Skip to main content
SpringerLink
Log in
Book cover

Therapeutic Enzymes: Function and Clinical Implications pp 55–80Cite as

Quality Control and Downstream Processing of Therapeutic Enzymes

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1148))

Abstract

Therapeutic enzymes are a commercially minor but clinically important area of biopharmaceuticals. An array of therapeutic enzymes has been developed for a variety of human diseases, including leukaemia and enzyme-deficiency diseases such as Gaucher’s disease. Production and testing of therapeutic enzymes is strictly governed by regulatory bodies in each country around the world, and batch-to-batch consistency is crucially important. Manufacture of a batch starts with the fermentation or cell culture stage. After expression of the therapeutic enzyme in a cell culture bioreactor, robust and reproducible protein purification, or downstream processing (DSP) of the target product, is critical to ensuring safe delivery of these medicines. Modern processing technology, including the use of disposable processing equipment, has greatly improved the DSP development pathway in terms of robustness and speed to clinic. Once purified, the drug substance undergoes rigorous quality control (QC) testing according to current regulatory guidance, to enable release to the clinic and patient. QC testing is conducted to ensure the safety, purity, identity, potency and strength of the medicinal product, requiring multiple analytical methods that are rigorously validated and monitored for robust performance. Several case studies, including L-asparaginase and asfotase alfa, are discussed to illustrate the methods described herein.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

2D-GE:

Two-dimensional gel electrophoresis

ABG:

Acid β-glucosidase

ADA:

Anti-drug antibodies

ADC:

Antibody-drug conjugates

AUC:

Analytical ultracentrifugation

CFU:

Colony-forming units

CGE:

Capillary gel electrophoresis

CHO:

Chinese hamster ovary

cIEF:

Capillary isoelectric focussing

CM:

Carboxymethyl

CNS:

Central nervous system

DEAE:

Diethyl amino ethyl

DNA:

Deoxyribonucleic acid

DOE:

Design of experiments

DP:

Drug product

DS:

Drug substance

DSP:

Downstream processing

ELISA:

Enzyme-linked immunosorbent assay

EMA:

European medicines agency

ERT:

Enzyme replacement therapy

EU:

Endotoxin units

Fc :

Constant domain (antibody)

FDA:

United States Food and Drug Administration

GD:

Gaucher’s disease

GMP:

Good manufacturing practice

HCP:

Host cell proteins

HER2:

Human epidermal growth factor receptor 2

HIC:

Hydrophobic interaction chromatography

HPLC:

High-pressure liquid chromatography

HPP:

Hypophosphatasia

HVAC:

Heating, ventilation and air conditioning

ICH:

International Council on Harmonisation

IEX:

Ion-exchange

IEX-HPLC:

Ion-exchange high-pressure liquid chromatography

IgG:

Immunoglobulin

IMAC:

Immobilised-metal affinity chromatography

ITC:

Isothermal calorimetry

IU:

International unit (of enzymatic activity)

k cat :

Enzyme catalytic constant

K M :

Michaelis constant

LAL:

Limulus amoebocyte lysate

LAL-D:

Lysosomal acid lipase deficiency

LC-MS:

Liquid chromatography coupled mass spectrometry

LOD:

Limit of detection

mAbs:

Monoclonal antibodies

MALDI:

Matrix-assisted laser desorption/ionisation

MF:

Microfiltration

MS:

Mass spectrometry

MS/MS:

Tandem mass spectrometry

NAD:

Nicotinamide adenine dinucleotide

NADP:

Nicotinamide adenine dinucleotide phosphate

NCPPB:

National Collection of Plant Pathogenic Bacteria (UK)

PCR:

Polymerase chain reaction

PEG:

Poly(ethylene glycol)

pI:

Isoelectric point

PMDA:

Japanese Pharmaceuticals and Medical Devices Agency

Q:

Quaternary ammonium

QA:

Quality assurance

QbD:

Quality by design

QC:

Quality control

QMS:

Quality management system

qPCR:

Quantitative polymerase chain reaction

R&D:

Research and development

RP-HPLC:

Reversed-phase high-pressure liquid chromatography

RT-PCR:

Real-time polymerase chain reaction

S:

Sulphopropyl

SDS-PAGE:

Sodium dodecyl sulphate polyacrylamide gel electrophoresis

SEC:

Size-exclusion chromatography

SOP:

Standard operating procedures

SPR:

Surface plasmon resonance

TFF:

Tangential-flow filtration

TFF-MF:

Tangential-flow filtration – microfiltration

TNALP:

Tissue-nonspecific alkaline phosphatase

U:

Units (of enzyme activity)

US:

United States

UV:

Ultraviolet

Vmax :

Maximum enzymatic reaction velocity

References

  • Aghaiypour K, Wlodawer A, Lubkowski J (2001) Structural basis for the activity and substrate specificity of Erwinia chrysanthemi L-asparaginase. Biochemistry 40(19):5655–5664

    CAS  PubMed  Google Scholar 

  • Allison N, Richards J (2014) Current status and future trends for disposable technology in the biopharmaceutical industry. J Chem Technol Biotechnol 89(9):1283–1287

    CAS  Google Scholar 

  • Aviezer D, Brill-Almon E, Shaaltiel Y et al (2009) A plant-derived recombinant human glucocerebrosidase enzyme – a preclinical and phase I investigation. PLoS One 4(3):e4792

    PubMed  PubMed Central  Google Scholar 

  • Balasundaram B, Harrison S, Bracewell DG (2009) Advances in product release strategies and impact on bioprocess design. Trends Biotechnol 27(8):477–485

    CAS  PubMed  Google Scholar 

  • Bierau H, Hinton RJ, Lyddiatt A (2001) Direct process integration of cell disruption and fluidised bed adsorption in the recovery of labile microbial enzymes. Bioseparation 10(1):73–85

    CAS  PubMed  Google Scholar 

  • Bracewell DG, Boychyn M, Baldascini H et al (2008) Impact of clarification strategy on chromatographic separations: pre-processing of cell homogenates. Biotechnol Bioeng 100(5):941–949

    CAS  PubMed  Google Scholar 

  • Broome JD (1968) Studies on the mechanism of tumor inhibition by L-asparaginase: effects of the enzyme on asparagine levels in the blood, normal tissues, and 6C3HED lymphomas of mice: differences in asparagine formation and utilization in asparaginase-sensitive and-resistant lymphoma cells. J Exp Med 127(6):1055–1072

    CAS  PubMed  PubMed Central  Google Scholar 

  • Buck PW, Elsworth R, Miller GA et al (1971) The batch production of L-asparaginase from Erwinia carotovora. J Gen Microbiol 65:i

    CAS  PubMed  Google Scholar 

  • Burnouf T, Radosevich M, Goubran HA et al (2005) Place of nanofiltration for assuring viral safety of biologicals. Cur Nanosci 1(3):189–201

    CAS  Google Scholar 

  • Carta G, Jungbauer A (2010) Protein chromatography: process development and scale-up. Wiley, Hoboken

    Google Scholar 

  • Clonis YD, Labrou NE, Kotsira VP et al (2000) Biomimetic dyes as affinity chromatography tools in enzyme purification. J Chromatogr A 891(1):33–44

    CAS  PubMed  Google Scholar 

  • Cuatrecasas P, Wilchek M, Anfinsen CB (1968) Selective enzyme purification by affinity chromatography. Proc Natl Acad Sci U S A 61(2):636–643

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cummins PM, O’Connor BF (2011) Hydrophobic interaction chromatography. In: Walls D, Loughran S (eds) Protein chromatography. Humana Press, New York, pp 431–437

    Google Scholar 

  • Darling A (2002) Validation of biopharmaceutical purification processes for virus clearance evaluation. Mol Biotechnol 21(1):57–83

    CAS  PubMed  PubMed Central  Google Scholar 

  • Darling AJ, Boose JA, Spaltro J (1998) Virus assay methods: accuracy and validation. Biologicals 26(2):105–110

    CAS  PubMed  Google Scholar 

  • Dewan SS, Sullivan LL (2016) Protein therapeutics market – technology advances spur market growth of protein therapies. Drug Dev Deliv 16(9):44–47

    Google Scholar 

  • DiPaolo B, Pennetti A, Nugent L et al (1999) Monitoring impurities in biopharmaceuticals produced by recombinant technology. Pharm Sci Technol Today 2(2):70–82

    CAS  PubMed  Google Scholar 

  • Dolník V (1997) Capillary zone electrophoresis of proteins. Electrophoresis 18(12–13):2353–2361

    PubMed  Google Scholar 

  • Doonan S (1996) Chromatography on hydroxyapatite. In: Doonan S (ed) Protein purification protocols. Humana Press, New York, pp 211–215

    Google Scholar 

  • Dullah EC, Ongkudon CM (2017) Current trends in endotoxin detection and analysis of endotoxin–protein interactions. Crit Rev Biotechnol 37(2):251–261

    CAS  PubMed  Google Scholar 

  • Dvir H, Harel M, McCarthy AA et al (2003) X-ray structure of human acid-β-glucosidase, the defective enzyme in Gaucher disease. EMBO Rep 4(7):704–709

    CAS  PubMed  PubMed Central  Google Scholar 

  • Edmunds T (2005) β-glucocerebrosidase, ceredase and cerezyme. Dir Ther Enzymes 12:117–133

    Google Scholar 

  • Epshtein NA (2004) Validation of HPLC techniques for pharmaceutical analysis. Pharm Chem J 38(4):212–228

    CAS  Google Scholar 

  • European Medicines Agency (2015) Public assessment report for Strensiq. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003794/WC500194340.pdf. Accessed 7 Mar 2018

  • European Medicines Agency Public Assessment Report for Strensiq 25 June (2015). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003794/WC500194340.pdf. Accessed 7 Mar 2018

  • Farshid M, Taffs RE, Scott D et al (2005) The clearance of viruses and transmissible spongiform encephalopathy agents from biologicals. Cur Opin Biotechnol 16(5):561–567

    CAS  Google Scholar 

  • Fekete S, Beck A, Veuthey JL et al (2014) Theory and practice of size exclusion chromatography for the analysis of protein aggregates. J Pharm Biomed Anal 101:161–173

    CAS  PubMed  Google Scholar 

  • Fekete S, Beck A, Veuthey JL et al (2015) Ion-exchange chromatography for the characterization of biopharmaceuticals. J Pharm Biomed Anal 113:43–55

    CAS  PubMed  Google Scholar 

  • Gao Y, Allison N (2016) Extractables and leachables issues with the application of single use technology in the biopharmaceutical industry. J Chem Technol Biotechnol 91(2):289–295

    CAS  Google Scholar 

  • Gervais D (2016) Protein deamidation in biopharmaceutical manufacture: understanding, control and impact. J Chem Technol Biotechnol 91(3):569–575

    CAS  Google Scholar 

  • Gervais D, Foote N (2014) Recombinant deamidated mutants of Erwinia chrysanthemi L-asparaginase have similar or increased activity compared to wild-type enzyme. Mol Biotechnol 56(10):865–877

    CAS  PubMed  Google Scholar 

  • Gervais D, Allison N, Jennings A et al (2013) Validation of a 30-year-old process for the manufacture of L-asparaginase from Erwinia chrysanthemi. Bioprocess Biosyst Eng 36(4):453–460

    CAS  PubMed  Google Scholar 

  • Gervais D, King D, Kanda P et al (2015) Structural characterisation of non-deamidated acidic variants of Erwinia chrysanthemi L-asparaginase using small-angle X-ray scattering and ion-mobility mass spectrometry. Pharm Res 32(11):3636–3648

    CAS  PubMed  Google Scholar 

  • Gervais D, Downer A, King D et al (2017) Robust quantitation of basic-protein higher-order aggregates using size-exclusion chromatography. J Pharm Biomed Anal 139:215–220

    CAS  PubMed  Google Scholar 

  • Grabowski GA, Golembo M, Shaaltiel Y (2014) Taliglucerase alfa: an enzyme replacement therapy using plant cell expression technology. Mol Genet Metab 112(1):1–8

    CAS  PubMed  Google Scholar 

  • Graham ML (2003) Pegaspargase: a review of clinical studies. Adv Drug Del Rev 55(10):1293–1302

    CAS  Google Scholar 

  • Hage DS, Cazes J (eds) (2005) Handbook of affinity chromatography. CRC Press, Boca Raton

    Google Scholar 

  • Hagel L (2001) Gel-filtration chromatography. Cur Prot Mol Biol 44(1):10.9.1–10.9.2

    Google Scholar 

  • Harmatz PR, Garcia P, Guffon N et al (2014) Galsulfase (Naglazyme®) therapy in infants with mucopolysaccharidosis VI. J Inherit Metab Dis 37(2):277–287

    CAS  PubMed  Google Scholar 

  • Hassan S, Van Dolleweerd CJ, Ioakeimidis F et al (2008) Considerations for extraction of monoclonal antibodies targeted to different subcellular compartments in transgenic tobacco plants. Plant Biotechnol J 6:733–748

    CAS  PubMed  Google Scholar 

  • Heartlein M, Kimura A (2014) Discovery and clinical development of idursulfase (Elaprase®) for the treatment of mucopolysaccharidosis II (Hunter syndrome). Orphan Drugs Rare Dis 38:164

    Google Scholar 

  • Hentz NG (2013) Pharmaceutical bioburden testing. In: Flickinger MC (ed) Encyclopedia of industrial biotechnology. Wiley, New York, pp 757–774. https://doi.org/10.1002/9780470054581.eib655

    Chapter  Google Scholar 

  • Hermans MM, Wisselaar HA, Kroos MA et al (1993) Human lysosomal alpha-glucosidase: functional characterization of the glycosylation sites. Biochem J 289(3):681

    CAS  PubMed  PubMed Central  Google Scholar 

  • Holdgate G, Geschwindner S, Breeze A et al (2013) Biophysical methods in drug discovery from small molecule to pharmaceutical. In: Williams M, Daviter T (eds) Protein-ligand interactions. Methods in molecular biology (methods and protocols) 1008. Humana Press, Totowa

    Google Scholar 

  • Hong P, Koza S, Bouvier ES (2012) A review, size-exclusion chromatography for the analysis of protein biotherapeutics and their aggregates. J Liq Chromatogr Rel Technol 35(20):2923–2950

    CAS  Google Scholar 

  • Houde D, Kauppinen P, Mhatre R et al (2006) Determination of protein oxidation by mass spectrometry and method transfer to quality control. J Chromatogr A 1123(2):189–198

    CAS  PubMed  Google Scholar 

  • Hu B, Sellers J, Kupec J et al (2014) Optimization and validation of DNA extraction and real-time PCR assay for the quantitative measurement of residual host cell DNA in biopharmaceutical products. J Pharm Biomed Anal 88:92–95

    CAS  PubMed  Google Scholar 

  • Hubert C, Houari S, Rozet E et al (2015) Towards a full integration of optimization and validation phases: an analytical-quality-by-design approach. J Chromatogr A 1395:88–98

    CAS  PubMed  Google Scholar 

  • International Conference on Harmonisation (2009) Q8(R2), Pharmaceutical Development

    Google Scholar 

  • Janson JC (ed) (2012) Protein purification: principles, high resolution methods, and applications. Wiley, New York

    Google Scholar 

  • Jin M, Szapiel N, Zhang J et al (2010) Profiling of host cell proteins by two-dimensional difference gel electrophoresis (2D-DIGE): implications for downstream process development. Biotechnol Bioeng 105(2):306–316

    CAS  PubMed  Google Scholar 

  • Kågedal L (2011) Immobilized metal ion affinity chromatography. In: Janson J (ed) Protein purification. Wiley-VCH, New York, pp 183–201

    Google Scholar 

  • Kakkis E (2005) α-L-Iduronidase: the development of Aldurazyme (Laronidase). Dir Ther Enzymes 12:239–260

    Google Scholar 

  • Kennedy RM (1995) Hydrophobic-interaction chromatography. Cur Prot Protein Sci 00(1):8.4.1-8.4.21

    Google Scholar 

  • Kuberkar VT, Davis RH (2001) Microfiltration of protein-cell mixtures with crossflushing or backflushing. J Membr Sci 183(1):1–4

    CAS  Google Scholar 

  • Labrou NE (2003 Jun 25) Design and selection of ligands for affinity chromatography. J Chromatogr B 790(1–2):67–78.

    Google Scholar 

  • Lee SM, Wroble MH, Ross JT (1989) L-asparaginase from Erwinia carotovora. Appl Biochem Biotechnol 22(1):1–1

    CAS  PubMed  Google Scholar 

  • Lee K, Jin X, Zhang K et al (2003) A biochemical and pharmacological comparison of enzyme replacement therapies for the glycolipid storage disorder Fabry disease. Glycobiology 13(4):305–313

    PubMed  Google Scholar 

  • Lee JH, Shin JS, Bae JE (2010) Quantitative detection of residual E. coli host cell DNA by real-time PCR. J Microbiol Biotechnol 20(10):1463–1470

    CAS  PubMed  Google Scholar 

  • Levesley JA, Hoare M (1999) The effect of high frequency backflushing on the microfiltration of yeast homogenate suspensions for the recovery of soluble proteins. J Membr Sci 158(1):29–39

    CAS  Google Scholar 

  • McGettrick AF, Worrall DM (2004) Dye-ligand affinity chromatography. In: Cutler P (ed) Protein purification protocols. Humana Press, Totowa, pp 151–157

    Google Scholar 

  • Middelberg AP (1995) Process-scale disruption of microorganisms. Biotechnol Adv 13(3):491–551

    CAS  PubMed  Google Scholar 

  • Millán JL, Whyte MP (2016) Alkaline phosphatase and hypophosphatasia. Calcif Tissue Int 98(4):398–416

    PubMed  Google Scholar 

  • Millán JL, Narisawa S, Lemire I et al (2008) Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res 23(6):777–787

    PubMed  Google Scholar 

  • Minton NP, Bullman HM, Scawen MD et al (1986) Nucleotide sequence of the Erwinia chrysanthemi NCPPB 1066 L-asparaginase gene. Gene 46(1):25–35

    CAS  PubMed  Google Scholar 

  • Mor TS (2015) Molecular pharming’s foot in the FDA’s door: Protalix’s trailblazing story. Biotechnol Lett 37(11):2147–2150

    CAS  PubMed  PubMed Central  Google Scholar 

  • Noble JE, Knight AE, Reason AJ et al (2007) A comparison of protein quantitation assays for biopharmaceutical applications. Mol Biotechnol 37(2):99–111

    CAS  PubMed  Google Scholar 

  • Parnham CS, Davis RH (1996) Protein recovery from bacterial cell debris using crossflow microfiltration with backpulsing. J Membr Sci 118(2):259–268

    CAS  Google Scholar 

  • Parr MK, Schmidt AH (2018) Life cycle management of analytical methods. J Pharm Biomed Anal 147:506–517

    CAS  PubMed  Google Scholar 

  • Patterson DM, Lee SM (2010) Glucarpidase following high-dose methotrexate: update on development. Expert Opin Biol Ther 10(1):105–111

    CAS  PubMed  Google Scholar 

  • Pettersen EF, Goddard TD, Huang CC et al (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25(13):1605–1612

    CAS  PubMed  Google Scholar 

  • Porath J (1992) Immobilized metal ion affinity chromatography. Protein Expr Purif 3(4):263–281

    CAS  PubMed  Google Scholar 

  • Quirk AV, Woodrow JR (1984) Investigation of the parameters affecting the separation of bacterial enzymes from cell debris by tangential flow filtration. Enz Microb Technol 6(5):201–206

    CAS  Google Scholar 

  • Rauenbusch E, Bauer K, Kaufmann W et al (1970) Isolation and crystallisation of L-asparaginase from E. coli. In: Grundmann E, Oettgen HF (eds) Experimental and clinical effects of L-Asparaginase. Springer, Berlin, pp 31–38

    Google Scholar 

  • Razinkov VI, Treuheit MJ, Becker GW (2013) Methods of high throughput biophysical characterization in biopharmaceutical development. Cur Drug Disc Technol 10(1):59–70

    CAS  Google Scholar 

  • Rodriguez-Diaz R, Wehr T, Zhu M (1997) Capillary isoelectric focusing. Electrophoresis 18(12–13):2134–2144

    CAS  PubMed  Google Scholar 

  • Rustandi RR, Wang Y (2011) Use of CE-SDS gel for characterization of monoclonal antibody hinge region clipping due to copper and high pH stress. Electrophoresis 32(21):3078–3084

    CAS  PubMed  Google Scholar 

  • Salazar O, Asenjo JA (2007) Enzymatic lysis of microbial cells. Biotechnol Lett 29(7):985–994

    CAS  PubMed  Google Scholar 

  • Salzer WL, Asselin BL, Plourde PV et al (2014) Development of asparaginase Erwinia chrysanthemi for the treatment of acute lymphoblastic leukemia. Ann N Y Acad Sci 1329(1):81–92

    CAS  PubMed  Google Scholar 

  • Sanford M, Lo JH (2014) Elosulfase alfa: first global approval. Drugs 74(6):713–718

    CAS  PubMed  Google Scholar 

  • Santos JH, Flores-Santos JC, Meneguetti GP et al (2018) In situ purification of periplasmatic L-asparaginase by aqueous two phase systems with ionic liquids (ILs) as adjuvants. J Chem Technol Biotechnol 93(7):1871–1880

    CAS  Google Scholar 

  • Schenauer MR, Flynn GC, Goetze AM (2012) Identification and quantification of host cell protein impurities in biotherapeutics using mass spectrometry. Anal Biochem 428(2):150–157

    CAS  PubMed  Google Scholar 

  • Scopes RK (2013) Protein purification: principles and practice. Springer, Berlin

    Google Scholar 

  • Shaaltiel Y, Bartfeld D, Hashmueli S et al (2007) Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher’s disease using a plant cell system. Plant Biotechnol J 5(5):579–590

    CAS  PubMed  Google Scholar 

  • Shang TQ, Saati A, Toler KN et al (2014) Development and application of a robust N-glycan profiling method for heightened characterization of monoclonal antibodies and related glycoproteins. J Pharm Sci 103(7):1967–1978

    CAS  PubMed  Google Scholar 

  • Shukla AA, Jiang C, Ma J et al (2008) Demonstration of robust host cell protein clearance in biopharmaceutical downstream processes. Biotechnol Prog 24(3):615–622

    CAS  PubMed  Google Scholar 

  • Su K, Donaldson E, Sharma R (2016) Novel treatment options for lysosomal acid lipase deficiency: critical appraisal of sebelipase alfa. Appl Clin Genet 9:157

    CAS  PubMed  PubMed Central  Google Scholar 

  • Taverniers I, De Loose M, Van Bockstaele E (2004) Trends in quality in the analytical laboratory. II. Analytical method validation and quality assurance. Trends Anal Chem 23(8):535–552

    CAS  Google Scholar 

  • Tekoah Y, Tzaban S, Kizhner T et al (2013) Glycosylation and functionality of recombinant β-glucocerebrosidase from various production systems. Biosci Rep 33(5):e00071

    PubMed  PubMed Central  Google Scholar 

  • Tekoah Y, Shulman A, Kizhner T et al (2015) Large-scale production of pharmaceutical proteins in plant cell culture—the protalix experience. Plant Biotechnol J 13(8):1199–1208

    CAS  PubMed  Google Scholar 

  • Tobin JJ, Walsh G (2008) Good manufacturing practice. In: Tobin JJ, Walsh G (eds) Medical product regulatory affairs: pharmaceuticals, diagnostics, medical devices. Wiley, New York, pp 209–235

    Google Scholar 

  • Torosantucci R, Schöneich C, Jiskoot W (2014) Oxidation of therapeutic proteins and peptides: structural and biological consequences. Pharm Res 31(3):541–553

    CAS  PubMed  Google Scholar 

  • Tscheliessnig AL, Konrath J, Bates R et al (2013) Host cell protein analysis in therapeutic protein bioprocessing–methods and applications. Biotechnol J 8(6):655–670

    CAS  PubMed  Google Scholar 

  • Valera CR, Chen JW, Xu Y (2003) Application of multivirus spike approach for viral clearance evaluation. Biotechnol Bioeng 84(6):714–722

    CAS  PubMed  Google Scholar 

  • Van Reis R, Zydney A (2001) Membrane separations in biotechnology. Curr Opin Biotechnol 12(2):208–211

    PubMed  Google Scholar 

  • van Tricht E, Geurink L, Pajic B et al (2015) New capillary gel electrophoresis method for fast and accurate identification and quantification of multiple viral proteins in influenza vaccines. Talanta 144:1030–1035

    PubMed  Google Scholar 

  • Voisard D, Meuwly F, Ruffieux PA et al (2003) Potential of cell retention techniques for large-scale high-density perfusion culture of suspended mammalian cells. Biotechnol Bioeng 82(7):751–765

    CAS  PubMed  Google Scholar 

  • Wade HE (1972) Extraction of asparaginase from bacterial culture. US Patent 3,660,238. 2 May 1972

    Google Scholar 

  • Wagener JS, Kupfer O (2012) Dornase alfa (Pulmozyme). Curr Opin Pulm Med 18(6):609–614

    PubMed  Google Scholar 

  • Wang X, Hunter AK, Mozier NM (2009) Host cell proteins in biologics development: identification, quantitation and risk assessment. Biotechnol Bioeng 103(3):446–458

    CAS  PubMed  Google Scholar 

  • Wang X, Morgan DM, Wang G et al (2012) Residual DNA analysis in biologics development: review of measurement and quantitation technologies and future directions. Biotechnol Bioeng 109(2):307–317

    CAS  PubMed  Google Scholar 

  • Wei Z, Tous G, Yim A et al (2005) Validation of peptide mapping with electrospray mass spectrometry for recombinant proteins of biopharmaceutical interest and its applications as an identity test and a characterization tool. Dev Biol 122:29–47

    CAS  Google Scholar 

  • Wilken LR, Nikolov ZL (2012) Recovery and purification of plant-made recombinant proteins. Biotechnol Adv 30(2):419–433

    CAS  PubMed  Google Scholar 

  • World Health Organisation (2013) Guidelines on the quality, safety and efficacy of biotherapeutic protein products prepared by recombinant DNA technology. Geneva

    Google Scholar 

  • Yang H (2013) Establishing acceptable limits of residual DNA. PDA J Pharm Sci Technol 67(2):155–163

    CAS  PubMed  Google Scholar 

  • Yang J, Wang S, Liu J et al (2007) Determination of tryptophan oxidation of monoclonal antibody by reversed phase high performance liquid chromatography. J Chromatogr A 1156(1–2):174–182

    CAS  PubMed  Google Scholar 

  • Yao H, Vancoillie J, D’Hondt M et al (2016) An analytical quality by design (QbD) approach for a l-asparaginase activity method. J Pharm Biomed Anal 117:232–239

    CAS  PubMed  Google Scholar 

  • Yao H, Vandenbossche J, Sänger-van de Griend CE et al (2018) Development of a capillary zone electrophoresis method to quantify E. coli l-asparaginase and its acidic variants. Talanta 182:83–91

    CAS  PubMed  Google Scholar 

  • Yu LX, Amidon G, Khan MA et al (2014) Understanding pharmaceutical quality by design. AAPS J 16(4):771–783

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Chou CP, Moo-Young M (2011) Disulfide bond formation and its impact on the biological activity and stability of recombinant therapeutic proteins produced by Escherichia coli expression system. Biotechnol Adv 29(6):923–929

    CAS  PubMed  Google Scholar 

  • Zhu-Shimoni J, Yu C, Nishihara J et al (2014) Host cell protein testing by ELISAs and the use of orthogonal methods. Biotechnol Bioeng 111(12):2367–2379

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Porton Biopharma Limited, Salisbury, Wiltshire, UK

    David Gervais

Authors
  1. David Gervais
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Gervais .

Editor information

Editors and Affiliations

  1. Department of Biotechnology, Agricultural University of Athens, Athens, Greece

    Nikolaos Labrou

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gervais, D. (2019). Quality Control and Downstream Processing of Therapeutic Enzymes. In: Labrou, N. (eds) Therapeutic Enzymes: Function and Clinical Implications. Advances in Experimental Medicine and Biology, vol 1148. Springer, Singapore. https://doi.org/10.1007/978-981-13-7709-9_3

Download citation

Publish with us

Policies and ethics

Search

Navigation