PAT-based batch statistical process control of a manufacturing process for a pharmaceutical ointment.

In this study, a process analytical technology (PAT)-based batch statistical process control (BSPC) model was developed for the laboratory-scale manufacturing process of a commercially available pharmaceutical ointment. The multivariate BSPC model was developed based on the in-line measured viscosity (viscometer), product temperature (viscometer), particle size distribution (PSD) (focused beam reflectance measurement (FBRM)) and active pharmaceutical ingredient (API) concentration (Raman spectroscopy) of four reference batches using a partial least squares (PLS) approach. From this in-line collected data, the characteristic trajectory of the batch process under normal operating conditions was acquired. To assess the capability of the process analyzers and BSPC model to detect deviations from the expected batch trajectory, two test batches with induced process and formulation disturbances were monitored in-line. The elevated process temperature in test batch 1 resulted in a deviating viscosity, product temperature and number of small particles (<100 µm). After correcting the process temperature, the viscosity and product temperature were within the control interval, while the particle size was smaller compared to the reference batches. For test batch 2, API was added at three different time points, whereas the same amount of API was added in one step during manufacturing of the reference batches. The induced disturbance was reflected in the in-line measured viscosity, PSD and API concentration. The combination of process analyzers and multivariate batch modelling enabled early fault detection and real-time process adjustments, thereby preventing batch loss or reprocessing. In addition, the feasibility of the investigated process analyzers to measure certain quality attributes in-line during manufacturing of an ointment was demonstrated.

Continuous manufacturing of a pharmaceutical cream: Investigating continuous powder dispersing and residence time distribution (RTD).

Recently, an innovative continuous manufacturing technology for a pharmaceutical oral suspension was proposed, based on two consecutive mixing units. A limitation of this technology is the need to dissolve or disperse powder-based raw materials in a liquid via a batch step before continuous manufacturing. Therefore, the aim of the current study was to develop and investigate a method to introduce powders continuously into the existing equipment via the implementation of two upstream continuous unit operations: a powder feeder and powder dispersing unit. A pharmaceutical cream was selected as model formulation to demonstrate the flexibility of the continuous manufacturing technology towards different types of semi-solid and liquid formulations. The ability to continuously feed and disperse active pharmaceutical ingredient (API) using the proposed method was assessed via an experimental design, in which the impact of several process parameters of the powder dispersing unit on the API concentration (relative error (RE) and relative standard deviation (RSD)) was examined. A Raman spectroscopic method was developed to quantify the API concentration in-line after the powder dispersing step. The API concentration was independent of the process parameters and fell within the acceptance limits, except for two experimental runs where a deviating API concentration was observed. These results demonstrate that the continuous powder feeding and dispersing method was suitable, and that a completely continuous manufacturing system was obtained. To achieve raw material traceability and understanding the mixing behavior, the residence time distribution (RTD) of a tracer inside the continuous manufacturing equipment was determined using a colorimetric technique. The time required to remove all tracer from the powder dispersing unit operation was very long (1481 s) and therefore the volume inside this unit operation should be reduced by designing new equipment with smaller dimensions. At the two consecutive mixing units, the peak and mean residence time were influenced by throughput, whereas mixing speed in both mixing units had a significant impact on the degree of axial mixing. Finally, the continuously manufactured cream had a similar rheological behavior as the original batch-wise manufactured cream.

A multivariate approach to predict the volumetric and gravimetric feeding behavior of a low feed rate feeder based on raw material properties.

In this study, the volumetric and gravimetric feeding behavior of 15 pharmaceutical powders on a low feed rate feeder was correlated with their material properties through a multivariate approach. The powders under investigation differ substantially in terms of material properties, making the selected powders representative for powders typically used in pharmaceutical manufacturing. The material properties were described by 25 material property descriptors, obtained from a rational selection of critical characterization techniques that provided maximal information with minimal characterization effort. From volumetric feeding experiments (i.e., powder feed rate not controlled), the maximum feeding capacity (maximum feed factor (FFmax)) and optimal hopper fill level at which the feeder should be refilled during gravimetric feeding (feed factor decay (FFdecay)) were obtained. During gravimetric feeding experiments (i.e., powder feed rate controlled), the variability on the feed rate (relative standard deviation (RSD)) and the difference between the setpoint and mean feed rate (relative error (RE)) were determined. Partial least squares (PLS) regression was applied to correlate the volumetric and gravimetric feeding responses (Y) with the material property descriptors (X). The predictive ability of the developed PLS models was assessed by predicting the feeding responses of two new powders (i.e., validation set). Overall, the volumetric feeding responses (FFmax and FFdecay) were predicted better than the gravimetric feeding responses (RSD and RE), since in gravimetric mode the impact of material properties on the feeding behavior is reduced due to the control system of the feeder. Especially RE was weakly correlated with material properties as RE of most powders varied around zero with only a small numerical variation. Interestingly, this confirms that the control system is working properly and that the feeder is capable of feeding different powders accurately at low feed rates. The developed models allowed to predict the feeding behavior of new powders based on their material properties. Consequently the number of feeding experiments during process development can be greatly reduced, thereby leading to a more efficient and faster development of new drug products.

A continuous manufacturing concept for a pharmaceutical oral suspension.

The aim of this study was to investigate the applicability of an innovative continuous manufacturing system for semi-solid and liquid pharmaceutical formulations. A commercially available pharmaceutical oral suspension was selected as model formulation. Premixes of the raw materials were dosed via peristaltic pumps to the mixing compartment, which consists of two consecutive mixing units. An experimental design was used to study the influence of several process parameters (throughput, mixing speed in mixing unit 1 and mixing speed in mixing unit 2) on the quality attributes of the oral suspension. The pH, density, active pharmaceutical ingredient (API) concentration, sedimentation after 30 days (expressed by the sedimentation volume) and rheological characteristic (yield stress) of the suspension were determined. No significant influence of the process parameters on the pH, density and API concentration was observed. The throughput and mixing speed in mixing unit 1 had a significant impact on both the sedimentation volume and yield stress, and were therefore critical to acquire physical stable suspensions. Furthermore, the yield stress measured one day after production was predictive for the occurrence of sedimentation in the suspensions after 30 days. When selecting the optimal process settings, the continuously manufactured suspension had a similar product quality as the original batch-processed suspension and even possessed a higher yield stress. This study demonstrated that the investigated innovative continuous manufacturing technology is suitable for the manufacturing of a commercially available pharmaceutical suspension and that the product quality can be optimized by adjusting the process parameters.

Pain threshold in patients with rheumatoid arthritis and effect of manual oscillations.

Using a pressure algometer pain threshold (PT) measurements were carried out in the paraspinal area as well as at the knee and ankle joints in 30 adults with active rheumatoid arthritis (RA) and in 30 healthy adults. The group of RA patients was then randomly divided in two. In 15 RA patients a manual oscillation technique was applied at T12 and L4 for 12 minutes. The 15 other patients were resting. Immediately after the experimental procedure the PT was measured again at the same points in all patients. The RA patients showed a significantly (p < 0.05) lower PT than the healthy adults at all investigated points, which suggests that in RA certain changes arise in the peripheral and central nociceptive processing system, as mentioned in the literature. In the second measurement session for the RA patients the PT was significantly higher (p<0.05) after manual oscillations than after rest, at the paraspinal area of T6, L1 and L3. Further research into the long-term effect of repeated manual oscillation sessions is warranted.

Spinal analgesia in terminal care: risk versus benefit.

Cancer pain treatment is well established. The World Health Organization provides clinicians an "analgesic ladder" scheme to optimize cancer pain treatment. At the beginning of the pain treatment, oral analgesic administration is preferred. The analgesic dose must be individualized. Many published papers describe the spinal administration of opioids in combination with various other drugs such as bupivacaine in selected patients with cancer pain. Although complications have been reported to be few, some recent reports debate this idea. We first describe a population of 92 cancer patients, 13 of whom received intrathecal morphine. We then present our experience with a separate group of 33 cancer patients who were also managed using intrathecal morphine. Based on this experience, the generally accepted indications for the technique appeared to be justified. Concern about spinal infection is well considered, however. Three out of those patients developed meningitis, a complication rate that is far too high.

Neuropathic pain in a cancer patient responding to subcutaneously administered lignocaine.

OBJECTIVE: To demonstrate difficulties encountered in alleviating neuropathic pain in a terminally ill cancer patient, with the very tentative diagnosis of postherpetic neuralgia. SETTING: A multidisciplinary pain department in a university hospital. PATIENTS: A patient with Hodgkin's lymphoma and leiomyosarcoma in the liver developed an unusual manifestation of neuropathic pain. INTERVENTION: Oral drug treatment with morphine associated with amitriptyline, valproic acid, mexilitine, flufenazine, and methylprednisolone failed to suppress pain attacks. Only the subcutaneous instillation of lidocaine (2 mg/kg/h) could partially suppress pain. A dorsal root entry zone lesion intervention could only temporary stop the pain attacks. Infiltration and nervous stimulation techniques were not helpful. OUTCOME MEASURES: In determining pain control, the visual analog scale rating scale and the number of attacks per hour were considered. RESULTS: Only the subcutaneous administration of lignocaine could partially suppress pain. Because of the patient's poor hepatic circulation, variable lidocaine plasma concentrations were responsible for intolerable side effects. CONCLUSIONS: Subcutaneous lignocaine administration remains a useful method in treating neuropathic cancer pain. The poor metabolic condition of the patient can lead to deleterious high plasma levels. A dorsal root entry zone lesion could only temporarily stop the pain.