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Page 22 of 26 June 2019 BioPharm International eBook 23 Single-Use Systems Extractables and Leachables trometry (GC/MS), CI-GC, liquid chromatography–MS and Fourier transform infrared spectroscopy, total organic carbon, inductively coupled plasma optical emission spectroscopy (ICP– OES) or ICP– MS, and ion chromatography. The principal E&L assessment steps are: • P r of i le e x t r ac t a ble s ac c or d - ing to standard protocols (e.g., U n i t e d S t a t e s P h a r m a c o p e i a <665> and <1665> Poly mer ic Components and Systems Used in the Manufacturing of Drug Products). • Re c he c k qu a l it y of e x t r ac t- able data, and supplement data when required. • Perform risk analysis—identify critical SUS and determine risk controls. • Determine toxicological limits for the critical target leachables based on: o Pe r m it te d d a i ly e x p o s u r e (PDE) values for identified sub- stances o T h reshold of tox icolog ica l concern/safety concern thresh- old (TTC/SCT) for unidentified substances • I d e n t i f y s a m p l i n g p o i n t s along the production process. This means sampling after the last filling step; the sampling should take place at the begin- ning, in the middle, and at the end of the process. • S em i-va l id ate t he a na ly t ic a l methods to be used on DP and demonstrate suitability of non- validated screening methods. • Conduct quantitative and quali- tative E&L correlation. • Finalize r isk assessment and, where necessary, enforce correc- tive and preventative actions. T here a re considerable c ha l- le nges i nvolve d i n t he ide nt i- f icat ion of leac hables by ma ss spectrometry and sample prepa- ration. For example, background compounds may yield ions that overlap with the leachables (spec- tral interference), which may pro- hibit the accurate quantification and identification of a leachable. A n example of chemical inter- ference might be the presence of mat r i x components t hat eit her suppress or enhance the detector response of the leachables through a chemical process. This would reduce the accuracy of the quanti- tative analysis and alter the spec- trum quality. Extractables studies assess the performance of the material in the SUS, thereby determining what substances the patient may become exposed to during the taking of the medicine. To ensure a DP retains quality and is safe for the consumer, the manufacturer using the SUS must: • D i s t i n g u i s h b e t we e n l i ke l y leachables—substances that are part of chemical construction of the material (extractables). • Filter extractables as probable leachables into releva nt a nd non-relevant using simulation strategies. • W he n re qu i re d for comple x drug formulations, use (semi-) validated target analysis (e.g., validated limit test). • T he tox icolog ica l ca lc u lated l i m it (a n a ly t ic a l e v a lu at ion threshold [AET] [PDE]) should not to be equated with the ana- lytical limit. It is important that analytical uncertainty is taken in account and specified accu- rately. • If a substance is detected above the default AET (TTC/SCT) but cannot be identified, the TTC/ SCT default must be assumed correct. A s SUS become prog ressively prevalent in the biologics indus- t r y, a nd esp ec ia l ly a s t hey a re introduced into downstream pro- cessi ng, t he quest ion of sa fet y becomes increasingly important. Ma nu fac t u rers need to demon- st rate to reg u lator y aut hor it ies a nd i nter na l qua l it y assu ra nce systems that the DP is unaffected by E & L; va l id at ion st ud ies a re required. T he issue is made more com- plex by the fact each manufac- t urer w ill rely upon a different process for each DP. Because these processes will also differ between manufacturers, it is clear to see why no single test, or set of tests, c a n ef fe c t ively demonst rate to reg u lators t hat t he DP is u na f- fected by E&L. Without a clear specification or guidance document issued by an approval agency mandating test- ing protocols or setting levels for compl ia nce, ma nu fac t u rers a re advised to partner with a contract resea rch orga n i zat ion w it h t he breadth of experience to ensure accurate comprehensive testing of the relevant materials. REFERENCES 1. E. Langer and R. Rader, "Biopharmaceutical Manufacturing is Shifting to Single-Use Systems. Are the Dinosaurs, the Large Stainless-Steel Facilities, Becoming Extinct?" www. , Oct. 23, 2018. 2. ICH, Q10 Pharmaceutical Quality System (ICH, June 2008). BP

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