Bio Products Laboratory

BackgroundIntravenous immunoglobulin is a replacement therapy for patients living with primary immunodeficiencies. Each batch of intravenous immunoglobulin is required by the Food and Drug Administration to contain threshold levels of measles neutralising antibodies. Widespread use of the measles vaccine has decreased measles antibody potency in the United States plasma supply. There is limited data on measles antibody trough levels in treated primary immunodeficiency patients. The aim of this sub-analysis was to evaluate the measles antibody trough levels in treated primary immunodeficiency patients.MethodsGMX07 was an open-label, two-period, crossover bioequivalence study which randomized 33 adult patients with primary immunodeficiency disease in 16 centres across the United States, the United Kingdom and Hungary. Eligible adult patients received five infusions of Gammaplex® 5% followed by five infusions of Gammaplex® 10%, or vice versa, on either a 21- or 28-day dosing regimen. The trial included 15 paediatric patients who were not randomized, receiving only five infusions of 10% product. This sub-analysis measured trough levels of measles neutralising antibodies using a Vero cell-based measles virus neutralisation assay.ResultsMedian measles antibody trough levels were ~ 1300 mIU/mL with no significant difference between Gammaplex 5% and Gammaplex 10% treatment (p > 0.9) or the 21-day or 28-day dosing regimen (p > 0.3). There was also no difference between mean measles neutralising antibody levels following Gammaplex 10% in adult or paediatric patients.ConclusionsLevels of measles neutralising antibodies in the 5% and 10% formulations of this intravenous immunoglobulin product provided protective antibodies well above accepted thresholds and were similar in adult and paediatric patients across both 21-day and 28-day dosing regimens. Switching between Gammaplex products did not affect antibody levels.Trial registrationClinicalTrials.gov NCT01963143.

During subarachnoid haemorrhage, a blood clot forms in the subarachnoid space releasing extracellular haemoglobin (Hb), which causes oxidative damage and cell death in surrounding tissues. High rates of disability and cognitive decline in SAH survivors are attributed to loss of neurons and functional connections during secondary brain injury. Haptoglobin sequesters Hb for clearance, but this scavenging system is overwhelmed after a haemorrhage. Whilst exogenous haptoglobin application can attenuate cytotoxicity of Hb in vitro and in vivo, the functional effects of sub-lethal Hb concentrations on surviving neurons and whether cellular function can be protected with haptoglobin treatment remain unclear. Here we use cultured neurons to investigate neuronal health and function across a range of Hb concentrations to establish the thresholds for cellular damage and investigate synaptic function. Hb impairs ATP concentrations and cytoskeletal structure. At clinically relevant but sub-lethal Hb concentrations, we find that synaptic AMPAR-driven currents are reduced, accompanied by a reduction in GluA1 subunit expression. Haptoglobin co-application can prevent these deficits by scavenging free Hb to reduce it to sub-threshold concentrations and does not need to be present at stoichiometric amounts to achieve efficacy. Haptoglobin itself does not impair measures of neuronal health and function at any concentration tested. Our data highlight a role for Hb in modifying synaptic function in surviving neurons, which may link to impaired cognition or plasticity after SAH and support the development of haptoglobin as a therapy for subarachnoid haemorrhage.

For aseptically filled products, as well as for many terminally filled products, the sterility test is a mandatory product release test. It is, however, statistically poor at detecting anything other than gross contamination (this limitation has been addressed in a number of studies (1)). This limitation relates to the few numbers of articles tested (2). For batches in excess of 500 filled containers, the pharmacopeia only require that twenty samples are included in the sterility test set. This sample size appears to have been set arbitrarily, and it does not provide a statistically significant population with which to estimate sterility (3). Although it is unclear how this sample size was derived, the number is grounded, in part, through the sterility test being a destructive test (each article tested via the sterility test is not available for the patient) and therefore to maximise the availability of the batch by using as few units as possible. It remains, nonetheless, that the sample size of 20 provides no confidence that the sterility of a batch of pharmaceutical items has not been compromised. In relation to sampling, limitations not only apply to the low number of samples tested but also to the difficulties in selecting a sample representative of all significant events during batch filling (4). This is important because contamination is unlikely to be uniformly distributed throughout the batch and thus random sampling cannot detect contamination with absolute certainty. This is of particular importance with aseptic filling where batch specific events can occur. It is possible that certain events can be captured, such as interventions into the aseptic core, where the vials exposed at the time of the activity can be incorporated into the sterility test set (notwithstanding that all events cannot be captured in this way).

modified Hemophilia Well-being Index (HWBI) and the Menorrhagia Impact Questionnaire (MIQ).The SF-12 is used to assess overall QoL.Sub-group analysis of patients who have experienced heavy menstrual bleeding was conducted and descriptive results are presented.

There are different elements that contribute to good aseptic technique within the cleanroom and the laboratory. One such element is the donning of gloves (1), handling items appropriately, and keeping gloves regularly disinfected (2). Glove disinfection is an essential step for bacteriological control, although how successful control is maintained is dependent upon the type of disinfectant (these are generally alcohols for gloved hands) (3), frequency of application, volume of disinfectant, application technique and the contact time. Other variables include purchasing gloves of a suitable material and design, and appropriate training. Aa an added control with more critical areas, the gloves are pre sterilised before donning (often purchased sterile by radiation or ethylene oxide). As with other types of disinfection, the aim is not ‘sterilisation’ but to bring any bacterial density present on the gloves down to a level that is as low as possible (what is sometimes referred to as the "irreducible minimum") (4). Assessment, when required, is commonly through the use of agar contact plates onto the fingertips of each gloved hand (four fingers and the thumb) to create the ‘finger plate’ or ‘finger dab’. To avoid false negatives, the agar needs to be formulated with an appropriate disinfectant neutraliser. For cleanroom and laboratory managers seeking to maximise the maintenance of asepsis, glove control is an important element. This should take the form of a good practice schema and for this to be transitioned into a training module, supported by regular prompts in practice. In terms of what such a schema should look like, this article appraises the research that underpins an appropriate glove ‘sanitisation’ schema. This includes the central concerns of when and how effective glove disinfection is to be achieved (5). The key findings are that a 30 second disinfection time is suitable for both cleanroom and laboratory operations, provided a suitable technique is deployed and an alcohol-based disinfectant used. However, controls need to be in place to avoid the over disinfection of gloves since repeated applications increase the likelihood of microperforations occurring and thereby effective glove disinfection needs to be supported by a regular glove change procedure.