Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite.

Since late 2019, concerns regarding trace levels of the probable human carcinogen N-dimethylnitrosamine (NDMA) in Metformin-containing pharmaceuticals have been an issue if they exceeded the maximum allowable intake of 96 ng/day for a medicine with long-term intake. Here, we report results from an extensive analysis of NDMA content along the active pharmaceutical ingredient (API) manufacturing process as well as two different drug product manufacturing processes. Our findings confirm that Metformin API is not a significant source of NDMA found in Metformin pharmaceuticals and that NDMA is created at those steps of the drug product manufacturing that introduce heat and nitrite. We demonstrate that reduction of nitrite from excipients is an effective means to reduce NDMA in the drug product. Limiting residual dimethylamine in the API has proven to be another important factor for NDMA control as dimethylamine leads to formation of NDMA in the drug products. Furthermore, analysis of historical batches of drug products has shown that NDMA may increase during storage, but the levels reached were not shelf-life limiting for the products under study.

NDMA analytics in metformin products: Comparison of methods and pitfalls.

BACKGROUND: For nearly three years, the concerns regarding trace levels of N-nitrosamines in pharmaceuticals and the associated cancer risk have significantly expanded and are a major issue facing the global pharmaceutical industry. N-nitrosodimethylamine (NDMA) found in formulations of the popular anti-diabetic drug metformin is a prominent example. This has resulted in product recalls raising the profile within the media. Issues of method robustness, sample preparation and several unexpected sources of nitrosamine contamination have been highlighted as false positive risks. It has become apparent that the identification of the root causes of artefactual formation of nitrosamines must be identified to mitigate risk associated with the analysis. METHODS: A comparison study between four laboratories, across three companies was designed, employing orthogonal mass spectrometric methods for the quantification of NDMA in two metformin immediate release (IR) formulations and one extended release (XR) formulation. These were 2x LC-MS/MS, GC-MS/MS and GC-HRMS. RESULTS: Good agreement of results was obtained for the IR formulations. However, we measured higher concentrations of NDMA in the XR formulation using GC-MS/MS compared to LC-MS/MS. We could show that this was due to artefactual (in situ) formation of NDMA when samples were extracted with dichloromethane. Removal of dimethylamine (DMA) and nitrite from the extracted sample or the addition of a nitrosation scavenger are shown to be effective remedies. NDMA in situ formation was not observed in 10% MeOH or acetonitrile. CONCLUSION: Metformin pharmaceuticals contain traces of the API impurity DMA as well as inorganic nitrite from excipients. This can lead to artefactual formation of NDMA and hence false positive results if DCM is used for sample extraction. Similar artefacts are likely also in other pharmaceuticals if these contain the secondary amine precursor of the respective nitrosamine analyte.

Comparison of Malated Ringer's with Two Other Balanced Crystalloid Solutions in Resuscitation of Both Severe and Moderate Hemorrhagic Shock in Rats.

In preclinical treatment of polytraumatized patients crystalloids are preferentially used. To avoid metabolic acidosis, metabolizable anions like lactate or acetate are used to replace chloride in these solutions. We here studied the effects of malated Ringer's in resuscitation of both shock severities in comparison to lactated and acetated Ringer's. Male Wistar rats underwent severe (mean arterial blood pressure (MAP) of 25-30 mmHg) or moderate (MAP 40-45 mmHg) hemorrhagic shock. Adjacent to the shock period animals were resuscitated with acetated (AR), lactated (LR), or malated Ringer's (MR) and observed for 150 min. MR improved survival compared with LR and AR in severe hemorrhagic shock whereas it was equally effective to LR and superior to AR in moderate hemorrhagic shock. In all other parameters tested, MR was also effective similar to the other solutions under these conditions. We conclude that MR is preferable to AR and LR in resuscitation of hemorrhagic shock independent of shock depth. The positive effects of MR may stem from the absence of any adverse impact on energy metabolism under both conditions.

Prehospital volume therapy as an independent risk factor after trauma.

BACKGROUND: Prehospital volume therapy remains widely used after trauma, while evidence regarding its disadvantages is growing. The primary objective of this study was to investigate the volume administered in a prehospital setting as an independent risk factor for mortality. MATERIAL AND METHODS: Patients who met the following criteria were analyzed retrospectively: Injury Severity Score=16, primary admission (between 2002 and 2010), and age=16 years. The following data had to be available: volume administered (including packed red cells), blood pressure, Glasgow Coma Scale, therapeutic measures, and laboratory results. Following a univariate analysis, independent risk factors for mortality after trauma were investigated using a multivariate regression analysis. RESULTS: A collective of 7,641 patients met the inclusion criteria, showing that increasing volumes administered in a prehospital setting were an independent risk factor for mortality (odds ratio: 1.34). This tendency was even more pronounced in patients without severe traumatic brain injury (TBI) (odds ratio: 2.71), while the opposite tendency was observed in patients with TBI. CONCLUSIONS: Prehospital volume therapy in patients without severe TBI represents an independent risk factor for mortality. In such cases, respiratory and circulatory conditions should be stabilized during permissive hypotension, and patient transfer should not be delayed.

Mortality in severely injured children: experiences of a German level 1 trauma center (2002 - 2011).

BACKGROUND: Trauma in pediatric patients is a major cause of death. This study investigated differences between decedents and survivors. Furthermore, an analysis of preventable and potential preventable trauma deaths was conducted and errors in the acute trauma care were investigated. METHODS: All patients aged less than 16 years with an Injury Severity Score (ISS) ≥ 16 upon primary admission to the hospital between July 2002 and December 2011 were included in this study. Decedents were compared with survivors and an analysis of deceased children for preventable and potential preventable deaths was conducted. The acute trauma care was investigated regarding errors in treatment. RESULTS: Significant differences were found in Glasgow Coma Scale, Injury Severity Score, Revised Trauma Score, New ISS, Revised Injury Severity Classification, and Trauma and Injury Severity Score. Decedents had a worse head trauma with associated coagulopathy. The overall mortality rate was 13.4%. The majority of death occurred soon after arrival. No long term intensive care unit stay was found.No preventable but one potential preventable death was analyzed. Most errors occurred in fluid volume management and in a delay of starting the therapy for hemorrhage and coagulopathy.Prolonged preclinical rescue time and surgery time within the first 24 hours was found. CONCLUSIONS: Head trauma is the determinant factor for mortality in severely injured pediatric patients. Death occurred shortly after arrival and long term intensive care stays might be an exception. In treatment of severely injured children volume management, hemorrhage and coagulopathy management, rescue time, and total surgery time should receive more attention.

Gender-specific differences in severely injured patients between 2002 and 2011: data analysis with matched-pair analysis.

INTRODUCTION: Previous studies reported divergent results concerning the effect of gender on patient outcome after severe injury. Results suggest that women have better outcomes because they have lower rates of sepsis and multi-organ failure. The objective of this analysis was to study gender differences in a Level 1 trauma center in Germany. METHODS: Patients who were admitted to hospital between 2002 and 2011 with an Injury Severity Score (ISS) ≥16 were included. Data were collected from the Trauma Registry of the German Society for Trauma Surgery and from hospital records. The effects of gender on a variety of parameters were investigated. To eliminate the influence of differences in ISS, an analysis of groups with similar ISS was performed. Also, a matched-pair analysis of 422 patients was performed. RESULTS: A total of 962 patients met the inclusion criteria. The mortality rate was lower in male patients (25.4% versus 36.59%). Female patients had more severe head injuries, received less fluid volume and had a lower rate of sepsis. Men were more frequently involved in motorcycle accidents and sustained more penetrating trauma. Women were more frequently involved in pedestrian accidents and sustained more falls from under 3 m. The effects of gender were reduced when the data were analyzed by matching ISS. The mortality rate was significantly different in the ISS 26 to 35 group but in mostly all groups, the mortality rate was higher in women. In the matched-pair analysis, the rate of sepsis and the length of the ICU stay were significantly lower in women and the mortality rate showed no significant difference (28.1% for male patients versus 33.01% for female patients). Women died after an average of 5.22 days, and men died after an average of 9.02 days. CONCLUSIONS: Gender-based differences in patient outcome after severe trauma were observed in this study. Women are more likely to die in the first days after trauma. Upon extended hospital stay, women had a better survival rate because they had a lower rate of sepsis. No significant differences in mortality rate could be found, but there was a trend towards a higher rate in female patients.