gathering; Protocol design and approval; Study Material to Solvent Ratio Extraction process (refluxing / heating / incubation) Estimation of AET & permissible extractables limit Analytical methodology to be used.

Extractables Quantification. 16. Extraction Solvents Polarity, pH Extraction Time & Temperature Sonication Incubation.

Volatiles. GC-MS with TD for VOCs (direct TD, no extraction).

Volatiles. GC-ALS-MS for SVOCs (after extraction).

Nitrosamine. Feedstock for Fungicide, Antioxidant, Plasticizer.

Siloxane tubing. Mold release agent. Volatiles Quantitation – Non-Targeted.

Volatiles Quantitation – Correlation. 21. *Nitroaniline Acenaphthylene Dimethyl Phthalate 1.2 -Dinitrobenzene 1,4-Dinitrobenzene.

Non-Volatiles. LC-MS/MS LC-QTOF. 22. o o o o.

Non-Volatiles. 23. NVOCs Targeted Antioxidants Phthalates APCI Non-Targeted ESI (+ ve /- ve ).

Non-Volatiles :: Targeted Phthalates. 24. Note: All values in ug/g (ppm)..

Non-Volatiles :: Non-Targeted. 25. Note: All values in µg/g (ppm). Total 18 targeted NVOC compounds were studied, of which 2 were identified. Total 11 compounds were identified in ESI+ve , 10 in ESI- ve and 7 in APCI..

Elementals. ICP-MS (0.1N HCl as extraction medium) < USP 661 >.

Silicone tubing. Platinum cured. Elemental Quantitation.

Other techniques. Ion – Chromatography FTIR NVR. 28.

Leachables Testing. 29. Leachables Study Goals To help establish an extractables / leachables correlation. To understand the trend in leachables level over shelf life. To determine maximum leachables level up to proposed shelf life. To support a comprehensive safety evaluation of drug product. To establish leachables specification for routine QC testing..

Leachables Testing. 30. Leachable Study Design. Extractables > AET AMD + AMV Leachables Screening Correlation of E&L Routine QC & Change Ctrl..

Thank you. 31. Related image. GRÅciÄSfi*TAANK TINGKI ARIGATOi SHUKURIA GOZAIMASHTA iOLZiN MERCI.