Sterile Drug Products Research Articles

Current and Future Pharmacopoeial Requirements for the Quality of Extemporaneous Medicinal Products: A Review of Regulatory Standards

INTRODUCTION. The organisation of extemporaneous compounding in pharmacies is currently considered to be a priority for the national healthcare system. Extemporaneous medicinal products used by patients should meet high quality, safety, and efficacy standards. Provision of consistent and science-based requirements for the quality of medicines, particularly those compounded in pharmacies, is a key area of concern for standardisation.AIM. This study aimed to analyse international experience and determine areas for the improvement of standardisation approaches of the State Pharmacopoeia of the Russian Federation to the quality of medicinal products compounded in pharmacies.DISCUSSION. The study investigated the common and distinctive properties of extemporaneous preparations compounded in pharmacies (and not subject to registration) and medicinal products manufactured by pharmaceutical companies. The authors analysed the requirements and recommendations for compounding and quality assurance of extemporaneous medicinal products provided by the regulatory and pharmacopoeial authorities of the Russian Federation, the Republic of Belarus, the European Union, the United Kingdom, the USA, and Canada. The United States Pharmacopeia includes circa 150 individual monographs for non-sterile compounded drug products with particular compositions and over 20 individual monographs for sterile compounded drug products. The European Pharmacopoeia requires that extemporaneous preparation should be organised within the quality assurance framework of a pharmacy after a proper risk assessment. In the Republic of Belarus, extemporaneous medicinal products are compounded in line with the requirements of the Good Compounding Practices and the State Pharmacopoeia of the Republic of Belarus, which provide rapid testing procedures for extemporaneous medicinal products.CONCLUSIONS. The study identified the following areas for the development of requirements for the quality of medicinal products compounded in pharmacies: the determination of rapid testing approaches; the development of pharmacopoeial monographs for active pharmaceutical substances used in extemporaneous compounding, with the Identification section supplemented with an additional subsection on pharmacy-specific analytical procedures; and the development of pharmacopoeial monographs for frequently used compounding formulae.

Rapid Sterility Test Systems in the Pharmaceutical Industry: Applying a Structured Approach to Their Evaluation, Validation and Global Implementation.

The current compendial sterility test has a 14-day incubation time and is often the time-limiting step in the Assess and Release Process of pharmaceutical products. There is an ever-increasing number of technologies available on the market that have benefits in addition to faster Time to Result, such as standardization and automation of readout (eliminating analyst subjectivity) and improved data integrity (including eliminating the need for contemporaneous verification of the result by another analyst). Regulators have been encouraging the pharmaceutical industry to adopt these innovative systems; however, it has taken a considerable time before receiving the first approvals from various health authorities (including both the European Medicines Agency and Food and Drug Administration) for the use of an alternative and rapid sterility test for the release of sterile drug product lots. This article describes a systematic 9-step approach to the evaluation, equipment qualification, validation, and deployment of alternative sterility tests that can be applied by pharmaceutical companies wanting to take advantage of the numerous benefits of alternative sterility tests. Two case studies are presented to illustrate the validation and implementation approach, including statistical methods. Although most of the steps toward implementation are aligned, the validation and transfer have been approached differently for each of the case studies because of differences in the chosen technology as well as independent company internal decisions to comply with validation guidelines. However, both case studies show successful implementation of an alternative sterility test for sterile drug products with an ∼50% reduced incubation time.

Data-Driven Approach toward Long-Term Equipment Condition Assessment in Sterile Drug Product Manufacturing.

A two-stage data-driven methodology for long-term equipment condition assessment in drug product manufacturing is presented with a case study for a commercially operating aseptic filling line. The methodology leverages process monitoring data. Sensor measurements are partitioned using process information and maintenance schedules that are available on different databases. Data is processed to tackle heterogeneity in sources and formats. The data is cleaned to remove the effects of short-term variabilities and to enhance underlying long-term trends. Two approaches are presented for data analysis: first, anomaly detection using independent component analysis (ICA), where clusters of outliers are identified. The frequency and timing of such outliers yield important insights regarding maintenance schedules and actions. The second approach enables condition monitoring using principal component analysis (PCA). Long-term operational baselines are identified and shifts therein are linked with different process and equipment faults. This approach highlights the impact of equipment deterioration on shifting operational data baselines and shows the potential for the combined application of ICA and PCA for equipment condition monitoring. It can be applied within predictive maintenance applications where the installation of new specialized sensors is difficult, like in the pharmaceutical industry.

Data-driven equipment condition monitoring and reliability assessment for sterile drug product manufacturing: Method and application for an operating facility

Data-driven equipment condition monitoring is difficult to apply in operating pharmaceutical manufacturing plants. The required revalidation costs and efforts hinder the installation of dedicated sensors. This work proposes a three-step methodology to exploit the existing process monitoring infrastructure to infer equipment condition-related information. The developed methodology addresses the challenges imposed by using process monitoring data for a secondary application. In the detection step of the methodology, batch variations are separated from changes due to underlying equipment deterioration. Principal component analysis is conducted followed by slow feature analysis to extract long-term equipment variations. After identifying relevant shifts in the slow feature baselines, the sources of variations in equipment conditions are traced back to sets of installed sensors in the localization step. The identified sensor sets are used to determine the location and physical type of cause of the changes. Last, in the prevention step, tailored maintenance actions are proposed to avoid potential equipment-related failures. Two case studies are presented to demonstrate the application of the methodology with real industrial data. Data from historical maintenance records in the facility were used to verify the findings from the case study. The successful application provides lessons-learned to include maintenance as part of holistic system design and is an important step towards data-driven equipment reliability assessment and maintenance planning in pharmaceutical manufacturing.

Considerations for Defining the Intravenous Administration Procedure for Nano-dose Sterile Drug Product in Clinical Studies

The loss of active substance, both small and large molecules, from sterile liquid drug products after contact with an administration kit has been extensively reported in the literature. This loss has been reported to be caused by incompatibility of the active substances with the contact surfaces of the administration kit and adsorption or sticking of the active substance to the surfaces of the administration kit. This paper investigates the mechanism for loss of a highly potent active substance based on the type and design of the administration kit. Two administration kits (syringe/Insyte Catheter and syringe/Nexiva Catheter) of different designs were used to administer a solution formulation of an ultra-low dose (nanograms) of a model hydrophobic active substance Compound X. The Nexiva Catheter was longer with tubing and Y connectors while the Insyte Catheter was shorter with no split septum tubing. Dose recovery from both administration kits was determined using high pressure liquid chromatography. The results indicated that the full dose was recovered from the syringes and Insyte Catheter. However, there was a significant loss of active substance from the Nexiva Catheter configuration even after post administration flush, which was due to holdup volume of the formulation within dead spaces of the Nexiva Catheter. It was also demonstrated that the dose recovery from the Nexiva Catheter can be significantly increased with increase in the post administration flush volume, which further confirms that the observed loss of active substance was not due to incompatibility or surface adsorption. The significance of this work is to provide awareness to formulation scientists that closed system Catheter design with Y connectors can be the main contributor for the loss in active substance, especially at ultra-low doses, and therefore dose recovery experiments should be expanded to include proper flushing of the Y connectors to expel any holdup volume from the Catheter.

Effects of different air change rates on cleanroom ‘in operation’ status

The objective of this experimental study is to analyze non-viable and viable particle loads in a pharmaceutical cleanroom under ‘in operation’ conditions using different air change rates (ACRs). Regulatory guidelines give limit values for particles/m3 and colony forming units (CFUs)/m3. A widely used ACR is 20 h−1 as this value is recommended by the Food and Drug Administration (FDA) in its guidance for industry on sterile drug products. However, this value may be too high, resulting in increased costs for energy. A typical pharmaceutical cleanroom was used for this study, and operations were simulated with a process unit and two operators in the room. The experiments were conducted twice with four different ACRs and four different types of operator garments, resulting in 32 trials in total. Particle load and CFUs were measured by calibrated particle counters and microbial air samplers. The results give evidence that an ACR of 20 h−1 is not required. ACR 10 h−1 is sufficient without compromising the demanded air quality. Furthermore, it was found that regulatory agencies should reevaluate the expected limits as these currently give a high buffer between the required and actual values, which potentially cover up problems in aseptic manufacturing.

Lead-time and risk reduction assessment of a sterile drug product manufacturing line using simulation

Digital Twins are finding their way into more and more parts of supply chains. Especially in highly regulated manufacturing processes of the pharmaceutical industry, they are becoming an increasingly valuable tool for improving processes without inducing prolonged downtimes, e.g. through virtual tests and virtual scenario analyses.Simulation can serve as a powerful foundation for digital twins, as it e. g. allows for probabilistic assessments and multi-dimensional optimization of highly complex and dynamic processes.In this study, a simulation model is developed as part of the EU research and innovation programme Horizon 2020. The goal is to explore the benefits of a simulation-based approach and quantify the potential for later adoption in a scalable Digital Twin system. The model is applied as a case study on a sterile drug product manufacturing line of the Roche Diagnostics GmbH in Mannheim, Germany.With the model, sensitivity analyses of process steps, campaign building and batch change scenarios, different shift models, scheduling approaches and delivery breakdown risk assessments were conducted. Results underlined the benefits of simulation-based analyses and the potential for adoption of digital twin technologies in the pharmaceutical industry.

Process validation, current good manufacturing practice production, dosimetry, and toxicity studies of the carbonic anhydrase IX imaging agent [111 In]In-XYIMSR-01 for phase I regulatory approval.

[111 In]In-XYIMSR-01 is a promising single-photon emission computed tomography (SPECT) imaging agent for identification of tumors that overexpress carbonic anhydrase IX. To translate [111 In]In-XYIMSR-01 to phase I trials, we performed animal toxicity and dosimetry studies, determined the maximum dose for human use, and completed the chemistry, manufacturing, and controls component of a standard regulatory application. The production process, quality control testing, stability studies, and specifications for sterile drug product release were based on United States Pharmacopeia chapters <823> and <825>, FDA 21 CFR Part 212. Toxicity was evaluated by using nonradioactive [113/115 In]In-XYIMSR-01 according to 21 CFR Part 58 guidelines. Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) was used to calculate the maximum single dose for human studies. Three process validation runs at starting radioactivities of ~800 MBq were completed with a minimum concentration of 407 MBq/ml and radiochemical purity of ≥99% at the end of synthesis. A single intravenous dose of 55 μg/ml of [113/115 In]In-XYIMSR-01 was well tolerated in male and female Sprague-Dawley rats. The calculated maximum single dose for human injection from dosimetry studies was 390.35 MBq of [111 In]In-XYIMSR-01. We have completed toxicity and dosimetry studies as well as validated a manufacturing process to test [111 In]In-XYIMSR-01 in a phase I clinical trial.

Strategies for Implementing New Drying & Packaging Technology for Sterile Injectable Drug Products.

There are exciting new technologies becoming available that could revolutionize drying and packaging of sterile injectable products. Key emerging drying technologies include spray freeze-drying,1,2 continuous vial lyophilization,3 continuous spin freezing and drying,4,5 microwave-assisted drying,6,7 lyospheres6–8 and sterile spray drying.9 There are also new dual-chamber delivery devices in development for closed-system reconstitution.10,11 These devices can be filled with lyospheres or the small pellets or powders produced by spray freeze-drying or spray drying.

Exposure assessment of pharmaceutical powders based on an environmental monitoring method: a pilot study.

About 8 million healthcare workers in the USA are potentially exposed to hazardous drugs or their toxic metabolites over a long period of time despite the fact that both the Occupational Safety and Health Administration and the European Parliament recommend the monitoring of exposure among workers dealing with substances which have carcinogenic, mutagenic or toxic effects on the reproductive system. The objective of this study is to determine exposure to active pharmaceutical ingredients (APIs) among pharmaceutical industry workers, and to develop a methodology which promotes the accurate monitoring, evaluation and control of exposure to active pharmaceutical ingredients, also in compliance with good manufacturing practice. The pilot study was designed in accordance with "Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice," issued by the U.S. Food and Drug Administration. The samples were collected with the swab technique which was recommended in the "Validation of Cleaning Processes (7/93)" guideline. The minimum numbers of locations (NL = 9) and sampling points (NL(T) = 63) were determined according to ISO 14644-1:2015 "Cleanrooms and Associated Controlled Environments" issued by the International Organization for Standardization. The samples were analyzed using an ultra performance liquid chromatography system, with an analytical method which was developed and validated according to "Q7A, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients" issued by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. The low limit of quantification of the employed method (17 ng/ml) enables the determination of exposure at low concentrations. While contamination was detected in 43 (68.3%) of the 63 samples collected, 20 (31.7%) could not be detected. The environmental monitoring results ranged 0-15 000 ng/cm2 and the potential risk of exposure to API was considered to be >2 g. The results clearly prove and reveal the magnitude of the hazard, both objectively and scientifically, when compared to the research which suggests that 10 ng/cm2 should be considered the prohibitory risk level in quantitative terms. Med Pr. 2020;71(6):649-63.

Impact of H2O2 Sorption by Polymers on the Duration of Aeration in Pharmaceutical Decontamination

As part of manufacturing a sterile drug product, we quantified the impact of H2O2 sorption by polymers on the duration of aeration in pharmaceutical decontamination. Five polymers, which are typically used as materials/parts in sterile isolators, were investigated: polyethylene, polyvinyl chloride, Silicone, polyoxymethylene (POM), and chlorosulfonated polyethylene. Experiments were performed to estimate the storage capacity and diffusion coefficients of H2O2 in the polymer. Considering these key properties of sorption/desorption, mathematical models were developed to simulate the duration of aeration to achieve the target H2O2 concentration, which is the indicator to minimize. The models were used to create a map-out of the duration given the properties of the polymers, including the five polymers. In the simulated setup, POM and Silicone were found to require prolonged aeration. Thus, when using these polymers in the isolator, the size/amount should be carefully investigated. Another practical finding was that the superiority of the polymers changed depending on the target H2O2 concentration. This result motivates an early incorporation of the product information in the isolator design, to achieve a rapid decontamination/aeration cycle.

Integrated Design of H2O2 Decontamination Processes and Scheduling in Sterile Drug Product Manufacturing

We explored the integrated design of H2O2 decontamination processes and scheduling in sterile drug product manufacturing, considering productivity and product quality. Models were developed that (i) deal with the scheduling of filling and the changeover of multiple batches/products and (ii) configure the aqueous H2O2 injection rate into the isolator as a process parameter. The total production time for all planned batches and the sterility assurance level of the products were defined as the objective functions for productivity and product quality, respectively. The models were applied to a multiobjective evaluation of the decontamination and scheduling options in the production of 15 batches (different products and batch sizes). Pareto-optimal solutions were obtained that indicated a trade-off between the two objectives. The inclination of the Pareto frontier increased when the product became more vulnerable to residual H2O2 after aeration and when the batch size became smaller. The quantitative results confirmed an increased impact of the configuration of the decontamination process on both productivity and product quality. The small batch-size production of H2O2-sensitive products is increasingly popular, especially for biopharmaceuticals, and the results of this study encourage the collaborative development of decontamination processes and production schedules in sterile drug product manufacturing.

Assessment of Intravenous Drugs Admixtures Incompatibilities at Nekemte Referral Hospital, West Ethiopia

Intravenous admixtures are the preparations consisting of sterile drug products added to an IV fluid (s) for medication purposes. Especial concerns are required for such drugs since the reversal of toxicity and/or unwanted effects following incompatibilities are cumbersome to deal with. Concern drugs that may cause irritation or toxicity when given as a rapid direct IV injection are also prepared as IV admixtures. The ultimate goal of this assessment was to figure out the actual practices on the ground in IV medications administered in NRH with IV fluids emphasizing on incidence and prevalence of incompatibility between drugs themselves or with IV fluids. This study was a cross-sectional prospective observational study which investigated the potential incompatibilities associated with IV admixture, & the incidence of IV drug administration errors using available evidence-based medicine sources at Nekemte Referral Hospital in West Ethiopia. The data was collected from patient medication Charts and prescription papers for patients treated within a period of 2 months. The study period was from February 2017 to April 2017 at the medical and pediatrics wards of NRH. About patients using IV admixtures were followed within this study period. The prevalence of identified incompatibility among IV admixtures ingredients was 28.94%. The identified compatibility was only 25.43%, while 38.59%were undocumented combinations, and 7.01% were variable. The most commonly encountered incompatible drug-solute combinations were Ringer lactate (61.8%), Insulin + DNS (29.4) and Ceftriaxone + Phenytoin + 0.9% NaCl (8.8%). Also, the incompatible drug-drug combinations detected in this study were Ceftriaxone+ heparin and clopidgrel+cimetidine combinations. Based on the findings of this study, the following can be concluded; there is a high prevalence of incompatibilities among IV admixtures. The types of incompatibilities were both drug-solute and drug-drug incompatibilities. Prescribers and administrators of IV admixtures were recommended to check plausibility before administration to prevent such incompatibilities which can compromise the treatment outcome of patients.

Preuse/Poststerilization Integrity Testing (PUPSIT): To Do or Not to Do?

In manufacture of heat labile sterile drug products, the final step involves filtration through sterilizing grade filters. It is the drug manufacturer's responsibility to check whether an integral filter has been used. One method used widely to check the integrity of a filter is the bubble point test. To confirm that the filter used is integral, the postuse integrity test is made obligatory by regulatory bodies. However, preuse/poststerilization integrity testing (PUPSIT) of filters remains debatable for the risks associated in its execution. Although PUPSIT is recommended by regulatory bodies, it poses a risk of compromising downstream sterility and involves high costs to mitigate such risks. This study highlights the impact of filter clogging on bubble point values with the consequent possibility of a nonintegral filter passing postuse integrity testing. The results clearly show an increase in postuse bubble point values, which can camouflage a possible flaw in sterilizing filters. The fluid streams 20% dextrose, 0.001% bentonite, paclitaxel, and 0.05% sodium hyaluronate were selected based not only on the commonality of their clogging propensity but also on the different nature of streams that influence the clogging of sterilizing filters. Paclitaxel is an injectable for oncotherapy, and 0.05% sodium hyaluronate is an ophthalmic. The study was conducted with 0.2 μm sterilizing filters from four different manufacturers. It was observed that some fluid streams show a significant increase in the postuse bubble point test values over the preuse bubble point values. This establishes the necessity of performing PUPSIT in certain cases based on the postfiltration shift in bubble point values. As part of the filter validation studies with specific drug products, additional testing should be carried out to establish the need for PUPSIT on a case-by-case basis.

AmEx Pharmacy agrees to recall all sterile drug products

AmEx Pharmacy agrees to recall all sterile drug products

Option to run outsourcing facility gains ground for hospitals, health systems.

A new guidance document from FDA creates a path for a hospital or health system to compound patient-specific products and also register as an outsourcing facility that compounds sterile drug products in accordance with Current Good Manufacturing Practice (CGMP) regulations. Registration as an

Design-oriented regression models for H2O2 decontamination processes in sterile drug product manufacturing considering rapidity and sterility

We developed regression models for designing rapid and effective H2O2 decontamination processes in the manufacturing of sterile drug products such as injectables. Decontamination, which is typically performed by using H2O2, is a critical changeover process used to establish a sterile environment for filling products. In the process, there is a trade-off relationship between the duration of the process and the level of sterility assurance that needs to be considered in the design. Our model defines these two items as objective functions and the parameters describing the profile of H2O2 injection and the initial humidity as design variables. Our model also considers aeration, i.e., removal of H2O2 from the environment, as a part of the entire process. This design-oriented modeling considering the entire process is the novelty of the work. Experiments were performed using an industrial isolator to develop and validate a set of regression models that describe the relationship between the design variables and the objective functions. In the application of the model, Pareto-optimal conditions could be indicated given the target H2O2 concentration in aeration, which is useful for the makers of drugs and/or isolators for designing decontamination processes.

Erratum to: Decision-Support Method for the Choice Between Single-Use and Multi-Use Technologies in Sterile Drug Product Manufacturing

Single-use technology has been applied to sterile drug product manufacturing processes as a new technology in contrast with the conventional multi-use technology. This study proposes a decision-support method for choosing between these two technologies in sterile drug product manufacturing. The proposed method consists of four steps: create process evaluation models, calculate evaluation results, perform what-if analysis, and interpret results. We created models for evaluating the production cost and life cycle CO2 emissions of processes using either technology. “What-if” analysis quantifies the effect of the input parameters on the evaluation results, which supports more informed decision-making. Here, it is recommended that the filling speed, which was found to have a significant impact on filling accuracy—a critical quality attribute of sterile drug products—should be investigated. As a case study, the method was applied in two cases of technology selection: (i) single-batch production of a product with different batch sizes and (ii) single-batch production with different production patterns. The single-use technology showed its economic superiority in producing small batches and in producing multiple small-scale products, whereas in the environmental evaluation, it was always better than multi-use technology. What-if analyses revealed the impact of changing input parameters on the economy, environment, and quality. Our method can support the choice of single-use and multi-use technologies in plants having both technologies independently. In the case study, economic evaluation showed a critical point in each design case, whereas the environmental evaluation result was always better in single-use technology.

Process Model for Enhancing Yield in Sterile Drug Product Manufacturing

Purpose We present a process model for enhancing the yield in the manufacturing of sterile drug products, such as injectables, eye drops, or intravenous bags. The process typically consists of compounding, filtration, filling, and visual inspection and involves raw materials of active pharmaceutical ingredients, water for injection, excipients, and packaging materials.

Innovative approach for identifying root causes of glass defects in sterile drug product manufacturing

In sterile drug product manufacturing, scratched and broken glass containers (i.e., vials) cause product losses, glass particles, equipment contamination and additional cleaning efforts. However, mechanical resistance and exposure of vials to mechanical stress are not sufficiently understood, and no systematic approach for reducing glass-related losses is established. Manufacturers may tackle glass-related losses more rationally if (i) frequencies for inflicting disqualifying damages to drug product containers are known for given forces, (ii) actual exposure in industrial filling lines is quantified and (iii) process enhancements are derived based on collected information.In this work, an innovative approach for exploiting these opportunities, identifying glass defect root causes and reducing glass defects is provided. Devices for quantifying (i) damaging frequencies and (ii) actual exposure are presented and then applied in an industrial case study on sterile drug product manufacturing; finally, (iii) process enhancements are derived and implemented. In the case study, frequencies for scratching vials at given forces as well as breaking forces have been determined. Peak exposure in the investigated filling line was detected at 6 N. As a result of the case study, key machine parts were identified and adjusted.