Stability of IgG1 Monoclonal Antibodies in Intravenous Infusion Bags Under Clinical In-Use Conditions

Sreedhara, Alavattam; Glover, Zephania Kwong; Piros, Nicole; Xiao, Nina; Patel, Ankit R.; Kabakoff, Bruce

doi:10.1002/jps.22739

Cited by 79 publications

(60 citation statements)

References 15 publications

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“…2 For this reason, in-use stability studies must be conducted prior to administration of drug in a clinical setting to assess the stability of the diluted product, the compatibility of the product or dosing solution to clinically-relevant materials of construction, and the recovery and quality of active compound when prepared using the intended method for dose preparation and administration. [13][14][15][16][17] Otelixizumab drug product was formulated at a concentration of 0.2 mg/mL in a histidine-based buffer. Based on in-house experience and literature reports, an apparent administration risk, i.e., underdosing, was identified.…”

Section: Discussionmentioning

confidence: 99%

“…In-use stability studies for clinical trials, also referred to as compatibility, practical stability, or post-dilution studies, are critical studies conducted as a means to confirm maintenance of protein quality and quantity, thus ensuring that handling results in a diluted product that is both safe and efficacious. [12][13][14][15][16][17] Of particular importance to the clinic is confirmation that the subjects consistently receive the desired dose (i.e., no underdose or variable dose).…”

Section: Introductionmentioning

confidence: 99%

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Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

Morar-Mitrica

Puri

Sassi

et al. 2015

mAbs

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The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

Morar-Mitrica

Puri

Sassi

et al. 2015

mAbs

View full text Add to dashboard Cite

show abstract

“…In most cases the admixtures are prepared at the dosing site but there may be a requirement of transportation of the admixture containers from one site to another (Kupfer et al 2009 ;Sreedhara et al 2011 ). Sreedhara et al ( 2011 ) showed that severe instabilities were caused by subjecting an IgG1 monoclonal antibody admixture in normal saline. Even though each protein is unique, however, in general the agitation of admixtures should be avoided as much as possible.…”

Section: Other Challengesmentioning

confidence: 98%

Intravenous Admixture Compatibility for Sterile Products: Challenges and Regulatory Guidance

Sharma

Cheung

Dabbara

et al. 2013

Sterile Product Development

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Intravenous (IV) administration of many sterile drug products requires admixture preparation using a diluent, brief storage in an IV container, and dosing through an infusion device. To ensure patient safety and drug effi cacy, regulatory agencies require that the sterile drug product is compatible with the diluents and the infusion devices. Therefore, admixture compatibility and stability studies are key components of the pharmaceutical development process. On the surface these studies may seem straightforward, but in practice they require detailed planning, meticulous execution, and appropriate data analysis. The purpose of this chapter is to discuss various requirements and challenges associated with conducting IV admixture studies and the related regulatory guidance. IntroductionIntravenous (IV) administration of many sterile drug products requires admixture preparation using a diluent prior to administration. A pharmaceutical admixture consists of a drug product mixed with an appropriate diluent in a suitable dosing/ delivery device for the purpose of parenteral infusion to the patient. Regulatory agencies, as a part of registration requirements, have listed specifi c requirements for the demonstration of the compatibility of the drug product with the diluents and with the infusion devices. For example, as per ICH Q8 guideline, the compatibility of the drug product with reconstitution diluents should cover the recommended in-use shelf life, at the recommended storage temperature and at the likely extremes of concentration (ICH 2009 ). Similarly, guidance for industry from the U.S.

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“…It was also shown that PVC IV bags caused more particle formation than the PO bags. Sreedhara et al discussed the need for clinical in-use studies of IV bag preparations (Sreedhara et al, 2012). The pharmacist has the responsibility to ensure product stability in the final administered form and the setting of a "beyond-use" date based on the United States Pharmacopeia 797 where the "beyond-use" date is defined as the time the compounded sterile preparation must be used to avoid loss of potency, contamination, and safety risks.…”

Section: Mab Aggregation and Particulate Formation During IV Administmentioning

confidence: 99%

“…b % difference = [(x 1 − x 2 )/(x 1 + x 2 )/2] × 100 where x 1 and x 2 are measurements from each bag. Reproduced fromSreedhara et al (2012).…”

mentioning

confidence: 98%

Challenges in the intravenous (IV) administration of monoclonal antibodies (mAbs)

Shire¹

2015

Monoclonal Antibodies

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Stability of IgG1 Monoclonal Antibodies in Intravenous Infusion Bags Under Clinical In-Use Conditions

Cited by 79 publications

References 15 publications

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

Intravenous Admixture Compatibility for Sterile Products: Challenges and Regulatory Guidance

Challenges in the intravenous (IV) administration of monoclonal antibodies (mAbs)

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