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1장 — 아이디어에서 환자까지: 전체 여정​

  1. Shukla AA, Thömmes J. (2010). Recent advances in large-scale production of monoclonal antibodies and related proteins. Trends in Biotechnology 28(5):253-261. https://doi.org/10.1016/j.tibtech.2010.02.001
  2. CMC Biotech Working Group. (2009). A-Mab: A Case Study in Bioprocess Development (Version 2.1). CASSS / ISPE, Emeryville CA, 30 October 2009. https://ispe.org/sites/default/files/attachments/public/a-mab-case-study-version.pdf
  3. FDA (U.S. Food and Drug Administration). (2024). 21 CFR 312.21 — Phases of an investigation (Investigational New Drug Application). U.S. Code of Federal Regulations, Title 21, Part 312, Subpart B; eCFR current edition. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312/subpart-B/section-312.21
  4. DiMasi JA, Grabowski HG, Hansen RW. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics 47:20-33. https://doi.org/10.1016/j.jhealeco.2016.01.012
  5. Konstantinov KB, Cooney CL. (2015). White Paper on Continuous Bioprocessing (May 20-21, 2014 Continuous Manufacturing Symposium). Journal of Pharmaceutical Sciences 104(3):813-820. https://doi.org/10.1002/jps.24268
  6. FDA (U.S. Food and Drug Administration). (2024). 21 CFR Part 211 Subpart J — Records and Reports (incl. 211.188 Batch production and control records). U.S. Code of Federal Regulations, Title 21, Part 211, Subpart J; eCFR current edition. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-J
  7. ICH (International Council for Harmonisation). (2009). ICH Harmonised Tripartite Guideline Q8(R2): Pharmaceutical Development. ICH, Current Step 4, August 2009. https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdf
  8. ICH (International Council for Harmonisation). (2008). ICH Harmonised Tripartite Guideline Q10: Pharmaceutical Quality System. ICH, Current Step 4, June 2008. https://database.ich.org/sites/default/files/Q10%20Guideline.pdf
  9. FDA (U.S. Food and Drug Administration). (2004). Guidance for Industry — PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. FDA CDER/CVM/ORA, September 2004. https://www.fda.gov/media/71012/download
  10. FDA (U.S. Food and Drug Administration). (2024). 21 CFR 211.192 — Production record review (Current Good Manufacturing Practice for Finished Pharmaceuticals). U.S. Code of Federal Regulations, Title 21, Part 211, Subpart J. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-J/section-211.192
  11. FDA (U.S. Food and Drug Administration). (2024). Inspection Observations (Form FDA 483) and Warning Letters. FDA Office of Regulatory Affairs / CDER, compliance and enforcement resources. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters

2장 — 바이오의약품이란? (그리고 항체란?)​

  1. Rathore AS, Winkle H. (2009). Quality by design for biopharmaceuticals. Nature Biotechnology 27(1):26-34. https://doi.org/10.1038/nbt0109-26
  2. Köhler G, Milstein C. (1975). Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256(5517):495-497. https://doi.org/10.1038/256495a0
  3. Jefferis R. (2009). Glycosylation as a strategy to improve antibody-based therapeutics. Nature Reviews Drug Discovery 8(3):226-234. https://doi.org/10.1038/nrd2804
  4. Walsh G, Walsh E. (2022). Biopharmaceutical benchmarks 2022. Nature Biotechnology 40(12):1722-1760. https://doi.org/10.1038/s41587-022-01582-x
  5. ICH (International Council for Harmonisation). (2023). ICH Q5A(R2): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. ICH Harmonised Guideline, Step 4, adopted 1 November 2023. https://database.ich.org/sites/default/files/ICH_Q5A(R2)_Guideline_2023_1101.pdf
  6. ICH (International Council for Harmonisation). (1999). ICH Q6B: Specifications — Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. ICH Harmonised Tripartite Guideline, Step 4 (CPMP/ICH/365/96), adopted 10 March 1999. https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf
  7. Shukla AA, Hubbard B, Tressel T, Guhan S, Low D. (2007). Downstream processing of monoclonal antibodies — Application of platform approaches. Journal of Chromatography B 848(1):28-39. https://doi.org/10.1016/j.jchromb.2006.09.026
  8. Kelley B. (2009). Industrialization of mAb production technology: the bioprocessing industry at a crossroads. mAbs 1(5):443-452. https://doi.org/10.4161/mabs.1.5.9448
  9. EMA CHMP (Committee for Medicinal Products for Human Use). (2012). Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies — Non-Clinical and Clinical Issues. EMA/CHMP/BMWP/403543/2010, adopted May 2012, effective 1 December 2012. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-monoclonal-antibodies-non-clinical-and-clinical-issues_en.pdf
  10. CMC Biotech Working Group. (2009). A-Mab: A Case Study in Bioprocess Development (Version 2.1). CASSS / ISPE, Emeryville CA, 30 October 2009. https://ispe.org/sites/default/files/attachments/public/a-mab-case-study-version.pdf

3장 — 큰 그림: 업스트림, 다운스트림, 충전·마감​

  1. Shukla AA, Thömmes J. (2010). Recent advances in large-scale production of monoclonal antibodies and related proteins. Trends in Biotechnology 28(5):253-261. https://doi.org/10.1016/j.tibtech.2010.02.001
  2. Liu HF, Ma J, Winter C, Bayer R. (2010). Recovery and purification process development for monoclonal antibody production. mAbs 2(5):480-499. https://doi.org/10.4161/mabs.2.5.12645
  3. Shukla AA, Hubbard B, Tressel T, Guhan S, Low D. (2007). Downstream processing of monoclonal antibodies — Application of platform approaches. Journal of Chromatography B 848(1):28-39. https://doi.org/10.1016/j.jchromb.2006.09.026
  4. ICH (International Council for Harmonisation). (1999). ICH Harmonised Tripartite Guideline Q6B: Specifications — Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. ICH, Step 4 (10 March 1999). https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf
  5. ICH (International Council for Harmonisation). (2009). ICH Harmonised Tripartite Guideline Q8(R2): Pharmaceutical Development. ICH, Step 4 (August 2009). https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf
  6. FDA (U.S. Food and Drug Administration). (2004). Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. FDA CDER/CVM/ORA (September 2004). https://www.fda.gov/media/71012/download
  7. FDA (U.S. Food and Drug Administration). (2024). 21 CFR 211.188 — Batch production and control records (Subpart J, Records and Reports), Current Good Manufacturing Practice for Finished Pharmaceuticals. U.S. Code of Federal Regulations, Title 21, Part 211, Subpart J. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-J/section-211.188
  8. ASME (American Society of Mechanical Engineers). (2022). ASME BPE-2022: Bioprocessing Equipment. American Society of Mechanical Engineers, New York (ANSI-approved 21 March 2022). https://www.asme.org/codes-standards/find-codes-standards/bpe-bioprocessing-equipment-(1)
  9. Konstantinov KB, Cooney CL. (2015). White Paper on Continuous Bioprocessing. May 20-21, 2014 Continuous Manufacturing Symposium. Journal of Pharmaceutical Sciences 104(3):813-820. https://doi.org/10.1002/jps.24268
  10. ICH (International Council for Harmonisation). (2004). ICH Harmonised Tripartite Guideline Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process. ICH, Step 4 (18 November 2004). https://database.ich.org/sites/default/files/Q5E%20Guideline.pdf
  11. ICH (International Council for Harmonisation). (2023). ICH Harmonised Guideline Q5A(R2): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. ICH, Step 4 (adopted 1 November 2023). https://database.ich.org/sites/default/files/ICH_Q5A%28R2%29_Guideline_2023_1101.pdf

4장 — 모든 것은 표적에서 시작된다​

  1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177-182. https://doi.org/10.1126/science.3798106
  2. Emmerich CH, Gamboa LM, Hofmann MCJ, Bonin-Andresen M, Arbach O, Schendel P, Gerlach B, Hempel K, Bespalov A, Dirnagl U, Parnham MJ. (2021). Improving target assessment in biomedical research: the GOT-IT recommendations. Nature Reviews Drug Discovery 20(1):64-81. https://doi.org/10.1038/s41573-020-0087-3
  3. Crescioli S, Kaplon H, Chenoweth A, Wang L, Visweswaraiah J, Reichert JM. (2024). Antibodies to watch in 2024. mAbs 16(1):2297450. https://doi.org/10.1080/19420862.2023.2297450
  4. FDA (U.S. Food and Drug Administration), Center for Drug Evaluation and Research. (2007). Guidance for Industry and Review Staff: Target Product Profile — A Strategic Development Process Tool (Draft Guidance). FDA/CDER, Docket FDA-2007-D-0256, March 2007. https://fda.report/media/72566/Target-Product-Profile----A-Strategic-Development-Process-Tool.pdf
  5. ICH (International Council for Harmonisation). (2009). ICH Harmonised Tripartite Guideline Q8(R2): Pharmaceutical Development. ICH, Step 4, August 2009. https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf
  6. Rathore AS, Winkle H. (2009). Quality by design for biopharmaceuticals. Nature Biotechnology 27(1):26-34. https://doi.org/10.1038/nbt0109-26
  7. USP (United States Pharmacopeia). (2024). USP General Chapter <129> Analytical Procedures for Recombinant Therapeutic Monoclonal Antibodies. USP-NF, United States Pharmacopeial Convention. https://doi.usp.org/USPNF/USPNF_M6297_02_01.html
  8. Konstantinov KB, Cooney CL. (2015). White paper on continuous bioprocessing. May 20-21, 2014 Continuous Manufacturing Symposium. Journal of Pharmaceutical Sciences 104(3):813-820. https://doi.org/10.1002/jps.24268
  9. FDA (U.S. Food and Drug Administration), Center for Drug Evaluation and Research. (2024). Guidance for Industry: Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in a Drug Application. FDA/CDER. https://www.fda.gov/regulatory-information/search-fda-guidance-documents

5장 — 항체를 찾아내기​

  1. Köhler G, Milstein C. (1975). Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256(5517):495-497. https://doi.org/10.1038/256495a0
  2. McCafferty J, Griffiths AD, Winter G, Chiswell DJ. (1990). Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348(6301):552-554. https://doi.org/10.1038/348552a0
  3. Jones PT, Dear PH, Foote J, Neuberger MS, Winter G. (1986). Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321(6069):522-525. https://doi.org/10.1038/321522a0
  4. Queen C, Schneider WP, Selick HE, Payne PW, Landolfi NF, Duncan JF, Avdalovic NM, Levitt M, Junghans RP, Waldmann TA. (1989). A humanized antibody that binds to the interleukin 2 receptor. Proceedings of the National Academy of Sciences USA 86(24):10029-10033. https://doi.org/10.1073/pnas.86.24.10029
  5. Frenzel A, Schirrmann T, Hust M. (2016). Phage display-derived human antibodies in clinical development and therapy. mAbs 8(7):1177-1194. https://doi.org/10.1080/19420862.2016.1212149
  6. Carter PJ. (2006). Potent antibody therapeutics by design. Nature Reviews Immunology 6(5):343-357. https://doi.org/10.1038/nri1837
  7. Jain T, Sun T, Durand S, Hall A, Houston NR, Nett JH, Sharkey B, Bobrowicz B, Caffry I, Yu Y, Cao Y, Lynaugh H, Brown M, Baruah H, Gray LT, Krauland EM, Xu Y, Vásquez M, Wittrup KD. (2017). Biophysical properties of the clinical-stage antibody landscape. Proceedings of the National Academy of Sciences USA 114(5):944-949. https://doi.org/10.1073/pnas.1616408114
  8. ICH (International Council for Harmonisation). (2011). ICH Harmonised Tripartite Guideline S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH, Step 4 (parent guideline 1997; R1 addendum incorporated June 2011). https://database.ich.org/sites/default/files/S6_R1_Guideline_0.pdf
  9. FDA (U.S. Food and Drug Administration), Center for Biologics Evaluation and Research. (1997). Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use. FDA/CBER, Docket 94D-0259, February 28, 1997. https://www.govinfo.gov/content/pkg/GOVPUB-HE20_4000-PURL-LPS113624/pdf/GOVPUB-HE20_4000-PURL-LPS113624.pdf
  10. Tiller KE, Tessier PM. (2015). Advances in Antibody Design. Annual Review of Biomedical Engineering 17:191-216. https://doi.org/10.1146/annurev-bioeng-071114-040733

6장 — 공장 세포 만들기​

  1. Wurm FM. (2004). Production of recombinant protein therapeutics in cultivated mammalian cells. Nature Biotechnology 22(11):1393-1398. https://doi.org/10.1038/nbt1026
  2. Lai T, Yang Y, Ng SK. (2013). Advances in Mammalian Cell Line Development Technologies for Recombinant Protein Production. Pharmaceuticals 6(5):579-603. https://doi.org/10.3390/ph6050579
  3. Frye C, Deshpande R, Estes S, Francissen K, Joly J, Lubiniecki A, Munro T, Russell R, Wang T, Anderson K. (2016). Industry view on the relative importance of "clonality" of biopharmaceutical-producing cell lines. Biologicals 44(2):117-122. https://doi.org/10.1016/j.biologicals.2016.01.001
  4. Wurm FM, Wurm MJ. (2017). Cloning of CHO Cells, Productivity and Genetic Stability—A Discussion. Processes 5(2):20. https://doi.org/10.3390/pr5020020
  5. ICH (International Council for Harmonisation). (1997). ICH Q5D: Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products. ICH Harmonised Tripartite Guideline, CPMP/ICH/294/95, Step 4 (16 July 1997). https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-5-d-derivation-and-characterisation-cell-substrates-used-production-biotechnologicalbiological-products-step-5_en.pdf
  6. ICH (International Council for Harmonisation). (2023). ICH Q5A(R2): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. ICH Harmonised Guideline, Step 4 (1 November 2023). https://database.ich.org/sites/default/files/ICH_Q5A%28R2%29_Guideline_2023_1101.pdf
  7. WHO (World Health Organization). (2013). Recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological medicinal products and for the characterization of cell banks (TRS 978, Annex 3). WHO Technical Report Series No. 978, Annex 3 (2013). https://cdn.who.int/media/docs/default-source/biologicals/documents/trs_978_annex_3.pdf
  8. FDA (U.S. Food and Drug Administration), CBER. (2010). Guidance for Industry: Characterization and Qualification of Cell Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease Indications. U.S. FDA, Center for Biologics Evaluation and Research (February 2010). https://www.fda.gov/media/78428/download
  9. ICH (International Council for Harmonisation). (1995). ICH Q5B: Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products. ICH Harmonised Tripartite Guideline, CPMP/ICH/139/95, Step 4 (30 November 1995). https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-5-b-analysis-expression-construct-cell-lines-used-production-r-dna-derived-protein-products-step-5_en.pdf
  10. Drexler HG, Uphoff CC. (2002). Mycoplasma contamination of cell cultures: Incidence, sources, effects, detection, elimination, prevention. Cytotechnology 39(2):75-90. https://doi.org/10.1023/A:1022913015916

7장 — 레시피 완성하기 (공정 개발)​

  1. ICH (International Council for Harmonisation). (2009). ICH Harmonised Tripartite Guideline Q8(R2): Pharmaceutical Development. ICH, Current Step 4 version, August 2009. https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdf
  2. Rathore AS, Winkle H. (2009). Quality by design for biopharmaceuticals. Nature Biotechnology 27(1):26-34. https://doi.org/10.1038/nbt0109-26
  3. Xing Z, Kenty BM, Li ZJ, Lee SS. (2009). Scale-up analysis for a CHO cell culture process in large-scale bioreactors. Biotechnology and Bioengineering 103(4):733-746. https://doi.org/10.1002/bit.22287
  4. Legmann R, Schreyer HB, Combs RG, McCormick EL, Russo AP, Rodgers ST. (2009). A predictive high-throughput scale-down model of monoclonal antibody production in CHO cells. Biotechnology and Bioengineering 104(6):1107-1120. https://doi.org/10.1002/bit.22474
  5. Shukla AA, Hubbard B, Tressel T, Guhan S, Low D. (2007). Downstream processing of monoclonal antibodies — Application of platform approaches. Journal of Chromatography B 848(1):28-39. https://doi.org/10.1016/j.jchromb.2006.09.026
  6. ICH (International Council for Harmonisation). (2012). ICH Harmonised Tripartite Guideline Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities). ICH, Current Step 4 version, 1 May 2012. https://database.ich.org/sites/default/files/Q11%20Guideline.pdf
  7. FDA (U.S. Food and Drug Administration). (2004). Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. FDA, CDER/CVM/ORA, September 2004 (notice of availability October 2004). https://www.fda.gov/media/71012/download
  8. USP (U.S. Pharmacopeia). (2017). General Chapter <1132> Residual Host Cell Protein Measurement in Biopharmaceuticals. United States Pharmacopeia–National Formulary (USP-NF), USP 39 published version, January 2017. https://www.usp.org/sites/default/files/usp/document/our-work/biologics/USPNF810G-GC-1132-2017-01.pdf
  9. CMC Biotech Working Group. (2009). A-Mab: A Case Study in Bioprocess Development (Version 2.1). CASSS / ISPE, Emeryville CA, 30 October 2009. https://ispe.org/sites/default/files/attachments/public/a-mab-case-study-version.pdf

8장 — 품질 측정과 단백질 안정화​

  1. Beck A, Wagner-Rousset E, Ayoub D, Van Dorsselaer A, Sanglier-Cianférani S. (2013). Characterization of Therapeutic Antibodies and Related Products. Analytical Chemistry 85(2):715-736. https://doi.org/10.1021/ac3032355
  2. ICH (International Council for Harmonisation). (1999). ICH Harmonised Tripartite Guideline Q6B: Specifications — Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. ICH, Step 4 version, 10 March 1999 (CPMP/ICH/365/96). https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf
  3. ICH (International Council for Harmonisation). (2023). ICH Harmonised Guideline Q14: Analytical Procedure Development. ICH, Step 4, adopted 1 November 2023. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q14-guideline-analytical-procedure-development-step-5-revision-1_en.pdf
  4. ICH (International Council for Harmonisation). (2003). ICH Harmonised Tripartite Guideline Q1A(R2): Stability Testing of New Drug Substances and Products. ICH, Step 4 version, 6 February 2003. https://database.ich.org/sites/default/files/Q1A(R2)%20Guideline.pdf
  5. FDA (U.S. Food and Drug Administration), CDER/CVM/ORA. (2004). Guidance for Industry — PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. FDA, Final, October 2004 (Docket FDA-2003-D-0032). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pat-framework-innovative-pharmaceutical-development-manufacturing-and-quality-assurance
  6. USP (U.S. Pharmacopeia). (2017). General Chapter <1225> Validation of Compendial Procedures. United States Pharmacopeia–National Formulary (USP-NF), official 1 August 2017. https://doi.usp.org/USPNF/USPNF_M99945_04_01.html
  7. FDA (U.S. Food and Drug Administration). (2024). 21 CFR 211.192 — Production record review. U.S. Code of Federal Regulations, Title 21, Part 211, Subpart J. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-J/section-211.192
  8. Carpenter JF, Randolph TW, Jiskoot W, Crommelin DJA, Middaugh CR, Winter G, et al. (2009). Overlooking subvisible particles in therapeutic protein products: gaps that may compromise product quality. Journal of Pharmaceutical Sciences 98(4):1201-1205. https://doi.org/10.1002/jps.21530
  9. Wang W, Singh S, Zeng DL, King K, Nema S. (2007). Antibody structure, instability, and formulation. Journal of Pharmaceutical Sciences 96(1):1-26. https://doi.org/10.1002/jps.20727
  10. Philo JS, Arakawa T. (2009). Mechanisms of protein aggregation. Current Pharmaceutical Biotechnology 10(4):348-351. https://doi.org/10.2174/138920109788488932
  11. USP (U.S. Pharmacopeia). (2012). General Chapter <788> Particulate Matter in Injections. United States Pharmacopeia–National Formulary (USP-NF), Rockville, MD: United States Pharmacopeia. https://www.usp.org/

9장 — 실험실 벤치에서 공장으로​

  1. García-Ochoa F, Gómez E. (2009). Bioreactor scale-up and oxygen transfer rate in microbial processes: An overview. Biotechnology Advances 27(2):153-176. https://doi.org/10.1016/j.biotechadv.2008.10.006
  2. Papoutsakis ET. (1991). Fluid-mechanical damage of animal cells in bioreactors. Trends in Biotechnology 9(12):427-437. https://doi.org/10.1016/0167-7799(91)90145-8
  3. Shukla AA, Thömmes J. (2010). Recent advances in large-scale production of monoclonal antibodies and related proteins. Trends in Biotechnology 28(5):253-261. https://doi.org/10.1016/j.tibtech.2010.02.001
  4. Xu J, Xu X, Huang C, Angelo J, Oliveira CL, Xu M, Xu X, Temel D, Ding J, Ghose S, Borys MC, Li ZJ. (2020). Biomanufacturing evolution from conventional to intensified processes for productivity improvement: a case study. mAbs 12(1):1770669. https://doi.org/10.1080/19420862.2020.1770669
  5. CMC Biotech Working Group. (2009). A-Mab: A Case Study in Bioprocess Development (Version 2.1). CASSS / ISPE, Emeryville CA, 30 October 2009. https://ispe.org/sites/default/files/attachments/public/a-mab-case-study-version.pdf
  6. ICH (International Council for Harmonisation). (2012). ICH Harmonised Tripartite Guideline Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities). ICH, Step 4, 1 May 2012. https://database.ich.org/sites/default/files/Q11%20Guideline.pdf
  7. FDA (U.S. Food and Drug Administration). (2011). Guidance for Industry: Process Validation: General Principles and Practices. FDA CDER/CBER/CVM, Current Good Manufacturing Practices, Revision 1, January 2011. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices

10장 — 세포 깨우기: 시드 트레인​

  1. ICH (International Council for Harmonisation). (1997). Q5D: Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products. ICH Harmonised Tripartite Guideline, Current Step 4 version, 16 July 1997. https://database.ich.org/sites/default/files/Q5D%20Guideline.pdf
  2. FDA (U.S. Food and Drug Administration). (2004). Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. FDA CDER/CBER/ORA, September 2004. https://www.fda.gov/media/71026/download
  3. FDA (U.S. Food and Drug Administration). (2024). 21 CFR Part 211, Subpart J — Records and Reports (Current Good Manufacturing Practice for Finished Pharmaceuticals). U.S. Code of Federal Regulations, Title 21, Chapter I, Subchapter C, Part 211, §§211.180–211.198. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-J
  4. USP (United States Pharmacopeia). (2017). General Chapter 〈63〉 Mycoplasma Tests. USP-NF, Rockville, MD: United States Pharmacopeia. https://doi.usp.org/USPNF/USPNF_M3687_01_01.html
  5. USP (United States Pharmacopeia). (2017). General Chapter 〈71〉 Sterility Tests. USP-NF, Rockville, MD: United States Pharmacopeia. https://doi.usp.org/USPNF/USPNF_M98810_01_01.html
  6. Drexler HG, Uphoff CC. (2002). Mycoplasma contamination of cell cultures: Incidence, sources, effects, detection, elimination, prevention. Cytotechnology 39(2):75–90. https://doi.org/10.1023/A:1022913015916
  7. Dahodwala H, Lee KH. (2019). The fickle CHO: a review of the causes, implications, and potential alleviation of the CHO cell line instability problem. Current Opinion in Biotechnology 60:128–137. https://doi.org/10.1016/j.copbio.2019.01.011
  8. Pohlscheidt M, Jacobs M, Wolf S, Thiele J, Jockwer A, Gabelsberger J, Jenzsch M, Tebbe H, Burg J. (2013). Optimizing capacity utilization by large scale 3000 L perfusion in seed train bioreactors. Biotechnology Progress 29(1):222–229. https://doi.org/10.1002/btpr.1672

11장 — 핵심 단계: 생산 바이오리액터​

  1. Bielser J-M, Wolf M, Souquet J, Broly H, Morbidelli M. (2018). Perfusion mammalian cell culture for recombinant protein manufacturing - A critical review. Biotechnology Advances 36(4):1328-1340. https://doi.org/10.1016/j.biotechadv.2018.04.011
  2. Garcia-Ochoa F, Gomez E. (2009). Bioreactor scale-up and oxygen transfer rate in microbial processes: an overview. Biotechnology Advances 27(2):153-176. https://doi.org/10.1016/j.biotechadv.2008.10.006
  3. CMC Biotech Working Group. (2009). A-Mab: A Case Study in Bioprocess Development (Version 2.1). CASSS / ISPE, Emeryville CA, 30 October 2009. https://ispe.org/sites/default/files/attachments/public/a-mab-case-study-version.pdf
  4. Clincke M-F, Molleryd C, Zhang Y, Lindskog E, Walsh K, Chotteau V. (2013). Very high density of CHO cells in perfusion by ATF or TFF in WAVE bioreactor. Part I. Effect of the cell density on the process. Biotechnology Progress 29(3):754-767. https://doi.org/10.1002/btpr.1704
  5. ICH (International Council for Harmonisation). (2009). ICH Harmonised Tripartite Guideline Q8(R2): Pharmaceutical Development. ICH, Current Step 4 version, August 2009. https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf
  6. ICH (International Council for Harmonisation). (2023). ICH Harmonised Guideline Q9(R1): Quality Risk Management. ICH, Step 4 version, adopted 18 January 2023. https://database.ich.org/sites/default/files/ICH_Q9(R1)_Guideline_Step4_2022_1219.pdf
  7. FDA (U.S. Food and Drug Administration). (2004). Guidance for Industry - PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. FDA CDER/CVM/ORA, September 2004. https://www.fda.gov/media/71012/download
  8. Abu-Absi NR, Kenty BM, Cuellar ME, Borys MC, Sakhamuri S, Strachan DJ, Hausladen MC, Li ZJ. (2011). Real time monitoring of multiple parameters in mammalian cell culture bioreactors using an in-line Raman spectroscopy probe. Biotechnology and Bioengineering 108(5):1215-1221. https://doi.org/10.1002/bit.23023
  9. WHO (World Health Organization). (2021). Guideline on data integrity (WHO Technical Report Series, No. 1033, Annex 4). World Health Organization, Geneva. https://www.who.int/publications/m/item/trs1033-annex4

12장 — 수확: 세포와 의약품 분리하기​

  1. Shukla AA, Kandula JR. (2008). Harvest and Recovery of Monoclonal Antibodies from Large-Scale Mammalian Cell Culture. BioPharm International 21(5):34-45. https://www.biopharminternational.com/view/harvest-and-recovery-monoclonal-antibodies-large-scale-mammalian-cell-culture
  2. Roush DJ, Lu Y. (2008). Advances in Primary Recovery: Centrifugation and Membrane Technology. Biotechnology Progress 24(3):488-495. https://doi.org/10.1021/bp070414x
  3. Singh N, Arunkumar A, Chollangi S, Tan ZG, Borys M, Li ZJ. (2016). Clarification technologies for monoclonal antibody manufacturing processes: Current state and future perspectives. Biotechnology and Bioengineering 113(4):698-716. https://doi.org/10.1002/bit.25810
  4. ICH (International Council for Harmonisation). (1999). Q6B: Specifications - Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. ICH Harmonised Tripartite Guideline, Step 4, 10 March 1999. https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf
  5. FDA (U.S. Food and Drug Administration). (2008). 21 CFR 211.67 - Equipment cleaning and maintenance (Current Good Manufacturing Practice for Finished Pharmaceuticals). U.S. Code of Federal Regulations, Title 21, Part 211, Subpart D. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-D/section-211.67
  6. ICH (International Council for Harmonisation). (2023). Q5A(R2): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. ICH Harmonised Guideline, Step 4, 1 November 2023. https://database.ich.org/sites/default/files/ICH_Q5A%28R2%29_Guideline_2023_1101.pdf
  7. Shukla AA, Thommes J. (2010). Recent advances in large-scale production of monoclonal antibodies and related proteins. Trends in Biotechnology 28(5):253-261. https://doi.org/10.1016/j.tibtech.2010.02.001
  8. Konstantinov KB, Cooney CL. (2015). White Paper on Continuous Bioprocessing. May 20-21, 2014 Continuous Manufacturing Symposium. Journal of Pharmaceutical Sciences 104(3):813-820. https://doi.org/10.1002/jps.24268
  9. Rathore AS, Winkle H. (2009). Quality by design for biopharmaceuticals. Nature Biotechnology 27(1):26-34. https://doi.org/10.1038/nbt0109-26
  10. Rouiller Y, Bielser J-M, Brühlmann D, Jordan M, Broly H, Stettler M. (2016). Screening and assessment of performance and molecule quality attributes of industrial cell lines across different fed-batch systems. Biotechnology Progress 32(1):160-170. https://doi.org/10.1002/btpr.2186
  11. PIC/S (Pharmaceutical Inspection Co-operation Scheme). (2021). PI 041-1: Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments. PIC/S, 1 July 2021. https://picscheme.org/en/publications

13장 — 포획: 항체 붙잡기 (프로테인 A)​

  1. Shukla AA, Hubbard B, Tressel T, Guhan S, Low D. (2007). Downstream processing of monoclonal antibodies — Application of platform approaches. Journal of Chromatography B 848(1):28-39. https://doi.org/10.1016/j.jchromb.2006.09.026
  2. Hober S, Nord K, Linhult M. (2007). Protein A chromatography for antibody purification. Journal of Chromatography B 848(1):40-47. https://doi.org/10.1016/j.jchromb.2006.09.030
  3. Linhult M, Gulich S, Graslund T, Simon A, Karlsson M, Sjoberg A, Nord K, Hober S. (2004). Improving the tolerance of a Protein A analogue to repeated alkaline exposures using a bypass mutagenesis approach. Proteins: Structure, Function, and Bioinformatics 55(2):407-416. https://doi.org/10.1002/prot.10616
  4. ICH (International Council for Harmonisation). (1999). Q6B: Specifications — Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. ICH Harmonised Tripartite Guideline, Step 4, 10 March 1999 (EU ref. CPMP/ICH/365/96). https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf
  5. Girard V, Hilbold N-J, Ng CKS, Pegon L, Chahim W, Rousset F, Monchois V. (2015). Large-scale monoclonal antibody purification by continuous chromatography, from process design to scale-up. Journal of Biotechnology 213:65-73. https://doi.org/10.1016/j.jbiotec.2015.04.026
  6. Konstantinov KB, Cooney CL. (2015). White Paper on Continuous Bioprocessing. May 20-21, 2014 Continuous Manufacturing Symposium. Journal of Pharmaceutical Sciences 104(3):813-820. https://doi.org/10.1002/jps.24268
  7. Kelley B. (2009). Industrialization of mAb production technology: the bioprocessing industry at a crossroads. mAbs 1(5):443-452. https://doi.org/10.4161/mabs.1.5.9448
  8. ICH (International Council for Harmonisation). (2023). Q5A(R2): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. ICH Harmonised Guideline, Step 4, 1 November 2023. https://database.ich.org/sites/default/files/ICH_Q5A(R2)_Guideline_2023_1101.pdf
  9. PIC/S (Pharmaceutical Inspection Co-operation Scheme). (2021). PI 041-1: Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments. PIC/S, 1 July 2021. https://picscheme.org/en/publications

14장 — 바이러스 안전 1단계: 저(低)pH 불활화​

  1. ICH (International Council for Harmonisation). (2023). ICH Harmonised Guideline Q5A(R2): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. ICH, Step 4 / adopted 1 November 2023. https://database.ich.org/sites/default/files/ICH_Q5A%28R2%29_Guideline_2023_1101.pdf
  2. FDA (U.S. Food and Drug Administration), CDER/CBER. (2024). Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin; Guidance for Industry. FDA, January 2024 (Docket FDA-2022-D-2512). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q5ar2-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-or-animal-origin
  3. ASTM International (Committee E55). (2012). ASTM E2888-12: Standard Practice for Process for Inactivation of Rodent Retrovirus by pH. ASTM International, West Conshohocken, PA (reapproved 2019, 2025). https://store.astm.org/e2888-12r19.html
  4. Brorson K, Krejci S, Lee K, Hamilton E, Stein K, Xu Y. (2003). Bracketed generic inactivation of rodent retroviruses by low pH treatment for monoclonal antibodies and recombinant proteins. Biotechnology and Bioengineering 82(3):321-329. https://doi.org/10.1002/bit.10574
  5. Mattila J, Clark M, Liu S, Pieracci J, Gervais TR, Wilson E, Galperina O, Li X, Roush D, Zoeller K, Brough H, Simpson-Platre C. (2016). Retrospective Evaluation of Low-pH Viral Inactivation and Viral Filtration Data from a Multiple Company Collaboration. PDA Journal of Pharmaceutical Science and Technology 70(3):293-299. https://doi.org/10.5731/pdajpst.2016.006478
  6. Jin W, Xing Z, Song Y, Huang C, Xu X, Ghose S, Li ZJ. (2019). Protein aggregation and mitigation strategy in low pH viral inactivation for monoclonal antibody purification. mAbs 11(8):1479-1491. https://doi.org/10.1080/19420862.2019.1658493
  7. Klutz S, Lobedann M, Bramsiepe C, Schembecker G. (2016). Continuous viral inactivation at low pH value in antibody manufacturing. Chemical Engineering and Processing: Process Intensification 102:88-101. https://doi.org/10.1016/j.cep.2016.01.002
  8. Brown M, Godfrey S, Creasy A, Salm J, Fahrner R. (2022). Continuous low pH viral inactivation: Operation and scaling strategy informs viral clearance study. Biotechnology and Bioengineering 119(8):2115-2121. https://doi.org/10.1002/bit.28117
  9. FDA (U.S. Food and Drug Administration). (2024). 21 CFR 211.192 - Production record review (Current Good Manufacturing Practice for Finished Pharmaceuticals). U.S. Code of Federal Regulations, Title 21, Part 211, Subpart J. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-J/section-211.192
  10. FDA (U.S. Food and Drug Administration). (2024). Inspection Observations (Form FDA 483) and Warning Letters. FDA compliance and enforcement resources, Office of Regulatory Affairs / CDER. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters

15장 — 폴리싱: 마지막 불순물 제거​

  1. Shukla AA, Hubbard B, Tressel T, Guhan S, Low D. (2007). Downstream processing of monoclonal antibodies — Application of platform approaches. Journal of Chromatography B 848(1):28-39. https://doi.org/10.1016/j.jchromb.2006.09.026
  2. Liu HF, Ma J, Winter C, Bayer R. (2010). Recovery and purification process development for monoclonal antibody production. mAbs 2(5):480–499. https://doi.org/10.4161/mabs.2.5.12645
  3. Hober S, Nord K, Linhult M. (2007). Protein A chromatography for antibody purification. Journal of Chromatography B 848(1):40–47. https://doi.org/10.1016/j.jchromb.2006.09.030
  4. Pezzini J, Joucla G, Gantier R, Toueille M, Lomenech AM, Le Sénéchal C, Garbay B, Santarelli X, Cabanne C. (2011). Antibody capture by mixed-mode chromatography: A comprehensive study from determination of optimal purification conditions to identification of contaminating host cell proteins. Journal of Chromatography A 1218(45):8197–8208. https://doi.org/10.1016/j.chroma.2011.09.036
  5. ICH (International Council for Harmonisation). (1999). ICH Harmonised Tripartite Guideline Q6B: Specifications — Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. ICH, Step 4 (10 March 1999); EMA ref CPMP/ICH/365/96, effective 1 Sep 1999. https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf
  6. FDA (U.S. Food and Drug Administration). (2024). 21 CFR Part 610 — General Biological Products Standards. U.S. Code of Federal Regulations, Title 21, Chapter I, Subchapter F. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-F/part-610
  7. Zydney AL. (2016). Continuous downstream processing for high value biological products: A Review. Biotechnology and Bioengineering 113(3):465–475. https://doi.org/10.1002/bit.25695
  8. Nitika N, Thakur G, Rathore AS. (2023). Continuous manufacturing of monoclonal antibodies: Dynamic control of multiple integrated polishing chromatography steps using BioSMB. Journal of Chromatography A 1690:463784. https://doi.org/10.1016/j.chroma.2023.463784
  9. Mazzer AR, Perraud X, Halley J, O'Hara J, Bracewell DG. (2015). Protein A chromatography increases monoclonal antibody aggregation rate during subsequent low pH virus inactivation hold. Journal of Chromatography A 1415:83-90. https://doi.org/10.1016/j.chroma.2015.08.068

16장 — 바이러스 안전 2단계: 바이러스 여과​

  1. ICH (International Council for Harmonisation). (2023). ICH Harmonised Guideline Q5A(R2): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. ICH, Step 4 adopted 1 November 2023; FDA Guidance for Industry, January 2024 (Docket FDA-2022-D-2512). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q5ar2-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-or-animal-origin
  2. PDA (Parenteral Drug Association) Virus Filtration Task Force. (2022). Technical Report No. 41 (Revised 2022): Virus Filtration. PDA Technical Report Series, Parenteral Drug Association, Bethesda, MD (ISBN 978-1-945584-34-3). https://www.pda.org/bookstore/product-detail/6725-tr-41-revised-virus-filtration
  3. USP (United States Pharmacopeia). (2016). General Chapter <1050.1> Design, Evaluation, and Characterization of Viral Clearance Procedures. United States Pharmacopeia–National Formulary (USP–NF), Rockville, MD. https://doi.usp.org/USPNF/USPNF_M7187_01_01.html
  4. Lute S, Aranha H, Tremblay D, Liang D, Ackermann H-W, Chu B, Moineau S, Brorson K. (2004). Characterization of Coliphage PR772 and Evaluation of Its Use for Virus Filter Performance Testing. Applied and Environmental Microbiology 70(8):4864–4871. https://doi.org/10.1128/AEM.70.8.4864-4871.2004
  5. EDQM (European Directorate for the Quality of Medicines & HealthCare). (2008). European Pharmacopoeia General Chapter 5.1.7: Viral Safety. European Pharmacopoeia (Ph. Eur.), reference 01/2008:50107, Council of Europe, Strasbourg. https://www.drugfuture.com/Pharmacopoeia/EP7/DATA/50107E.PDF
  6. FDA (U.S. Food and Drug Administration). (2024). 21 CFR Part 610 — General Biological Products Standards (Subpart B, General Provisions, §§ 610.10–610.14: potency, general safety, sterility, purity, identity). U.S. Code of Federal Regulations, Title 21, Chapter I, Subchapter F, Part 610, Subpart B (eCFR). https://www.ecfr.gov/current/title-21/chapter-I/subchapter-F/part-610/subpart-B
  7. Bohonak DM, Mehta U, Weiss ER, Voyta G. (2021). Adapting virus filtration to enable intensified and continuous monoclonal antibody processing. Biotechnology Progress 37(2):e3088. https://doi.org/10.1002/btpr.3088
  8. FDA (U.S. Food and Drug Administration). (2004). Guidance for Industry — Sterile Drug Products Produced by Aseptic Processing: Current Good Manufacturing Practice. U.S. Department of Health and Human Services, Food and Drug Administration (CDER/CBER/ORA), September 2004. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/sterile-drug-products-produced-aseptic-processing-current-good-manufacturing-practice

17장 — 최종 농축: 원료의약품 만들기​

  1. van Reis R, Zydney A. (2007). Bioprocess membrane technology. Journal of Membrane Science 297(1-2):16-50. https://doi.org/10.1016/j.memsci.2007.02.045
  2. Rosenberg E, Hepbildikler S, Kuhne W, Winter G. (2009). Ultrafiltration concentration of monoclonal antibody solutions: Development of an optimized method minimizing aggregation. Journal of Membrane Science 342(1-2):50-59. https://doi.org/10.1016/j.memsci.2009.06.028
  3. Wang W, Singh S, Zeng DL, King K, Nema S. (2007). Antibody structure, instability, and formulation. Journal of Pharmaceutical Sciences 96(1):1-26. https://doi.org/10.1002/jps.20727
  4. ICH (International Council for Harmonisation). (1999). ICH Harmonised Tripartite Guideline Q6B: Specifications - Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. ICH, Step 4, 10 March 1999. https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf
  5. USP (United States Pharmacopeial Convention). (2014). USP General Chapter <787> Subvisible Particulate Matter in Therapeutic Protein Injections. United States Pharmacopeia and National Formulary (USP-NF), official 1 August 2014. https://doi.usp.org/USPNF/USPNF_M6497_02_01.html
  6. FDA (U.S. Food and Drug Administration). (2024). 21 CFR 211.72 Filters (Current Good Manufacturing Practice for Finished Pharmaceuticals, Subpart D - Equipment). U.S. Code of Federal Regulations, Title 21, Chapter I, Subchapter C, Part 211. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-D/section-211.72
  7. Zydney AL. (2016). Continuous downstream processing for high value biological products: A Review. Biotechnology and Bioengineering 113(3):465-475. https://doi.org/10.1002/bit.25695
  8. Konstantinov KB, Cooney CL. (2015). White Paper on Continuous Bioprocessing. May 20-21, 2014 Continuous Manufacturing Symposium. Journal of Pharmaceutical Sciences 104(3):813-820. https://doi.org/10.1002/jps.24268
  9. Carpenter JF, Randolph TW, Jiskoot W, Crommelin DJA, Middaugh CR, Winter G, et al. (2009). Overlooking subvisible particles in therapeutic protein products: Gaps that may compromise product quality. Journal of Pharmaceutical Sciences 98(4):1201-1205. https://doi.org/10.1002/jps.21530
  10. FDA (U.S. Food and Drug Administration), CDER. (2021). Guidance for Industry: Inspection of Injectable Products for Visible Particulates. U.S. FDA, Pharmaceutical Quality/CMC, December 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/inspection-injectable-products-visible-particulates

18장 — 충전·마감: 벌크에서 바이알로 (완제의약품)​

  1. European Commission (EudraLex Volume 4, EU GMP). (2022). Annex 1: Manufacture of Sterile Medicinal Products. EudraLex - The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines for Good Manufacturing Practice; Brussels, 22.8.2022 C(2022) 5938 final; in operation 25 Aug 2023 (point 8.123 from 25 Aug 2024). https://health.ec.europa.eu/latest-updates/revision-manufacture-sterile-medicinal-products-2022-08-25_en
  2. FDA (U.S. Food and Drug Administration), CDER/CBER/ORA. (2004). Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice. U.S. FDA, Pharmaceutical Quality/Manufacturing Standards (CGMP), September 2004. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/sterile-drug-products-produced-aseptic-processing-current-good-manufacturing-practice
  3. U.S. Code of Federal Regulations (FDA). (2024). 21 CFR 211.113 - Control of microbiological contamination. Title 21, Chapter I, Subchapter C, Part 211, Subpart F (Production and Process Controls); current eCFR edition. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-F/section-211.113
  4. PDA (Parenteral Drug Association). (2025). Technical Report No. 26 (Revised 2025): Sterilizing Filtration of Liquids. Parenteral Drug Association (PDA), Bethesda, MD; PDA Technical Report TR-26, released Nov 2025. https://www.pda.org/bookstore/product-detail/8489-tr-no-26-revised-2025-sterilizing-filtration
  5. Wang W. (1999). Instability, stabilization, and formulation of liquid protein pharmaceuticals. International Journal of Pharmaceutics 185(2):129-188. https://doi.org/10.1016/S0378-5173(99)00152-0
  6. Wang W. (2000). Lyophilization and development of solid protein pharmaceuticals. International Journal of Pharmaceutics 203(1-2):1-60. https://doi.org/10.1016/S0378-5173(00)00423-3
  7. Carpenter JF, Randolph TW, Jiskoot W, Crommelin DJA, Middaugh CR, Winter G, et al. (2009). Overlooking subvisible particles in therapeutic protein products: Gaps that may compromise product quality. Journal of Pharmaceutical Sciences 98(4):1201-1205. https://doi.org/10.1002/jps.21530
  8. ICH (International Council for Harmonisation). (2023). ICH Harmonised Guideline Q9(R1): Quality Risk Management. ICH, Step 4, adopted 18 January 2023. https://database.ich.org/sites/default/files/ICH_Q9(R1)_Guideline_Step4_2022_1219.pdf

19장 — 포장, 라벨링, 일련번호 부여​

  1. WHO (World Health Organization). (2024). Substandard and falsified medical products (fact sheet). World Health Organization, Geneva; fact sheet, updated 2024. https://www.who.int/news-room/fact-sheets/detail/substandard-and-falsified-medical-products
  2. FDA (U.S. Food and Drug Administration), CDER/CBER/CVM. (2021). Inspection of Injectable Products for Visible Particulates; Draft Guidance for Industry. U.S. FDA, December 2021 (Docket FDA-2021-D-0241; announced 86 FR 71648, 17 Dec 2021); draft. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/inspection-injectable-products-visible-particulates
  3. USP (United States Pharmacopeia). (2024). General Chapters <790> Visible Particulates in Injections and <1790> Visual Inspection of Injections. United States Pharmacopeia-National Formulary (USP-NF), Rockville, MD. https://doi.usp.org/USPNF/USPNF_M7197_01_01.html
  4. ISO/IEC (International Organization for Standardization / International Electrotechnical Commission). (2006). ISO/IEC 16022:2006 Information technology - Automatic identification and data capture techniques - Data Matrix bar code symbology specification. ISO/IEC JTC 1/SC 31, Geneva (2nd ed.; superseded by ISO/IEC 16022:2024). https://www.iso.org/standard/44230.html
  5. GS1. (2024). GS1 General Specifications (Release 24.0, January 2024). GS1 AISBL, Brussels; foundational AIDC standard defining Application Identifiers and data carriers (current release at ref.gs1.org). https://ref.gs1.org/standards/genspecs/
  6. FDA (U.S. Food and Drug Administration). (2013). Drug Supply Chain Security Act (DSCSA), Title II of the Drug Quality and Security Act (Pub. L. 113-54). U.S. FDA; signed into law 27 Nov 2013, with package-level interoperable electronic tracing required from 27 Nov 2023. https://www.fda.gov/drugs/drug-supply-chain-integrity/drug-supply-chain-security-act-dscsa
  7. European Commission. (2016). Commission Delegated Regulation (EU) 2016/161 of 2 October 2015 supplementing Directive 2001/83/EC by laying down detailed rules for the safety features appearing on the packaging of medicinal products for human use. Official Journal of the European Union L 32, 9 Feb 2016, pp. 1-27 (implementing the Falsified Medicines Directive 2011/62/EU). https://eur-lex.europa.eu/eli/reg_del/2016/161/oj/eng
  8. ICH (International Council for Harmonisation). (1995). ICH Harmonised Tripartite Guideline Q5C: Quality of Biotechnological Products - Stability Testing of Biotechnological/Biological Products. ICH, Current Step 4, 30 November 1995 (EMA ref. CPMP/ICH/138/95). https://database.ich.org/sites/default/files/Q5C%20Guideline.pdf
  9. FDA (U.S. Food and Drug Administration). (2023). Standards for the Interoperable Exchange of Information for Tracing of Certain Human, Finished, Prescription Drugs: How to Exchange Product Tracing Information; Stabilization-Period Compliance Policy. U.S. FDA; the agency exercised enforcement discretion through a stabilization period (announced 26 Aug 2023) for the package-level DSCSA enhanced-drug-distribution-security requirements that took effect 27 Nov 2023. https://www.fda.gov/drugs/drug-supply-chain-security-act-dscsa/enhanced-drug-distribution-security-requirements-under-section-582g-1-fdc-act

20장 — 품질관리와 배치 출하 승인​

  1. ICH (International Council for Harmonisation). (1999). ICH Harmonised Tripartite Guideline Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. ICH, Step 4 version dated 10 March 1999 (CPMP/ICH/365/96). https://database.ich.org/sites/default/files/Q6B%20Guideline.pdf
  2. FDA (U.S. Food and Drug Administration). (2024). 21 CFR Part 211, Subpart I - Laboratory Controls (Sections 211.160-211.167): General requirements; Testing and release for distribution; Special testing requirements. U.S. Code of Federal Regulations, Title 21, Chapter I, Subchapter C, Part 211, Subpart I. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-I
  3. USP (United States Pharmacopeial Convention). (2024). General Chapter <71> Sterility Tests. United States Pharmacopeia and National Formulary (USP-NF). https://www.usp.org/harmonization-standards/pdg/general-methods/sterility-test
  4. USP (United States Pharmacopeial Convention). (2024). General Chapter <85> Bacterial Endotoxins Test. United States Pharmacopeia and National Formulary (USP-NF). https://www.usp.org/harmonization-standards/pdg/general-methods/bacterial-endotoxins
  5. FDA (U.S. Food and Drug Administration). (2012). Guidance for Industry: Pyrogen and Endotoxins Testing - Questions and Answers. FDA CDER/CBER/CVM, June 2012. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pyrogen-and-endotoxins-testing-questions-and-answers
  6. USP (United States Pharmacopeial Convention). (2013). General Chapter <1033> Biological Assay Validation. United States Pharmacopeia and National Formulary (USP-NF). https://www.usp.org/biologics/bioassays
  7. European Commission. (2015). EudraLex Volume 4, EU GMP Guide Annex 16: Certification by a Qualified Person and Batch Release. European Commission, EU Guidelines for Good Manufacturing Practice; effective 15 April 2016. https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en
  8. FDA (U.S. Food and Drug Administration). (2004). Guidance for Industry: PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. FDA CDER/CVM/ORA, September 2004. https://www.fda.gov/media/71012/download
  9. Eon-Duval A, Broly H, Gleixner R. (2012). Quality attributes of recombinant therapeutic proteins: an assessment of impact on safety and efficacy as part of a quality by design development approach. Biotechnology Progress 28(3):608-622. https://doi.org/10.1002/btpr.1548
  10. FDA (U.S. Food and Drug Administration). (2006). Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production. FDA CDER, October 2006. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigating-out-specification-oos-test-results-pharmaceutical-production
  11. PIC/S (Pharmaceutical Inspection Co-operation Scheme). (2021). PI 041-1: Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments. PIC/S, 1 July 2021. https://picscheme.org/en/publications
  12. U.S. Code of Federal Regulations. (2025). 21 CFR Part 11 - Electronic Records; Electronic Signatures. Title 21, Chapter I, Subchapter A, Part 11 (Subparts A-C, §§11.1-11.300). https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-11

21장 — 마지막 구간: 콜드체인으로 환자에게​

  1. ICH (International Council for Harmonisation). (1995). ICH Harmonised Tripartite Guideline Q5C: Quality of Biotechnological Products — Stability Testing of Biotechnological/Biological Products. ICH, Step 4 version, 30 November 1995. https://database.ich.org/sites/default/files/Q5C%20Guideline.pdf
  2. ICH (International Council for Harmonisation). (2003). ICH Harmonised Tripartite Guideline Q1A(R2): Stability Testing of New Drug Substances and Products. ICH, Step 4 version, 6 February 2003. https://database.ich.org/sites/default/files/Q1A%28R2%29%20Guideline.pdf
  3. Wang W, Singh S, Zeng DL, King K, Nema S. (2007). Antibody structure, instability, and formulation. Journal of Pharmaceutical Sciences 96(1):1-26. https://doi.org/10.1002/jps.20727
  4. WHO (World Health Organization). (2011). Model guidance for the storage and transport of time- and temperature-sensitive pharmaceutical products (Annex 9). WHO Technical Report Series No. 961, Annex 9, 2011. https://cdn.who.int/media/docs/default-source/medicines/norms-and-standards/guidelines/distribution/trs961-annex9-modelguidanceforstoragetransport.pdf
  5. European Commission. (2013). Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use (2013/C 343/01). Official Journal of the European Union C 343, 23.11.2013, pp. 1-14. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.C_.2013.343.01.0001.01.ENG
  6. PDA (Parenteral Drug Association). (2005). Technical Report No. 39: Cold Chain Guidance for Medicinal Products — Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment. PDA Journal of Pharmaceutical Science and Technology 59(3 Suppl TR39):1-12. https://pubmed.ncbi.nlm.nih.gov/16313059/
  7. USP (United States Pharmacopeia). (2021). General Chapter <1079> Risks and Mitigation Strategies for the Storage and Transportation of Finished Drug Products. United States Pharmacopeia–National Formulary (USP-NF), official 1 February 2021. https://www.usp.org/sites/default/files/usp/document/supply-chain/apec-toolkit/USP%20GC1079.pdf
  8. U.S. Code of Federal Regulations. (2024). 21 CFR Part 211 — Current Good Manufacturing Practice for Finished Pharmaceuticals: §211.150 Distribution procedures and §211.192 Production record review. Title 21, Chapter I, Subchapter C, Part 211, Subparts H and J (eCFR). https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-J/section-211.192
  9. FDA (U.S. Food and Drug Administration). (2024). Data Integrity and Compliance With Drug CGMP: Questions and Answers (Guidance for Industry); Inspection Observations (Form FDA 483) and Warning Letters. FDA, CDER/CBER/CVM, Office of Regulatory Affairs. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters

22장 — 모든 것을 감싸는 틀: 품질, 규제, 데이터​

  1. ICH (International Council for Harmonisation). (2009). ICH Harmonised Tripartite Guideline Q8(R2): Pharmaceutical Development. ICH, Current Step 4 version, August 2009. https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf
  2. Rathore AS, Winkle H. (2009). Quality by design for biopharmaceuticals. Nature Biotechnology 27(1):26-34. https://doi.org/10.1038/nbt0109-26
  3. ICH (International Council for Harmonisation). (2009). ICH Harmonised Tripartite Guideline Q10: Pharmaceutical Quality System (Guidance for Industry). ICH Step 4 (June 2008); FDA CDER/CBER guidance issued April 2009. https://www.fda.gov/media/71553/download
  4. FDA (U.S. Food and Drug Administration). (2004). Guidance for Industry: PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. FDA, CDER/CVM/ORA, September 2004. https://www.fda.gov/media/71012/download
  5. U.S. Code of Federal Regulations. (2025). 21 CFR Part 11 - Electronic Records; Electronic Signatures. Title 21, Chapter I, Subchapter A, Part 11 (Subparts A-C, §§11.1-11.300). https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-11
  6. FDA (U.S. Food and Drug Administration). (2018). Data Integrity and Compliance With Drug CGMP: Questions and Answers - Guidance for Industry. FDA, CDER/CBER/CVM, December 2018. https://www.fda.gov/media/119267/download
  7. ISPE (International Society for Pharmaceutical Engineering). (2023). ISPE Baseline Guide Volume 8: Pharma 4.0 (First Edition). ISPE, Tampa FL, 1st Edition, December 2023 (DOI 10.1002/9781946964724). https://ispe.org/publications/guidance-documents/baseline-guide-vol-8-pharma-40-1st-edition
  8. DiMasi JA, Grabowski HG, Hansen RW. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. Journal of Health Economics 47:20-33. https://doi.org/10.1016/j.jhealeco.2016.01.012
  9. Sofer G, Zabriskie DW (eds). (2000). Biopharmaceutical Process Validation. Marcel Dekker, New York (Biotechnology and Bioprocessing Series, Vol. 23) — deviation-management and failure-investigation framework for handling out-of-specification results and process drift.
  10. ICH (International Council for Harmonisation). (2005). ICH Harmonised Tripartite Guideline Q9: Quality Risk Management. ICH, Current Step 4 version, November 2005. https://database.ich.org/sites/default/files/Q9%20Guideline.pdf
  11. European Commission (EudraLex Volume 4, EU GMP). (2011). Annex 11: Computerised Systems. EudraLex — The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines for Good Manufacturing Practice; current version effective 30 June 2011 (revision in progress). The EU counterpart to 21 CFR Part 11, governing electronic records, audit trails, and electronic signatures in computerised systems. https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en

이미지 출처 및 판권​

이 가이드에 사용된 모든 이미지의 출처와 라이선스입니다. 사진은 명시된 퍼블릭 도메인 또는 크리에이티브 커먼즈(Creative Commons) 조건에 따라 저작자를 표시하여 사용했습니다. “저자 원본 도해(Original diagram by the authors)”로 표시된 도식은 모두 저자가 AI의 도움을 받아 직접 제작했으며, 출처를 표시하면 복제·재사용할 수 있습니다. 상업적 인쇄 출판 전 최종 법무 검토를 권장합니다.

  • “바이오의약품 제조의 두 가지 시간 척도: 일회성 승인 여정 대 반복되는 배치 주기로, 각각 cGMP와 Quality by Design의 적용을 받습니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 바이오의약품 생산 스위트. 이미지: Tehran Times, CC BY 4.0, Wikimedia Commons.
  • “단일클론항체의 구조: 질량 약 150 kDa의 Y자형 단백질로, 동일한 두 개의 항원 결합 팔(Fab 영역)과 하나의 신호 전달 꼬리(Fc 영역)로 이루어집니다. Asn297의 당화 부위(녹색)는 면역 반응을 조절합니다. 동일한 세포주에서 나온 모든 복제본은 서로 동일합니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 인간 인슐린 바이알. 이미지: Wesalius, CC BY 4.0, Wikimedia Commons.
  • “유가식 단일 배치 처리(왼쪽) 대 다중 컬럼 포획을 적용한 연속 집약형 관류(오른쪽): 바이오리액터 운전, 포획 동역학, 공정 소요 시간, 수율의 차이”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 제약 생산 라인. 이미지: Josep Lago (European Commission), CC BY 4.0, Wikimedia Commons.
  • “표적제품프로파일(Target Product Profile, TPP)은 질환 적응증, 환자 인구통계, 용량과 투여 경로, 유효기간과 보관 조건, 품질·역가 목표를 문서화하는 종합 희망사항 목록입니다. TPP의 모든 항목은 이후 다운스트림 제조 선택으로 연쇄적으로 이어집니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 자동화 신약 스크리닝 장비. 이미지: National Center for Advancing Translational Sciences, 퍼블릭 도메인, Wikimedia Commons.
  • “항체 발굴의 두 가지 경로: 면역 기반 하이브리도마 생성(왼쪽)과 시험관 내 파지 디스플레이(오른쪽)는 모두 선도물질 선별 깔때기로 수렴하며, 여기서 친화도·안정성·개발성 지표를 통해 수천 개의 후보가 제조의 출발점이 되는 단일 DNA 서열로 좁혀집니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 다중 웰 마이크로플레이트. 이미지: CSIRO, CC BY 3.0, Wikimedia Commons.
  • 위상차 현미경으로 관찰한 부착성 CHO 세포. 이미지: Alcibiades, 퍼블릭 도메인, Wikimedia Commons.
  • “단일 세포 클로닝은 클론성과 일관성을 보장합니다. 초기 산업용 풀과 달리, 현대 제약용 세포주는 하나의 시조 세포에서 유래하며, 높은 역가, 낮은 응집체, 유전적 안정성에 대해 시험을 거친 뒤 마스터(MCB) 및 워킹(WCB) 세포은행으로 동결됩니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 동물 세포를 배양하는 벤치탑 바이오리액터. 이미지: Karel Schmiedberger ml., CC BY 3.0, Wikimedia Commons.
  • “일반적인 mAb 제조 공정 개발 경로: 주요 파라미터를 모니터링하는 유가식 배양(왼쪽)이 다단계 크로마토그래피 포획 및 폴리싱(오른쪽)으로 연결됩니다. 화살표는 물질 흐름을 나타내고, 콜아웃 상자는 각 단계에서 추적하는 CQA와 CPP를 보여줍니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • Q-TOF LC/MS 질량분석기. 이미지: Michael Pereckas, CC BY 2.0, Wikimedia Commons.
  • “분석 시험 캐스케이드는 모든 핵심 품질 특성이 개발 단계부터 제조 출하까지 측정되고 규격 내에 유지되도록 보장합니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • “스케일업 과제: 산소, 혼합, 전단. 왼쪽 플라스크는 균일한 조건을 달성하지만, 오른쪽의 대형 탱크는 깊이에 따라 산소가 달라지고, 혼합 전선이 느리며, 임펠러 부근에서 전단력이 높습니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 벤치 스케일 바이오리액터. 이미지: Jonas Schenk, 퍼블릭 도메인, Wikimedia Commons.
  • 인큐베이터 셰이커 안의 배양 플라스크. 이미지: Diane A. Reid(National Cancer Institute), 퍼블릭 도메인, Wikimedia Commons.
  • “시드 트레인은 1–2 mL의 동결 바이알(WCB)에서 시작해 진탕 플라스크(125–500 mL), 웨이브 바이오리액터(2–5 L), 시드 바이오리액터(10–20 L)를 거쳐 유가식 모드로 4–7일에 걸쳐 물리적으로 진행됩니다. 각 단계는 무균 조건과 제어된 파라미터(온도, pH, 용존산소)를 유지하여 세포 생존율과 순도를 보호합니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • “통합 제어 루프를 갖춘 생산 바이오리액터의 단면도: 센서가 제어기에 신호를 보내고, 제어기는 가열기, 교반, 공급 펌프를 조정하여 설정값을 유지합니다. 삽입 그림은 스테인리스강 교반조(유가식)와 일회용 백(관류)을 비교합니다.”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 스테인리스 스틸 바이오리액터. 이미지: RickLawless, CC BY 3.0, Wikimedia Commons.
  • “2단계 수확: 디스크 적층형 원심분리(왼쪽)는 10,000–20,000 g로 세포를 방사상으로 침전시키고, 심층 여과(오른쪽)는 층상 매질 매트릭스 전반에서 미세 불순물을 포집합니다. 현대식 시스템은 둘을 하나의 cGMP 준수 스키드로 통합하여 온도, 압력, 청징도를 인라인으로 모니터링합니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 실험실 원심분리기. 이미지: Ivangiesen, CC0, Wikimedia Commons.
  • “프로테인 A 포획 주기: 항체를 Fc 줄기로 결합시키고, 불순물을 씻어 폐기물로 보내며, 낮은 pH에서 농축된 풀을 방출한 다음, 컬럼을 세척하여 재사용합니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 공정 크로마토그래피 스키드. 이미지: Kitmondo Lab, CC BY 2.0, Wikimedia Commons.
  • “저(低)pH 불활화는 모니터링되는 탱크에서의 배치 홀드 방식이나 코일에서의 연속 체류 방식으로 수행할 수 있습니다. 두 방식 모두 동일한 사멸 동역학을 달성하지만, 설치 면적과 처리량 모델에서 차이가 있습니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 실험실 pH 미터. 이미지: Hannes Grobe, CC BY 3.0, Wikimedia Commons.
  • “폴리싱 크로마토그래피 컬럼: 항체(Y자형)와 불순물(HCP, 응집체, DNA, 용출된 프로테인 A)이 레진 베드로 들어갑니다. 이온교환 비드는 pH와 염 농도에 따라 불순물이나 항체를 결합하며, 제품은 피크 용출로 수집됩니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 벤치탑 ÄKTA pure FPLC 크로마토그래피 시스템. 이미지: TheBartgry, CC0, Wikimedia Commons.
  • “바이러스 차단 나노필터의 구조와 메커니즘: 항체(10 nm)는 통과하고, 기공보다 큰 대부분의 바이러스는 차단되며, 경계 크기인 18–26 nm 파보바이러스조차 추가적인 정전기·흡착 작용으로 붙잡힙니다. 막 오염으로 인해 유량은 시간에 따라 감소합니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 막 필터 캡슐. 이미지: Stephane Lesbats (IFREMER), CC BY 4.0, Wikimedia Commons.
  • “TFF 시스템: 측면 교차 흐름이 투과성 막을 휩쓸고 지나가며, 농축액(농축된 항체)은 위로, 투과액(물 + 저분자)은 아래로 배출됩니다. 삽입 그림은 배치 홀드앤익스체인지(수 시간의 정지)와 연속 동시 공급 정용여과(버퍼 펌프를 통한 정상 상태)를 대조합니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 접선 흐름 여과 시스템. 이미지: Kitmondo Marketplace, CC BY 2.0, Wikimedia Commons.
  • “무균 충전·마감 청정실 배치: A등급 작업 구역(≤3,520 입자/m³)은 B등급 지원 구역과 분리되며, 단방향 HEPA 기류와 작업자 가운 착용 관리를 통해 미생물 유입을 방지합니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 청정실 실험실. 이미지: UCL Mathematical and Physical Sciences, CC BY 2.0, Wikimedia Commons.
  • “바이알용 일반적인 자동 포장 라인: 비전 검사(200–600 개/분), 변조 방지 기능을 갖춘 라벨링, 2D GS1 DataMatrix 일련번호 부여(예시 바코드와 함께 표시)”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 제약 생산 라인에서 포장 중인 바이알. 이미지: Sadegh Nikgostar, CC BY 4.0, Wikimedia Commons.
  • “출하 시험의 캐스케이드: 완제 바이알을 샘플링하여 확인시험, 순도, 역가, 무균, 엔도톡신, 외관에 대해 병렬로 시험하고, 그 결과를 분석성적서(Certificate of Analysis)로 정리한 뒤 자격을 갖춘 책임자(Qualified Person)가 최종 출하 결정을 내립니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 분석 실험실의 과학자들. 이미지: USDA, 퍼블릭 도메인, Wikimedia Commons.
  • 냉장 콜드체인 운송 컨테이너. 이미지: U.S. Army Medical Logistics Command, 퍼블릭 도메인, Wikimedia Commons.
  • “검증된 단열 운송 컨테이너(자격 인증 쿨러)는 의약품을 지정된 기간 동안 목표 온도 범위로 유지하도록 설계·시험됩니다. 내부에는 온도 데이터 로거가 함께 실려 규정 준수를 입증합니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • “배치 종료 시점 시험에서 실시간 품질 모니터링으로의 전환: 전통적인 출하 시험은 수 주를 기다려야 하지만, 유가식의 PAT는 공정 중간 의사결정을 가능하게 하고, 연속 관류는 실시간 롤링 풀링과 출하 결정을 가능하게 합니다”. 저자가 AI의 도움을 받아 직접 제작한 그림입니다.
  • 플랜트 관제실의 작업자들. 이미지: PEO ACWA, CC BY 2.0, Wikimedia Commons.