Challenges Related to Extractables/ Leachables During Bioprocessing
Main Article Content
Abstract
As the production of biologics grows, so does the need to control impurity contamination. Some compounds have the possibility to leach into the products during their manufacturing, hampering their production. The presence of these compounds in the final product may also have dangers to the end user if not removed. These compounds are either simple organic molecules or heavy metals, and are often utilized during production, or are part of the disposable plastics in the processing. Some of the organics can be broken down into toxic materials, while the metals are shown to lead to undesirable effects at higher concentrations. Hence, monitoring their presence and concentrations in the final product is necessary for bioproduction efficiency and ultimately patient safety. This review discusses the most common organic and metallic extractables/leachables found in plastics that are utilized in the synthesis of biologics.
Keywords:
Leachables; extractables; metals; organics; bioreactors
Article Details
How to Cite
OURFALIAN, Natalie et al.
Challenges Related to Extractables/ Leachables During Bioprocessing.
Medical Research Archives, [S.l.], v. 11, n. 11, nov. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4622>. Date accessed: 02 may 2024.
doi: https://doi.org/10.18103/mra.v11i11.4622.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Food and Drug Administration. 2008. Guidance for Industry Q3A Impurities in New Drug Substances. 11-12. https://www.fda.gov/media/71727/download.
Food and Drug Administration. 2018. What Are "Biologics" Questions and Answers. https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers
2. Jenke D., Jene J., Poss M., Story J., Tsilipetros T., Odufu A., Terbush W. “Accumulation of extractables in buffer solutions from a polyolefin plastic container.” Int. J. Pharm. 2005;297:120-133.
3. Jenke D. “An extractables/leachables strategy facilitated by collaboration between drug product vendors and plastic material/ system suppliers." PDA J Pharm Sci Techno. 2007;61(1):17-23.
4. Jenke D. “Linking extractables and leachables in container/closure applications.” PDA J Pharm Sci Techno. 2005;59(4):265-281.
5. Markovic I. “Evaluation of safety and quality impact of extractable and leachable substances in therapeutic biologic protein products: a risk-based perspective.” Expert Opin Drug Saf. 2007;6(5):487-491.
6. Djouani, F., Richaud, E., Fayolle, B., Verdu, J. “Modeling of thermal oxidation of phosphite stabilized polyethylene.” Polym Deg Stabil. 2011;96(7):1349-1360.
7. Kelly P., McSweeney, S., Coleman, O., Carillo, S., Henry, M., Chandran, D., Kellett, A., Bones, J., Clynes, M., Meleady, P., Barron, N. “Process-relevant concentrations of the leachable bdtbpp impact negatively on CHO cell production characteristics.” Biotechnol. Prog. 2016;32(6):1547- 1558.
8. Hammond, M., Nunn, H., Rogers, G., Lee, Hans., Marghitoiu, A., Perez, L., Nashed-Samuel, Y., Anderson, C., Vandiver, M., Kline, S. “Identification of a Leachable Compound Detrimental to Cell Growth in Single-Use Bioprocess Containers.” PDA J. Pharm. Sci. Technol. 2013;67(2):123-134
9. Gupta, S., Kass, G., Szegezdi, E., Bertrand, J. “The mitochondrial death pathway: a promising therapeutic target in diseases.” J Cell Mol Med. 2009;13:1004–1033.
10. Coleman, M., Marshall, C., Olson, M. “RAS and RHO GTPases in G1-phase cell-cycle regulation.” Nat Rev Mol Cell Biol. 2004;5:355–366
11. Rhind, N., Russell, P. “Signaling pathways that regulate cell division.” Cold Spring Harb Perspect Biol.2012;4:1101.
12. Hammond, M., Marghitoiu, L., Lee, H., Perez, L., Rogers, G., Nashed-Samuel, Y., Nunn, H., Kline, S. “A cytotoxic leachable compound from single-use bioprocess equipment that causes poor cell growth performance.” Biotechnol. Prog. 2014;30(2), 332-337.
13. Shah, R., Linville, T., Whynot, A., Brazel, C. “Evaluating the Toxicity of bDtBPP on CHO-K1 Cells for Testing of Single-Use Bioprocessing Systems Considering Media Selection, Cell Culture Volume, Mixing, and Exposure Duration.” Biotechnol. Prog. 2016;32(5):1318- 1323.
14. National Center for Biotechnology Information, 2010. PubChem Compound Summary for CID 64819. https://pubchem.ncbi.nlm.nih.gov/compound/Irganox-1010
15. Parris P., Martin EA., Stanard B., Glowienke S., Dolan DG., Li K., Binazon O., Giddings A., Whelan G., Masuda-Herrera M., Bercu J., Broschard T., Bruen U., Callis CM., Stults CLM., Erexson GL., Cruz MT., Nagao LM. “Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies.” Regul Toxicol Pharmacol. 2020;118:104802.
16. Ciba Specialty Chemicals, 2001. HPV Programme, Irganox 1010 Tetrakis-(methylene- (3,5-Di-(tert)-Butyl-4-Hydrocinnamate)) methane, CAS No. 6683-19-8.
17. Broschard TH., Glowienke S., Bruen US., Nagao LM., Teasdale A., Stults CLM., Li KL, Iciek LA., Erexson G., Martin EA., Ball DJ. “Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics - Current challenges and approaches.” Regul Toxicol Pharmacol. 2016;81:201-211.
18. Lake BG., Gangolli SD., Schmid K., Schweizer W., Stäubli W., Waechter F. “The induction of rat hepatic microsomal xenobiotic metabolism by n-octadecyl beta-(3',5'-di-tert-butyl-4'-hydroxyphenyl)-propionate.” Food Cosmet Toxicol. 1980;18(1):47-54.
19. Thirumangalathu R., Krishnan S., Ricci MS., Brems DN., Randolph TW., Carpenter JF. “Silicone oil- and agitation-induced aggregation of a monoclonal antibody in aqueous solution.” J Pharm Sci. 2009;98(9):3167-3181.
20. Jones LS., Kaufmann A., Middaugh CR. “Silicone oil induced aggregation of proteins.” J Pharm Sci. 2005;94(4):918-927.
21. Hassouna, F., Raquez, J., Addiego, F., Toniazzo, V., Dubois, P., Ruch, D. “New development on plasticized poly(lactide): Chemical grafting of citrate on PLA by reactive extrusion.” Eur. Polym. J. 2011;48:404-415.
22. Takeshita, A., Igarashi-Migitaka, J., Nishiyama, K., Takahashi, H., Takeuchi, Y., Koibuchi, N. “Acetyl Tributyl Citrate, the Most Widely Used Phthalate Substitute Plasticizer, Induces Cytochrome P450 3A through Steroid and Xenobiotic Receptor.” Toxicol. Sci. 2011;123(2):460-470.
23. Rasmussen, L., Sen, N., Liu, X., Craig, Z. “Effects of oral exposure to the phthalate substitute acetyl tributyl citrate on female reproduction in mice.” J Appl Toxicol. 2017;37(6):668–675.
24. Genter M., Doty R. “Chapter 22 - Toxic exposures and the senses of taste and smell.” Handbook of Clinical Neurology. 2019;164:389-408.
25. Liu D., Nashed-Samuel Y., Bondarenko P., Brems D., Ren D. “Interactions Between Therapeutic Proteins and Acrylic Acid Leachable.” PDA J Pharm Sci and Tech. 2012;66:12-19.
26. Ulsaker GA., Teien G. “Identification of caprolactam as a potential contaminant in parenteral solutions stored in overwrapped PVC bags.” J Pharm Biomed Anal. 1992;10(1):77-80.
27. Haned Z., Moulay S., Lacorte S. “Migration of plasticizers from poly(vinyl chloride) and multilayer infusion bags using selective extraction and GC-MS.” J Pharm Biomed Anal. 2018;156:80-87.
28. Allwood, M., Martin, H. “The extraction of diethylhexylphthalate (DEHP) from polyvinyl chloride components of intravenous infusion containers and administration sets by paclitaxel injection.” Int. J. Pharm. 1996;127:65-71.
29. Venkataramanan, R., Burckart, G., Ptachcinski, R., Blaha, R., Logue, L., Bahnson, A., Giam, C., Brady, J. “Leaching of diethylhexyl phthalate from polyvinyl chloride bags Into Intravenous cyclosporine solution.” Am J Hosp Pharm. 1986;43(11):2800-2802.
30. Faouzi, M., Dine, T., Luyckx, M., Brunet, C., Mallevais, M., Goudaleiz, F., Gressier, B., Cazin, M., Kablan, J., Cazin, J. “Stability, compatibility and plasticizer extraction of miconazole injection added to infusion solution and stored in PVC containers.” J Pharm Biomed Anal. 1995;13:1363-1372.
31. Prabhu, A., Gadgil, M. “Nickel, and cobalt affect galactosylation of recombinant IgG expressed in CHO cells.” Biometals. 2019;32(1):11-19.
32. Wang, W., Ignatius AA., Thakkar SV. “Impact of residual impurities and contaminants on protein stability.” J Pharm Sci. 2014;103(5):1315-1330.
33. Yuk, IH., Russell S., Tang Y., Hsu WT., Mauger JB., Aulakh RP., Luo J., Gawlitzek M., Joly JC. “Effects of copper on CHO cells: cellular requirements and product quality considerations.” Biotechnol Prog. 2015;31(1):226-238.
34. Qian Y., Khattak SF., Xing Z., He A., Kayne PS., Qian NX., Pan SH., Li ZJ. “Cell culture and gene transcription effects of copper sulfate on Chinese hamster ovary cells.” Biotechnol Prog. 2011;4:1190-1194.
35. Chaderjian WB., Chin ET., Harris RJ., Etcheverry TM. “Effect of copper sulfate on performance of a serum-free CHO cell culture process and the level of free thiol in the recombinant antibody expressed.” Biotechnol Prog. 2005;21(2):550-553.
36. Dorival-García N., Carillo S., Ta C., Roberts D, Comstock K., Lofthouse S., Ciceri E., D'Silva K., Kierans G., Kaisermayer C., Lindeberg A., Bones J. “Large-Scale Assessment of Extractables and Leachables in Single-Use Bags for Biomanufacturing.” Anal Chem. 2018;90(15):9006-9015.
37. Jenke, D., Chess, E., Zietlow, D., Rabinow, B. “Model for estimating the accumulation of solutes leaching from polymeric containers into parenteral solutions.” Int. J. Pharm. 1992;78 115-122.
Food and Drug Administration. 2018. What Are "Biologics" Questions and Answers. https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers
2. Jenke D., Jene J., Poss M., Story J., Tsilipetros T., Odufu A., Terbush W. “Accumulation of extractables in buffer solutions from a polyolefin plastic container.” Int. J. Pharm. 2005;297:120-133.
3. Jenke D. “An extractables/leachables strategy facilitated by collaboration between drug product vendors and plastic material/ system suppliers." PDA J Pharm Sci Techno. 2007;61(1):17-23.
4. Jenke D. “Linking extractables and leachables in container/closure applications.” PDA J Pharm Sci Techno. 2005;59(4):265-281.
5. Markovic I. “Evaluation of safety and quality impact of extractable and leachable substances in therapeutic biologic protein products: a risk-based perspective.” Expert Opin Drug Saf. 2007;6(5):487-491.
6. Djouani, F., Richaud, E., Fayolle, B., Verdu, J. “Modeling of thermal oxidation of phosphite stabilized polyethylene.” Polym Deg Stabil. 2011;96(7):1349-1360.
7. Kelly P., McSweeney, S., Coleman, O., Carillo, S., Henry, M., Chandran, D., Kellett, A., Bones, J., Clynes, M., Meleady, P., Barron, N. “Process-relevant concentrations of the leachable bdtbpp impact negatively on CHO cell production characteristics.” Biotechnol. Prog. 2016;32(6):1547- 1558.
8. Hammond, M., Nunn, H., Rogers, G., Lee, Hans., Marghitoiu, A., Perez, L., Nashed-Samuel, Y., Anderson, C., Vandiver, M., Kline, S. “Identification of a Leachable Compound Detrimental to Cell Growth in Single-Use Bioprocess Containers.” PDA J. Pharm. Sci. Technol. 2013;67(2):123-134
9. Gupta, S., Kass, G., Szegezdi, E., Bertrand, J. “The mitochondrial death pathway: a promising therapeutic target in diseases.” J Cell Mol Med. 2009;13:1004–1033.
10. Coleman, M., Marshall, C., Olson, M. “RAS and RHO GTPases in G1-phase cell-cycle regulation.” Nat Rev Mol Cell Biol. 2004;5:355–366
11. Rhind, N., Russell, P. “Signaling pathways that regulate cell division.” Cold Spring Harb Perspect Biol.2012;4:1101.
12. Hammond, M., Marghitoiu, L., Lee, H., Perez, L., Rogers, G., Nashed-Samuel, Y., Nunn, H., Kline, S. “A cytotoxic leachable compound from single-use bioprocess equipment that causes poor cell growth performance.” Biotechnol. Prog. 2014;30(2), 332-337.
13. Shah, R., Linville, T., Whynot, A., Brazel, C. “Evaluating the Toxicity of bDtBPP on CHO-K1 Cells for Testing of Single-Use Bioprocessing Systems Considering Media Selection, Cell Culture Volume, Mixing, and Exposure Duration.” Biotechnol. Prog. 2016;32(5):1318- 1323.
14. National Center for Biotechnology Information, 2010. PubChem Compound Summary for CID 64819. https://pubchem.ncbi.nlm.nih.gov/compound/Irganox-1010
15. Parris P., Martin EA., Stanard B., Glowienke S., Dolan DG., Li K., Binazon O., Giddings A., Whelan G., Masuda-Herrera M., Bercu J., Broschard T., Bruen U., Callis CM., Stults CLM., Erexson GL., Cruz MT., Nagao LM. “Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies.” Regul Toxicol Pharmacol. 2020;118:104802.
16. Ciba Specialty Chemicals, 2001. HPV Programme, Irganox 1010 Tetrakis-(methylene- (3,5-Di-(tert)-Butyl-4-Hydrocinnamate)) methane, CAS No. 6683-19-8.
17. Broschard TH., Glowienke S., Bruen US., Nagao LM., Teasdale A., Stults CLM., Li KL, Iciek LA., Erexson G., Martin EA., Ball DJ. “Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics - Current challenges and approaches.” Regul Toxicol Pharmacol. 2016;81:201-211.
18. Lake BG., Gangolli SD., Schmid K., Schweizer W., Stäubli W., Waechter F. “The induction of rat hepatic microsomal xenobiotic metabolism by n-octadecyl beta-(3',5'-di-tert-butyl-4'-hydroxyphenyl)-propionate.” Food Cosmet Toxicol. 1980;18(1):47-54.
19. Thirumangalathu R., Krishnan S., Ricci MS., Brems DN., Randolph TW., Carpenter JF. “Silicone oil- and agitation-induced aggregation of a monoclonal antibody in aqueous solution.” J Pharm Sci. 2009;98(9):3167-3181.
20. Jones LS., Kaufmann A., Middaugh CR. “Silicone oil induced aggregation of proteins.” J Pharm Sci. 2005;94(4):918-927.
21. Hassouna, F., Raquez, J., Addiego, F., Toniazzo, V., Dubois, P., Ruch, D. “New development on plasticized poly(lactide): Chemical grafting of citrate on PLA by reactive extrusion.” Eur. Polym. J. 2011;48:404-415.
22. Takeshita, A., Igarashi-Migitaka, J., Nishiyama, K., Takahashi, H., Takeuchi, Y., Koibuchi, N. “Acetyl Tributyl Citrate, the Most Widely Used Phthalate Substitute Plasticizer, Induces Cytochrome P450 3A through Steroid and Xenobiotic Receptor.” Toxicol. Sci. 2011;123(2):460-470.
23. Rasmussen, L., Sen, N., Liu, X., Craig, Z. “Effects of oral exposure to the phthalate substitute acetyl tributyl citrate on female reproduction in mice.” J Appl Toxicol. 2017;37(6):668–675.
24. Genter M., Doty R. “Chapter 22 - Toxic exposures and the senses of taste and smell.” Handbook of Clinical Neurology. 2019;164:389-408.
25. Liu D., Nashed-Samuel Y., Bondarenko P., Brems D., Ren D. “Interactions Between Therapeutic Proteins and Acrylic Acid Leachable.” PDA J Pharm Sci and Tech. 2012;66:12-19.
26. Ulsaker GA., Teien G. “Identification of caprolactam as a potential contaminant in parenteral solutions stored in overwrapped PVC bags.” J Pharm Biomed Anal. 1992;10(1):77-80.
27. Haned Z., Moulay S., Lacorte S. “Migration of plasticizers from poly(vinyl chloride) and multilayer infusion bags using selective extraction and GC-MS.” J Pharm Biomed Anal. 2018;156:80-87.
28. Allwood, M., Martin, H. “The extraction of diethylhexylphthalate (DEHP) from polyvinyl chloride components of intravenous infusion containers and administration sets by paclitaxel injection.” Int. J. Pharm. 1996;127:65-71.
29. Venkataramanan, R., Burckart, G., Ptachcinski, R., Blaha, R., Logue, L., Bahnson, A., Giam, C., Brady, J. “Leaching of diethylhexyl phthalate from polyvinyl chloride bags Into Intravenous cyclosporine solution.” Am J Hosp Pharm. 1986;43(11):2800-2802.
30. Faouzi, M., Dine, T., Luyckx, M., Brunet, C., Mallevais, M., Goudaleiz, F., Gressier, B., Cazin, M., Kablan, J., Cazin, J. “Stability, compatibility and plasticizer extraction of miconazole injection added to infusion solution and stored in PVC containers.” J Pharm Biomed Anal. 1995;13:1363-1372.
31. Prabhu, A., Gadgil, M. “Nickel, and cobalt affect galactosylation of recombinant IgG expressed in CHO cells.” Biometals. 2019;32(1):11-19.
32. Wang, W., Ignatius AA., Thakkar SV. “Impact of residual impurities and contaminants on protein stability.” J Pharm Sci. 2014;103(5):1315-1330.
33. Yuk, IH., Russell S., Tang Y., Hsu WT., Mauger JB., Aulakh RP., Luo J., Gawlitzek M., Joly JC. “Effects of copper on CHO cells: cellular requirements and product quality considerations.” Biotechnol Prog. 2015;31(1):226-238.
34. Qian Y., Khattak SF., Xing Z., He A., Kayne PS., Qian NX., Pan SH., Li ZJ. “Cell culture and gene transcription effects of copper sulfate on Chinese hamster ovary cells.” Biotechnol Prog. 2011;4:1190-1194.
35. Chaderjian WB., Chin ET., Harris RJ., Etcheverry TM. “Effect of copper sulfate on performance of a serum-free CHO cell culture process and the level of free thiol in the recombinant antibody expressed.” Biotechnol Prog. 2005;21(2):550-553.
36. Dorival-García N., Carillo S., Ta C., Roberts D, Comstock K., Lofthouse S., Ciceri E., D'Silva K., Kierans G., Kaisermayer C., Lindeberg A., Bones J. “Large-Scale Assessment of Extractables and Leachables in Single-Use Bags for Biomanufacturing.” Anal Chem. 2018;90(15):9006-9015.
37. Jenke, D., Chess, E., Zietlow, D., Rabinow, B. “Model for estimating the accumulation of solutes leaching from polymeric containers into parenteral solutions.” Int. J. Pharm. 1992;78 115-122.