Transportation of mAb Dosing Solution in Intravenous Bag: Impact of Manual, Vehicle, and Pneumatic Tube System Transportation Methods on Product Quality.

Monoclonal antibody (mAb) products for intravenous (IV) administration generally require aseptic compounding with a commercial diluent within a pharmacy. The prepared dosing solution in the IV bag may be transported to the dosing location via manual, vehicular, pneumatic tube system (PTS), or a combination of these methods. In this study, the type and level of physical stresses associated with these three methods and their product quality impact for relatively sensitive and stable mAbs were assessed. Vibration was found to be the main stress associated with manual and vehicle transportation methods, although this was at a relatively low level (<1 GRMS/Root-Mean-Square Acceleration). Shock and drop events, at relatively low levels, were also observed with these methods. PTS transportation showed substantially more intense shock, vibration, and drop stresses and the measured levels were up to 91 G/force of acceleration or deceleration, 3.7 GRMS and 39 G, respectively. Using a foam padding insert for PTS transportation reduced the shock level considerably (91 G to 59 G). Transportation of mAb dosing solutions in IV bags via different methods including PTS transportation variables caused a small increase in the subvisible particle counts and there was no change in submicrometer particle distribution. No visible particles and no significant change to soluble aggregate levels were observed after transportation. Strategies such as removal of IV bag headspace prior to transport and in-line filtration poststress reduced the subvisible particles counts. All tested transportation conditions showed negligible impact on other product quality attributes tested. Removal of IV bag headspace prior to PTS transport prevented formation of micro air bubbles and foaming compared to the unaltered IV bag. This study shows examples where manual, vehicle, and PTS transport methods did not significantly impact product quality, and provides evidence that mAb products that are appropriately stabilized in the dosing solution (e.g., with a surfactant) can be transported via a PTS.

Syringe Filling of High-Concentration mAb Products Using Peristaltic Pump-Based Mechanism: Challenges and Mitigation Strategies.

Syringe filling of high-concentration mAb formulation during manufacturing of large-scale drug product batches may present challenges such as product deposition onto the area of the syringe barrel where the stopper is inserted, product splashing or dripping, droplets left after the fill cycle, filling needle clogging, product build-up inside the needle during line stoppages, variation in fill weight/volume, and potential impact on product quality attributes. In this article, a summary of these issues and approaches to overcome them are summarized. Potential failure modes of the syringe filling process and appropriate in-process controls are provided. In addition to developing the filling process or resolving manufacturing issues, the pharmaceutical company developing the product and associated drug product manufacturing process may want to implement long-term strategic approaches to support the portfolio progression. Potential long-term approaches such as use of a viscosity reducing formulation development approach, improving peristaltic filling technology performance, building small-scale filling capability and establishing a streamlined filling process management cycle are also summarized. The aspects summarized in this article may be used to develop a robust filling process and control strategy for high-concentration mAb products and implement long-term strategic approaches to support the portfolio progression.

Stress Factors in Protein Drug Product Manufacturing and Their Impact on Product Quality.

Injectable protein-based medicinal products (drug products, or DPs) must be produced by using sterile manufacturing processes to ensure product safety. In DP manufacturing the protein drug substance, in a suitable final formulation, is combined with the desired primary packaging (e.g., syringe, cartridge, or vial) that guarantees product integrity and enables transportation, storage, handling and clinical administration. The protein DP is exposed to several stress conditions during each of the unit operations in DP manufacturing, some of which can be detrimental to product quality. For example, particles, aggregates and chemically-modified proteins can form during manufacturing, and excessive amounts of these undesired variants might cause an impact on potency or immunogenicity. Therefore, DP manufacturing process development should include identification of critical quality attributes (CQAs) and comprehensive risk assessment of potential protein modifications in process steps, and the relevant steps must be characterized and controlled. In this commentary article we focus on the major unit operations in protein DP manufacturing, and critically evaluate each process step for stress factors involved and their potential effects on DP CQAs. Moreover, we discuss the current industry trends for risk mitigation, process control including analytical monitoring, and recommendations for formulation and process development studies, including scaled-down runs.

Comprehensive Temperature Excursion Management Program for the Commercial Distribution of Biopharmaceutical Drug Products.

Biopharmaceutical drug products may be exposed to temperatures outside of the intended storage temperature range (typically 2-8°C) during commercial distribution due to uncontrolled variables and unexpected events. Pharmaceutical companies are expected to ensure that product quality and stability are not negatively impacted by temperature excursions defined as being acceptable for the product. It is imperative that all firms involved in the distribution understand key elements of the temperature excursion management program in place to overcome the challenges of global distribution and comply with regulatory requirements. Proactive implementation of a comprehensive temperature excursion management program is expected to help achieve successful commercial distribution. In this article, important aspects related to the key elements of a comprehensive temperature excursion management program are summarized, including standard stability testing, regulatory expectations related to the justification of temperature excursions, thermal cycling studies to assess and support potential temperature excursions (including how/when thermal cycling study data is used to support temperature excursions), good distribution practices to minimize temperature excursions and use of theoretical methods/mathematical simulation models to assess temperature excursions. A comprehensive temperature excursion management program is expected to ensure product quality and help minimize, assess, and justify temperature excursions more efficiently, ensure regulatory compliance and avoid business impact caused by the loss of products or inadequate supply.

Mixing of a mAb Formulation in a New Magnetically Coupled Single-Use Mixing System: Key Learnings of Preliminary Experimental and Computational Evaluation.

MilliporeSigma recently introduced a new magnetically coupled single-use mixing system (Mobius® Power MIX) for more efficient mixing of buffers and media in biopharmaceutical applications. Experimental and computational fluid dynamics (CFD) assessments were performed on the Power MIX 100 system to understand product quality impact, shear, and mixing efficiency. It was interesting to note slightly higher submicron (0.4-1 µm) and subvisible (1-54 µm) particle formation at the lower mixing speed (50 RPM) compared to higher mixing speeds (100/200 RPM). Mixing speed and time showed negligible impact on the other product quality attributes tested, including protein concentration, turbidity, general appearance, purity, and soluble aggregates. The CFD simulations provided useful information with respect to the impact of batch size (20-100 L), viscosity (2-50 cP), and impeller speed (100-300 RPM) on mixing time (mixing time ranged from 10 to 365 s) and shear (maximum shear rate was found to be localized around the impeller and it was about 30,260 s-1, whereas the average shear rate ranged from 4 to 36 s-1). Statistical analysis of the CFD results showed that natural-log transformation and quadratic fitting were found to be suitable statistical models to predict mixing time and shear within the design space of the parameters assessed in the present study.

Syringe Filling of a High-Concentration mAb Formulation: Experimental, Theoretical, and Computational Evaluation of Filling Process Parameters That Influence the Propensity for Filling Needle Clogging.

This article summarizes experimental, theoretical, and computational assessments performed to understand the effect of filling and suck-back cycle factors on fluid behaviors that increase the propensity for filling needle clogging. Product drying under ambient conditions decreased considerably when the liquid front was altered from a droplet or meniscus at the needle tip to a point approximately 5 mm inside the needle. Minimizing the variation in size of product droplet formed after the fill cycle is critical to achieve a uniform meniscus height after the suck-back cycle. Several factors were found to contribute to droplet size variability, including filling and suck-back pump speed, suck-back volume, and product temperature. Filling trials and the computational fluid dynamics simulations showed that product meniscus stability during the suck-back cycle can be improved by reducing the suck-back flow rate. The computational fluid dynamics simulations also showed that a decrease in contact angle had the greatest effect in reducing meniscus stability. As the number of filling line stoppages increases, the product buildup at the needle increases. The interaction between stoppages and the number of dispenses between stoppages was established to minimize product buildup at the filling needle. Improved suck-back control was shown to improve process capability of large-scale batches.

Japan-Specific Key Regulatory Aspects for Development of New Biopharmaceutical Drug Products.

Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies.

Syringe Filling of High-Concentration mAb Formulation: Slow Suck-Back Pump Speed Prevented Filling Needle Clogging.

Partial and complete clogging of filling needles occurred during syringe filling of a high-concentration mAb formulation. This caused nonvertical liquid flow, which eventually led to the termination of filling. Overcoming this phenomenon was essential to ensure minimal fill weight variation, product waste, and manufacturing downtime. The liquid behavior inside the filling needle was studied using glass and stainless steel needles and demonstrated that effective suck-back control was critical for preventing needle clogging. A key finding of our work is that the suck-back pump speed was a critical factor to achieve an effective suck back. More specifically, a slow suck-back pump speed (<10 rpm; liquid flow rate, <5 mL/min) was essential to improve suck-back control inside the conventional stainless steel filling needles. In contrast, higher suck-back pump speeds (>10 rpm; liquid flow rate, >5 mL/min) resulted in downward product migration within the filling needle leading to formation of a liquid plug at the needle tip, which was prone to rapid drying. Slowing the suck-back pump speed in conjunction with modifying the suck-back volume was effective at consistently withdrawing product into the stainless steel filling needles and prevented needle clogging.

Lyophilization cycle development for a high-concentration monoclonal antibody formulation lacking a crystalline bulking agent.

An efficient freeze-dry cycle was developed for a high concentration monoclonal antibody formulation lacking a crystalline bulking agent. The formulation, at multiple protein concentrations, was characterized using differential scanning calorimetry (DSC) and freeze-dry microscopy. At low protein concentrations the glass transition temperature of the maximally freeze-concentrated solution (T(g)') determined by DSC was similar to the collapse temperature determined by freeze-dry microscopy. However, at higher protein concentrations, the difference between collapse temperature and T(g)' became progressively larger. The difference between the onset temperature for collapse and the complete collapse temperature also became progressively larger as protein concentration increased. JMP Design of Experiment studies were used to assess the effect of freezing rate, primary drying shelf temperature, and chamber pressure on primary drying product temperature, length of primary drying, and product quality attributes. Primary drying was shortened significantly by adjusting to conditions where the product temperature substantially exceeded T(g)' without any apparent detrimental effect to the product.