Impact of Drug Formulation Variables on Silicone Oil Structure and Functionality of Prefilled Syringe System.

Use of prefilled syringes to self-administer biologics via subcutaneous administration provides convenience to patients. The barrel interior of prefilled syringes is typically coated with silicone oil for lubrication to aid plunger movement at the time of administration. This study intended to evaluate the impact of formulation variables on the silicone oil on the barrel interior surface. Characterization techniques including syringe glide force, break loose force, Schlieren imaging, contact angle, inductively coupled plasma spectrometry, and thin film interference reflectometry were used in assessing the interactions. Data indicated that formulation variables such as pH, buffer/tonicity agent type and concentration, and surfactant present in the formulation can effect silicone oil lubrication of prefilled syringes, leading to changes in functional properties of the syringe over time. Syringe samples containing acetate and histidine buffers showed an increase in glide force at accelerated storage temperature conditions, but the change was minimal at 5 °C. The samples with the highest glide force correlated with the presence of mannitol in combination with sodium acetate buffer. Sodium chloride had lesser impact on glide force than mannitol. Samples with higher glide force exhibited a substantial change in the silicone oil layer of the syringe, as observed with Schlieren imaging, as well as a significant reduction in surface hydrophobicity, as demonstrated through contact angle measurement. These data indicated that the structure of the siliconized surface can change over time in contact with different formulations. During formulation development of drug products in prefilled syringes, in addition to potential impact on molecule stability, the selection of formulation variables should also be guided by assessing the impact to syringe functionality with the glide force as one of the key parameters.LAY ABSTRACT: Self-administering drug products packaged in prefilled syringes provides convenience to patients. The interior of a prefilled glass syringe is typically lubricated with silicone oil for easy plunger movement during injection. This article discusses the impact of formulation excipients on silicone oil coating inside the syringe. Characterization techniques were used to assess the ease of plunger movement and structure of the silicone coating. Data indicate formulation excipients can affect silicone oil distribution of prefilled syringes, leading to an increase in plunger glide force at accelerated storage temperature conditions. The increase in glide force within a prefilled syringe with or without an auto-injector can have an impact on dose accuracy and user experience. Syringes with a higher plunger glide force appeared to exhibit a change over time in surface energy and structure of the silicone oil layer in contact with particular formulations.

A Demonstration of Mixing Robustness in a Direct Compression Continuous Manufacturing Process.

The purpose of this work was to assess the impact of continuous mixing on tablet critical quality attributes (CQAs) manufactured using a continuous, direct compression process. A 9-run design of experiments (DoE) that bracketed the range of commercially relevant mixer speeds, mixer orientations, and mass flow rates was executed using a formulation containing a cohesive drug substance at relatively low drug load. Drug substance dispensed concentration using loss-in-weight feeders was within 1% of target for each experiment with 30-s mass flow relative standard deviation values of 3.5% or less. Higher mass flow rates resulted in first off tablets closer to target potency, a shorter tablet potency startup phase, and greater assurance of passing content uniformity testing. Dissolution profiles from the DoE runs that bracketed mixer shear conditions were similar, indicating mixing had minimal impact on drug substance release from the tablets. None of the DoE parameters had a practical impact on the description CQA (tablet breaking force, friability, and appearance). Collectively, these results highlight that for this study continuous mixing within a direct compression process is robust and is assessed as low risk of adversely impacting drug product CQAs provided there is appropriate control of the continuous feeders.

Use of Bayesian Methods to Analyze and Visualize Content Uniformity Capability Versus United States Pharmacopeia and ASTM Standards.

The purpose of this work was to develop a straightforward and robust approach to analyze and summarize the ability of content uniformity data to meet different criteria. A robust Bayesian statistical analysis methodology is presented which provides a concise and easily interpretable visual summary of the content uniformity analysis results. The visualization displays individual batch analysis results and shows whether there is high confidence that different content uniformity criteria could be met a high percentage of the time in the future. The 3 tests assessed are as follows: (a) United States Pharmacopeia Uniformity of Dosage Units <905>, (b) a specific ASTM E2810 Sampling Plan 1 criterion to potentially be used for routine release testing, and (c) another specific ASTM E2810 Sampling Plan 2 criterion to potentially be used for process validation. The approach shown here could readily be used to create similar result summaries for other potential criteria.

Is HPLC assay for drug substance a useful quality control attribute?

HPLC is a generally accepted method for assay of drug substances. However, recent claims cast doubts on the utility of HPLC assay methods for characterizing quality [S. Görög, J. Pharm. Biomed. Anal. 36 (2005) 931-937]. This study examines the utility of the traditional drug substance HPLC assay as a quality control parameter. HPLC assay data from more than 100 batches for each of eight drug substances were compared to results from a mass balance approach (100-impurities%). Estimates of the variability of HPLC assays from our data and from the literature ranged from 0.6 to 1.1% R.S.D. This variability is an appreciable portion of a typical acceptance range (e.g., 98.0-102.0%) and frequently exceeds the variability of the manufacturing process. Therefore, the results of the HPLC assay are questionable at best to determine the acceptability of the drug substance batch. The high variability also can generate a significant percentage of false out-of-specification (OOS) results, even when the "true" purity is 99.0-100.0%. Each false OOS leads to inefficiencies because of unwarranted investigations for a root cause and/or implementation of countermeasures for a problem that does not exist. Lastly, low precision makes it nearly impossible to detect significant changes in the process mean and/or degradation during a stability study. The use of a mass balance approach for assay retains essentially the same average results as the HPLC assay but gives standard deviations that are up to 10 times less. Monitoring the assay by mass balance allows for more precise process and stability monitoring and facilitates more rapid and accurate identification of process changes.