Bio Products Laboratory (United Kingdom)

Background: Inadequate production of immunoglobulin G (IgG) antibodies renders patients with primary immunodeficiency susceptible to infection by numerous pathogens, some of which can lead to severe asthma exacerbation and possible death. These patients who are immunocompromised are often reliant on intravenous immunoglobulin (IVIG) therapies, which provide passive antibodies against various respiratory pathogens, including measles virus and encapsulated bacteria. Objective: We conducted a subanalysis of data from a multicenter, multinational, phase III, open-label bioequivalence study to compare protective concentrations of IgG antibodies provided by a 5% and a 10% IVIG product in patients with primary immunodeficiency. Methods: Patients on stable 21- or 28-day regimens of previous IVIG products were assigned to receive study treatment (adults: 5% IVIG and 10% IVIG; children: 10% IVIG) at doses of 300-800 mg/kg per infusion. Trough concentrations of total IgG, IgG subclasses, measles-neutralizing antibodies, and IgG against Haemophilus influenzae type b and Streptococcus pneumoniae serotypes were evaluated. Results: A total of 48 patients (33 adults ages 16-55 years; 15 children ages 2-15 years) were enrolled and received treatment. No statistically significant differences in trough concentrations of total IgG, IgG subclasses, measles-neutralizing antibodies, or IgG directed at encapsulated bacteria were observed between the 5% and 10% formulations in analyses by age (adult or pediatric) or infusion schedule (every 21 or 28 days). All evaluated patients had trough IgG concentrations above accepted thresholds for protection against disease. Conclusion: These findings support the conclusion that, at dose levels and infusion schedules prescribed in clinical practice, this 5% and 10% IVIG product provided consistent, predictable, and bioequivalent IgG concentrations for adult and pediatric patients with primary immunodeficiency disease. Both formulations delivered trough antibody concentrations of total IgG, measles-neutralizing antibodies, and antibodies against encapsulated bacteria that are above thresholds accepted as protective.Clinical trial NCT01963143, <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">www.clinicaltrials.gov</ext-link>.

Hereditary factor X deficiency is a rare bleeding disorder, with limited treatment options. This paper describes the approach to pre-clinical development and characterization of a high-purity plasma-derived factor X concentrate, to achieve orphan drug marketing authorization for the treatment of hereditary factor X deficiency. A chromatographic process was developed, to purify factor X from human plasma for fractionation. The product was characterized using in vitro, in vivo and ex vivo tests for potency, purity, thrombogenicity, immunogenicity, toxicity and stability. The production process complied with good pharmaceutical manufacturing practice. It achieved 6000-fold purification and 100-fold concentration of the factor X protein compared to human plasma. The factor X protein was 94%-96% pure. Other residual plasma proteins were well below levels in plasma, minimizing potential interference in hemostasis after therapeutic administration. Effective virus-reduction during manufacture, and the absence of thrombogenicity, toxicity and immunogenic potential were confirmed, addressing the main safety concerns historically associated with plasma-derived therapeutics. The freeze-dried product remained stable between +2°C and +30°C for at least three years. After reconstitution with water for injections, the factor X activity was maintained for at least 48h at +18°C to +22°C. Targeted pre-clinical development of the first highly-purified concentrate to treat hereditary factor X deficiency is described. Following international guidelines for nonclinical safety testing, particular strategies were adopted for unmodified products derived from human blood plasma. This approach may also be relevant to the development of other ultra-orphan medicinal products.

Is anaerobic environmental monitoring necessary? For obligate anaerobes the case for doing so is low. For facultative anaerobes, where aseptically filled parenteral products are involved, the case is far higher. Any such consideration should be based on a quality risk assessment taking into account the interactions between people and exposed product or product components and the opportunity for particle deposition. In many cases, the risk will not be known unless selective environmental monitoring has been performed given the slow growth rate of organisms like Cutibacterium acnes and the preferential growth obtained using an anaerobic atmosphere and a blood-based culture medium. The argument of this paper is not so much with whether anaerobic monitoring is necessary for aseptically filled products, but with how often should this be performed?

The COVID-19 pandemic changed home infusion nursing dramatically by increasing demand for home infusion nurses while decreasing their availability. Home infusion of intravenous immunoglobulin (IVIg) is an option for treatment of numerous conditions and requires considerable infusion time. Use of a higher-concentration IVIg product and shorter escalation increments may decrease required infusion time. The authors conducted a retrospective database analysis that identified 23 patients receiving IVIg before transitioning to a 10% IVIg product with a 15-minute rate escalation protocol (Gammaplex 10% IVIg) and evaluated the total infusion time before and after the transition. Among the 23 who received IVIg, the mean ± SD IVIg dose per dosing cycle before transitioning was 1.2 ± 0.7 g/kg given in 1 to 5 infusions per cycle. The mean ± SD time per infusion was 2.8 ± 0.8 hours before the transition and 2.6 ± 0.7 hours per infusion after the transition. The infusion time decreased after transition in 13 patients (56.5%), did not change in 5 patients (21.7%), and increased in 5 patients (21.7%). Nurse education on IVIg rate escalation may facilitate faster achievement of the maximum safe infusion rate and reduce infusion times. A trial transition to this 10% IVIg product with a 15-minute rate escalation protocol may also reduce infusion times.

The microbiological impurities are the most critical ones in a water system and are thus of special concern. In case of contamination of a purification unit or a distribution system, the user must react quickly. The authors have written down their experience and explain details about the typical microbiome of a water system. In addition, advice is given on how to remediate microbial contamination.