Impact of polymer chemistry on critical quality attributes of selective laser sintering 3D printed solid oral dosage forms.

The aim of this study is to investigate the influence of polymer chemistry on the properties of oral dosage forms produced using selective laser sintering (SLS). The dosage forms were printed using different grades of polyvinyl alcohol or copovidone in combination with indomethacin as the active pharmaceutical ingredient. The properties of the printed structures were assessed according to European Pharmacopoeia guidelines at different printing temperatures and laser scanning speeds in order to determine the suitable printing parameters. The results of the study indicate that the chemical properties of the polymers, such as dynamic viscosity, degree of hydrolyzation, and molecular weight, have significant impact on drug release and kinetics. Drug release rate and supersaturation can be modulated by selecting the appropriate polymer type. Furthermore, the physical properties of the dosage forms printed under the same settings are influenced by the selected polymer type, which determines the ideal manufacturing settings. This study demonstrates how the chemical properties of the polymer can determine the appropriate choice of manufacturing settings and the final properties of oral dosage forms produced using SLS.

Reasons for supply side driven drug shortages - A mixed-methods study on first-level, higher-level, and root causes from the perspective of marketing authorization holders.

BACKGROUND: Drug shortages impact multiple stakeholders and are detrimental to patient safety. Additionally, drug shortages are an extensive financial burden. In Germany, drug shortages, according to data from the federal ministry for drug and medical products (BfArM), have been increasing by 18% between 2018 and 2021. Studies show that shortages are most frequently supply side driven and that often reasons remain unknown. OBJECTIVE: The aim is to develop a holistic understanding of supply side causes for drug shortages in Germany from marketing authorization holders' perspectives and to derive implications for shortage mitigation. METHODS: A mixed-methods research design, with a grounded theory approach based on a structured literature review, BfArM data analysis, and semi-structured interviews, was used. RESULTS: Input factor supply issues, manufacturing issues, logistics issues, product recalls, and product discontinuations were identified as first-level causes. Furthermore, a theory on their connection to higher-level causes related to business decision-making, as well as root causes linked to regulations, company values, internal processes, market dynamics, external shocks, and macroeconomic factors, was developed. CONCLUSION: Actions to mitigate drug shortages in Germany (e.g., improving business processes, diversifying tender criteria) were derived. These may thus increase patient safety and decrease the financial burden on the healthcare system.

Tracing drugs from discovery to disposal.

The life cycle of a drug begins with discovery and ends with its disposal. Drug discovery companies, drug manufacturers, regulatory agencies, suppliers, pharmacies, patients, healthcare providers, and many more are involved in this process. Transparency, traceability, automation, and data security are some of the most crucial factors affecting how effectively and safely the transactions are conducted across all parties involved in the cycle. By contrast, scalability, energy consumption, regulation, standards, and complexity hamper the adoption of new technology that is expected to fulfil these requirements. Here, we highlight how blockchain technology can track, accelerate, and boost the efficiency of incredibly complicated operations, such as pharmaceutical development.

Selective laser sintering additive manufacturing of dosage forms: Effect of powder formulation and process parameters on the physical properties of printed tablets.

Large batches of placebo and drug-loaded solid dosage forms were successfully fabricated using selective laser sintering (SLS) 3D printing in this study. The tablet batches were prepared using either copovidone (N-vinyl-2-pyrrolidone and vinyl acetate, PVP/VA) or polyvinyl alcohol (PVA) and activated carbon (AC) as radiation absorbent, which was added to improve the sintering of the polymer. The physical properties of the dosage forms were evaluated at different pigment concentrations (i.e., 0.5 and 1.0 wt%) and at different laser energy inputs. The mass, hardness, and friability of the tablets were found to be tunable and structures with greater mass and mechanical strength were obtained with increasing carbon concentration and energy input. Amorphization of the active pharmaceutical ingredient in the drug-loaded batches, containing 10 wt% naproxen and 1 wt% AC, was achieved in-situ during printing. Thus, amorphous solid dispersions were prepared in a single-step process and produced tablets with mass losses below 1 wt%. These findings show how the properties of dosage forms can be tuned by careful selection of the process parameters and the powder formulation. SLS 3D printing can therefore be considered to be an interesting and promising technique for the fabrication of personalized medicines.

Developing Prioritization Criteria to Identify Target Drugs for CalRx, the California Generic Drugs Initiative.

OBJECTIVES: This study aimed to establish criteria to identify priority drugs for CalRx, a California-sponsored initiative to support the manufacture and distribution of affordable generic drugs. METHODS: A web-based ranking exercise was implemented with key stakeholders in August 2020, using pricing, spending, and public health criteria identified through a review of academic literature and public health agency reports. A total of 39 of 40 invited stakeholders in 4 different categories-patient advocates, healthcare providers, health insurers, and health policy and economic experts-participated in this study (98% response rate). RESULTS: Drugs that treat large populations, drugs that represent high cost to payors, and drugs that represent high cost to consumers were ranked a priority, receiving > 10% of ranking weights. Drugs that treat conditions with high morbidity or mortality, drugs without therapeutic alternatives, and drugs treating vulnerable populations represented criteria of further interest (9%-10% of weights). Shortage risk and curative effect (8%-9% of the weights), high price increases, communicable disease treatments, and high unit prices (< 8% of the weights) represented the bottom of the priority distribution. CONCLUSIONS: This study suggests that drugs that treat large populations, drugs that represent large costs to payors, and drugs that represent large costs to consumers should be the priority for California's CalRx generic drug initiative. A prioritizing algorithm will assist California in determining top drugs to target from a public health and spending perspective as it plans the rollout of the CalRx initiative and negotiates with drug manufacturers.

Transitioning Long-Acting Products to a Generic Marketplace: What's Missing?

Development of and increased access to generic oral medications to treat high-burden diseases including human immunodeficiency virus (HIV), tuberculosis, viral hepatitis, and malaria have had a major impact on reducing global morbidity and mortality. However, access and adherence to these life-saving treatments remains limited for some of the most vulnerable and underserved populations, for whom stigma, control, and discretion are critical to decisions around care. Current efforts to develop long-acting formulations to treat and prevent these conditions could overcome many of these barriers. However, generic manufacturing of these innovative products will be required to ensure affordable access to the communities and patients in greatest need. Strategic investments in new infrastructure will be required even before markets and manufacturing costs are clear, to ensure that access to these new products is not delayed, particularly for patients in low- and middle-income countries. Unlike conventional oral medications, long-acting products require greater investment for formulation, packaging, and delivery. The requirement for long-term bioequivalence studies will introduce additional delays in regulatory approval of generic long-acting products, and expedited approval pathways must be developed. Lessons learned from the development of long-acting hormonal contraceptives and long-acting antiretroviral products may provide a way forward.

Advancing pharmacy and healthcare with virtual digital technologies.

Digitalisation of the healthcare sector promises to revolutionise patient healthcare globally. From the different technologies, virtual tools including artificial intelligence, blockchain, virtual, and augmented reality, to name but a few, are providing significant benefits to patients and the pharmaceutical sector alike, ranging from improving access to clinicians and medicines, as well as improving real-time diagnoses and treatments. Indeed, it is envisioned that such technologies will communicate together in real-time, as well as with their physical counterparts, to create a large-scale, cyber healthcare system. Despite the significant benefits that virtual-based digital health technologies can bring to patient care, a number of challenges still remain, ranging from data security to acceptance within the healthcare sector. This review provides a timely account of the benefits and challenges of virtual health interventions, as well an outlook on how such technologies can be transitioned from research-focused towards real-world healthcare and pharmaceutical applications to transform treatment pathways for patients worldwide.

Science- and risk-based strategy to qualify prefillable autoclavable syringes as primary packaging material.

OBJECTIVES: To develop a science and risk based strategy to qualify a prefillable autoclavable cyclic olefin polymer (COP) syringe as a container for multiple drug products in a hospital pharmacy setting METHODS: Different extraction studies were performed with different solution characteristics: phosphate buffer batches (Na2HPO4 / NaH2PO4 in NaCl 0.9%) at different pH values, NaCl 0.9% batches, isopropyl alcohol (IPA) 5% in water and batches with Water For Injections (WFI) at different pH values. The filled syringes were terminally sterilised. The syringes were stored at room temperature (20°C±5°C).Following different monographs of the European Pharmacopoeia several tests were performed on the different batches. Analyses were performed at t=0, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 and 36 months for the general tests. For the subvisible particles, sterility and closure integrity a bracketing scheme was applied during 36 months. RESULTS: Low levels of extractables were measured for the different solutions. The test for subvisible particles, sterility and closure integrity all met predefined requirements. In the 5mL and 50mL syringes different concentrations of silicon were measured. Overall higher silicon concentrations were measured for the 50mL syringes. CONCLUSIONS: The chosen strategy for the qualification program provided an adequate understanding about the extractables that could leak from the syringes. The cyclic olefin polymer syringes including stopper and tip cap were found to be suitable as primary packaging materials for the production of water based products.

Digitalization in pharmaceutical industry: What to focus on under the digital implementation process?

Digitalization of any manufacture industry is a key step in any progress of the production process. The process of digitalization includes both increased use of robotics, automatization solutions and computerization, thereby allowing to reduce costs, to improve efficiency and productivity, and to be flexible to changes. Pharmaceutical Industry (PI) has however been resistant to digitalization, mainly due to fair experience and complexity of the entailed development and manufacture processes. Nevertheless, there is a clear need to digitalize PI as the demand in both traditional and new drugs is constantly growing. Contract Development Manufacture Organizations (CDMOs) have a special digitalizing challenge. Digitalization of PI, and CDMO precisely, should be tightly related to the main aspects of Good Manufacture Practice (GMP), and, to succeed in PI digitalizing requires constant focus on GMP. Close collaboration with constantly changing stakeholders is another important factor which should be in focus during digitalization of CDMO. This paper represents an overview over the main aspects of CDMO digitalization and discusses both the opportunities and challenges of the process, focusing on the practical solutions for successive digital implementation.

Refinement of an open-microcavity optical biosensor for bacterial endotoxin test.

The Limulus Amebocyte Lysate (LAL) test is an in vitro assay widely used in the pharmaceutical and biotechnology industries to detect bacterial endotoxins. Endotoxin is a structural component of the cell wall of Gram-negative bacteria, which has serious pathogenic effects in the body and may cause dysfunction of multiple organ systems and increased risk of mortality. To address the growing need for LAL assays due to the increased demand from drug and vaccine manufacturers, we have developed a new LAL assay approach. Our detection mechanism is different and improved from those currently used in the industry, leading to increased test sensitivity and reduced assay time. Our study utilizes an open-microcavity photonic-crystal biosensor to quantify endotoxin concentrations. It has demonstrated an improved LAL assay sensitivity by 10 fold compared to the commercial standard methods and reduced the time needed for the assay by more than half. In addition, this approach requires as little as 5 µL of LAL reagent per test, thereby decreasing costs and conserving horseshoe crabs. The results reported in this paper indicate the possibility of using the photonic-crystal biosensor based approach for significant enhancements of endotoxin testing.

A Non-Profit Approach to Address Foreign Dependence of Generic Drugs.

The COVID-19 pandemic has revealed the vulnerability of the US generic drug supply chain to foreign production. Many policies have been proposed to mitigate this vulnerability. In this article, we argue that nonprofit drug manufacturers have the potential to make important contributions.

Development, validation and regulatory acceptance of improved purification and simplified quality control of [13N] Ammonia.

BACKGROUND: [13N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [13N]ammonia cyclotron targets using a solution of 5 mM ethanol in water, there was a need to develop and validate an automated purification and formulation system for [13N]ammonia to be in a physiological compatible formulation of 0.9% sodium chloride since there is no widely available commercial system at this time. Due to its short half-life of 10 min, FDA and USP regulations allow [13N]ammonia to be tested in quality control (QC) sub-batches with limited quality control testing performed on the sub-batches for patient use. The current EP and the original USP method for the determination of the radiochemical purity and identity of [13N]ammonia depended on an HPLC method using a conductivity detector and a solvent free of other salts. This HPLC method created issues in a modern cGMP high volume PET manufacturing facility where the HPLC is used with salt containing mobile phase buffers for quality control analysis of other PET radiopharmaceuticals. Flushing of the HPLC system of residual salt buffers which may interfere with the [13N]ammonia assay can take several hours of instrument time. Since there are no mass limits on [13N]ammonia, a simplified TLC assay to determine radiochemical identity and purity could be developed to simplify and streamline QC. RESULTS: We have developed and validated a streamlined automated synthesis for [13N]ammonia which provides the drug product in 8 mL of 0.9% sodium chloride for injection. A novel radio-TLC method was developed and validated to demonstrate feasibility to quantitate [13N]ammonia and separate it from all known radiochemical impurities. CONCLUSIONS: The process for automated synthesis of [13N]ammonia simplifies and automates the purification and formulation of [13N]ammonia in a cGMP compliant manner needed for high-throughput manufacture of [13N]ammonia. The novel radio-TLC method has simplified [13N]ammonia quality control (QC) and now enables it to be tested using the same QC equipment as [18F]fludeoxyglucose (FDA/USP recognized name for 2-[18F]fluoro-2-deoxy-D-glucose). Both the streamlined automated synthesis of [13N]ammonia and the novel radio-TLC method have been accepted and approved by the US Food and Drug Administration (FDA) for the cGMP manufacture of [13N]ammonia.

Results of EAHP's 2019 Medicines Shortages Survey.

AIMS AND OBJECTIVES: The aim of the 2019 EAHP Medicines Shortages Survey was to collect information on reasons and management strategies for medicines shortages as well as details on their impact on patients. The survey targeted hospital pharmacists (HPs), physicians (PHYs), nurses (NRS) and other healthcare professionals (OHCPs). A separate set of questions addressed patients (PTNs). METHODS: A 28-question survey was conducted by EAHP, collecting information from European HPs, PTNs, NRS, PHYs and OHCPs on the shortage situation in their respective countries. The survey ran from 7 November 2019 to 13 January 2020. The results were analysed by EAHP. RESULTS: There were 2136 HP responses to the 2019 survey compared with 1666 in 2018. While 95% of HPs and 89% of OHCPs consider medicine shortages a current problem, only 71% of PHYs and 62% of NRS state the same. Shortages of active pharmaceutical ingredients (72%), manufacturing (72%) and supply chain problems (49%) are leading causes of shortages according to HPs, while PHYs (40%) and NRS (37%) consider the pricing to be their driver. Antimicrobials and oncology medicines were most affected by shortages in 2019. Compared to 2018, the percentage of respondents who reported shortages of oncology medicines increased from 39% to 47% in 2019. HPs (42%), PHYs (36%) and OHCPs (38%) consider delays in care as the main consequence of medication shortages. The satisfaction with reporting systems for medicine shortages decreased from 56% in 2018 to 48% in 2019 for HPs, while they remain low for PHYs (36%). CONCLUSIONS: Medicines shortages affect patient care and healthcare professionals' everyday tasks. Better enforcing of the mandatory early notification of shortages and structured mitigation response is recognised by all respondents as best strategy to tackle shortages.

Compatible stability of methylprednisolone sodium succinate and tropisetron in 0.9% sodium chloride injection.

Background: A combination of methylprednisolone sodium succinate and tropisetron hydrochloride is commonly used to treat the nausea and vomiting associated with antineoplastic therapy. The objective of this study was to investigate the stability of tropisetron hydrochloride and methylprednisolone sodium succinate in 0.9% sodium chloride injection for up to 48 hours. Methods: Commercial solutions of methylprednisolone sodium succinate and tropisetron hydrochloride were obtained and further diluted with 0.9% sodium chloride injection to final concentrations of either 0.4 or 0.8 mg/mL (methylprednisolone sodium succinate) and 0.05 mg/mL (tropisetron). The admixtures were assessed for periods of up to 48 hours after storage at 4°C with protection from light and at 25°C without protection from light. Physical compatibility was determined visually, and the chemical compatibility was measured with high-performance liquid chromatography (HPLC) and by measurement of pH values. Results: HPLC analysis demonstrated that methylprednisolone sodium succinate and tropisetron hydrochloride in the various solutions were maintained at 97% of the initial concentrations or higher during the testing period. There were no changes observed by physical precipitation or pH in any of the prepared solutions. Conclusions: Tropisetron hydrochloride injection and methylprednisolone sodium succinate injection in 0.9% sodium chloride injection are stable for up to 48 hours at 4°C and 25°C.

Microbiological validation of a robot for the sterile compounding of injectable non-hazardous medications in a hospital environment.

Objectives: To design and execute a comprehensive microbiological validation protocol to assess a brand-new sterile compounding robot in a hospital pharmacy environment, according to ISO and EU GMP standards. Methods: Qualification of the Class-A inner environment of the robot was performed through microbial air and surface quality assessment utilising contact plates, swabs and particulate matter monitoring. To evaluate the effectiveness of the microbial decontamination process (UV rays) challenge test against Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis spores and Candida albicans was used. The challenge Media Fill test was used to validate the aseptic processing. Results: After 3 hours, no microorganisms retained viability. Monitoring inside the equipment evidenced complete absence of microorganisms. The Media Fill test was always negative. Conclusions: According to our results, the APOTECAunit meets the requirements for advanced aseptic processing in the hospital pharmacies and the pharmaceutical industry in general, providing advantages in terms of safety for patients compared with conventional procedures of parenteral preparation production. The protocol has demonstrated to be a comprehensive and valuable tool in validating, from a microbial point of view, a sterile-compounding technology. This study might represent an important benchmark in developing a contamination control strategy, as required, for example, in the Performance Qualification of the GMP in the case of drug manufacturing.

New regulatory strategies to manage medicines shortages in Europe.

Medicine shortages have been spreading in European countries. In many cases, the unavailability of medicinal products has a substantial impact on the capability of National Healthcare Systems in ensuring the continuity of care. Shortages originate from multifactorial causes. In particular, they can be due to supply-related factors (e.g., manufacturing issues, regulatory issues, logistics, distribution) and demand-related ones (e.g., fluctuating drug demand, parallel market, tendering, price and reimbursement policies). However, some extraordinary geopolitical events (e.g., Brexit) may also affect medicines' availability. The capability of European Regulatory Authorities and other stakeholders, which are involved in the pharmaceutical distribution chain and the healthcare assistance services, to define suitable problem-solving strategies has been limited for years by the fragmentation of the European regulatory framework, starting from the lack of a univocal definition of a medicine shortage. Only in 2019, the EMA and HMA joint task force released the first harmonized "shortage" definition in the European Economic Area (EEA) and guidance on public communication. This manuscript aims to review the current European regulatory framework on medicine shortages. To support the activities of regulators, manufacturers and other healthcare professionals, an algorithm was also proposed to be used as a harmonized procedure to determine the shortage/unavailability impact on public health and to rationalize the problem-solving strategies adopted in all different settings.

A multistate investigation of health care-associated Burkholderia cepacia complex infections related to liquid docusate sodium contamination, January-October 2016.

BACKGROUND: Outbreaks of health care-associated infections (HAIs) caused by Burkholderia cepacia complex (Bcc) have been associated with medical devices and water-based products. Water is the most common raw ingredient in nonsterile liquid drugs, and the significance of organisms recovered from microbiologic testing during manufacturing is assessed using a risk-based approach. This incident demonstrates that lapses in manufacturing practices and quality control of nonsterile liquid drugs can have serious unintended consequences. METHODS: An epidemiologic and laboratory investigation of clusters of Bcc HAIs that occurred among critically ill, hospitalized, adult and pediatric patients was performed between January 1, 2016, and October 31, 2016. RESULTS: One hundred and eight case patients with Bcc infections at a variety of body sites were identified in 12 states. Two distinct strains of Bcc were obtained from patient clinical cultures. These strains were found to be indistinguishable or closely related to 2 strains of Bcc obtained from cultures of water used in the production of liquid docusate, and product that had been released to the market by manufacturer X. CONCLUSIONS: This investigation highlights the ability of bacteria present in nonsterile, liquid drugs to cause infections or colonization among susceptible patients. Prompt reporting and thorough investigation of potentially related infections may assist public health officials in identifying and removing contaminated products from the market when lapses in manufacturing occur.

Stability of daptomycin reconstituted vials and infusion solutions.

OBJECTIVES: Daptomycin is a cyclic lipopeptide with selective action against drug-resistant Gram-positive bacteria. The stability of daptomycin solutions in different containers while stored at different temperatures was assessed. METHODS: Daptomycin vials were reconstituted with NaCl (50 mg/mL). Daptomycin infusion solutions (5.6 and 14.0 mg/mL) were prepared in polypropylene infusion bags. All test solutions were stored either under refrigeration or at room temperature over 7 days. Samples were withdrawn on days 0, 2, 4 and 7 and assayed in triplicate using a stability-indicating high-performance liquid chromatography (HPLC) method. RESULTS: The HPLC analysis revealed no significant loss in daptomycin concentration in vials or bags when stored at 2-8°C. All samples remained clear and colourless and there were no significant changes in pH throughout the study period. CONCLUSIONS: Reconstituted daptomycin vials (50 mg/mL) and infusion bags (5.6 and 14 mg/mL) were found to be physicochemically stable over a period of 1 week when stored at 2-8°C.

Compatibility of proton pump inhibitors in a preservative-free suspending vehicle.

OBJECTIVES: To evaluate the microbiological and physicochemical compatibility of commonly used proton pump inhibitors (PPIs) esomeprazole, lansoprazole, omeprazole and pantoprazole compounded at a single concentration using SyrSpend SF Alka and stored at refrigerated temperatures (omeprazole was also stored at room temperature because it has the most widespread use). METHODS: Compatibility was assessed by measuring the per cent recovery at varying time points throughout a 90-day period. Quantification of the APIs was performed by a validated high performance liquid chromatography (HPLC-UV) method. This same assay was also used to determine the dosage content uniformity of the suspensions. Microbiological stability ('test in use') was assessed during 60 days and total aerobic microbial count (TAMC), total combined yeasts and moulds count (TYMC), detection of Escherichia coli and pH determination were performed. Antimicrobial effectiveness testing was determined following European Pharmacopoeia guidelines. RESULTS: Beyond-use dates of maximum 60 days for omeprazole (5 mg/mL), pantoprazole (3 mg/mL) and esomeprazole (3 mg/mL) were established. All suspensions that met the physicochemical criteria for stability also met the content uniformity criteria. The suspensions showed no antimicrobial efficiency against bacteria, yeasts and moulds as SyrSpend SF Alka is an unpreserved vehicle, but the 'test in use' showed that the suspensions can remain microbiologically stable for up to 60 days. CONCLUSIONS: SyrSpend SF Alka can be used to compound palatable (taste-masking properties) preservative-free oral suspensions with almost all commonly used PPIs.