Assessment of procurement, distribution, availability, and utilization of rabies biologicals for postexposure prophylaxis in seven states of India.

BACKGROUND: To achieve the elimination of dog-mediated human rabies by 2030, all bite victims shall have access to life-saving rabies biologicals across the country. The information on procurement, distribution, availability, and utilization of rabies biologicals for postexposure prophylaxis is insufficient. OBJECTIVES: The objective of the study is to assess the demand, procurement, distribution, availability, storage, and utilization of rabies biologicals and to appraise the monitoring and reporting of rabies biologicals at all the levels. METHODS: A multicentric survey was conducted from July to December 2017 in seven regional representative states across the country. The survey team visited the offices in-charge for logistics of rabies biologicals at the survey states and districts; information was collected using structured pro formas and perusing relevant records. District vaccine stores and health institutions in urban and rural areas were visited to assess the availability and stock-outs of rabies biologicals. RESULTS: Procurement, distribution, and availability of rabies biologicals grossly vary between states, since it is the state subject. In Gujarat, both vaccines and immunoglobulins were available even at the Primary Health Centre level; paradoxically, there was a scarcity of both at the district level in Manipur. Immunoglobulins were used only in nine of the surveyed 27 government health-care facilities (33.3%) and two of the eight private facilities (25%). The cold chain facility for storage of rabies biologicals was satisfactory; however, the monitoring and reporting of rabies biologicals were not complete. CONCLUSION: The procurement, distribution, availability, and utilization of rabies biologicals were not universal across the states. Frequent shortages of supply have to be improved to attain universal coverage.

Market mapping and landscape analysis of human rabies biologicals in India.

BACKGROUND: Rabies vaccines and immunoglobulins are lifesaving in humans following animal exposures. These biologicals should continuously be available throughout the year to prevent and eliminate human rabies by 2030. OBJECTIVES: The present study aimed at assessing availability of different kinds of human rabies biologicals in the country and undertaking market mapping and landscape analysis of human rabies biologicals in India. METHODS: The study comprising both quantitative and qualitative approach was conducted from May to November 2017 as a part of the Indian multicentric rabies survey by Association for Prevention and Control of Rabies in India. All stakeholders (agencies/personnel) associated with rabies biologicals were the study units/participants. Required data were generated through brainstorming sessions with key stakeholders; reviewing of databases/existing literature; conducting in-depth surveys; interviewing; focused group discussions, etc. RESULTS: Two types of cell culture rabies vaccines are available in the country manufactured by different pharmaceutical companies; most of the vaccines are indigenously produced and the market size of the rabies vaccines is about INR 125 crores with highest sales in the northern region followed by South. Likewise, there are 2 types of immunoglobulin available, i.e., equine rabies immunoglobulins (RIGs), which are indigenously produced and human RIGs, which are imported. The market value of RIGs is about INR 83 crores. A novel rabies monoclonal antibody is also been marketed in the country from November 2017. CONCLUSIONS: There are many lacunas in the market availability of rabies biologicals in different parts of the country; therefore, a significant expansion/shift in focus must be considered, through rigorous strategic planning process.

Evaluation of Vietnam's post-exposure prophylaxis delivery system, 2017.

BACKGROUND: Canine-mediated human rabies deaths typically occur in poor and rural populations with limited access to rabies biologics: vaccine and immunoglobulin. A critical aspect of reducing rabies deaths is understanding how these countries procure, deliver, and forecast rabies biologics. Vietnam is one of the few endemic countries where biologics is widely available. However, a formal evaluation of its current rabies biologics distribution system has not been conducted. METHODS: In 2017, we conducted a formal evaluation of Vietnam's rabies biologics distribution system. Our goals were (1) to identify centers providing rabies biologics (2) identify costs to the patient and centers and (3) assess the rabies biologic procurement and delivery system at eligible district and provincial centers (provides and orders biologics for itself and other centers directly from the manufacture). To conduct the formal evaluation, we developed a standardized survey that was distributed to centers. RESULTS: Of the 780 designated rabies biologics centers in Vietnam, 659 (84%) of them provide rabies immunoglobulin (eRIG), vaccine, or both. Of the 177 eligible centers, 90% (160) responded to the survey. The average costs to patients were $8.45 (range: 5.43-12.77) for one dose of IM injection, $13.90 (range: 11.86-16.71) for domestic eRIG, and $23 (21.11-27.11) for imported eRIG. Respondents reported experiencing delays in receiving vaccine in 50 centers and eRIG in 14 centers within the past year. Respondents stated their top three challenges in providing biologics were: delays or shortages from manufactures, lack of funds to pay for biologics, and the high cost of biologics. CONCLUSIONS AND RELEVANCE: Despite the wide availability of biologics in Vietnam, more work is needed to provide affordable and reliable supply of biologics to patients. This includes the expansion of ID injection use throughout the country to lower vaccine demand, and decrease the costs to centers and patients. Furthermore, a more coordinated effort to share biologics among centers, possibly through a more centralized system at the provincial level may alleviate delays and shortages.

Ensuring Product Quality, Consistency and Patient Supply over Time for a Large-Volume Biologic: Experience with Remicade®.

Biologics are produced from living organisms in complex, multi-stage manufacturing processes and contain inherent variability, which must be understood and controlled during manufacturing to avoid unexpected changes in key quality attributes that may contribute to clinically meaningful differences. The process must also meet large commercial demand, while simultaneously being able to accommodate change without sacrificing product consistency. The four key components of successful biologics manufacturing are (1) a stable, well-defined proprietary cell line; (2) a good manufacturing practice (GMP)-compliant supply chain with a process control strategy defining acceptable levels of variability for target product/process attributes and capable of managing complex material flows; (3) a tightly controlled procedure for implementation of proposed process changes that ensures product consistency; and (4) built-in redundancy and flexibility providing the ability to adapt rapidly to unexpected developments. This report describes the requirements for the manufacturing and distribution of biologics, using Remicade® (infliximab, Janssen Biotech, Horsham, PA, USA) as an example of best practices. Since Remicade's first marketing approval in 1998, Janssen has manufactured > 150 million vials used to treat > 2.6 million patients around the world for a variety of inflammatory diseases. Remicade displays a highly consistent quality attribute profile and meets all product/process specifications across multiple manufacturing sites and process scales. Janssen's experience with Remicade demonstrates that deep product knowledge, extensive manufacturing experience, diligent product/process monitoring and a sustained commitment to compliance and research are required to ensure quality, consistency and uninterrupted patient supply for large-volume biologics over the long term.

Propuesta de clasificación de insumos para la gestión de inventarios en la industria biofarmacéutica. Caso de Estudio en el Centro de Inmunología Molecular / A proposal for input classification for inventory management in the biopharmaceutical industry. Study case in the Molecular Immunology Center

El surgimiento del sector biotecnológico inició una revolución en las bases tradicionales de competencia en la industria farmacéutica en términos de desarrollo y fabricación de productos, orientados principalmente a salud humana. La gestión de inventarios en esta industria es muy compleja, con grandes volúmenes y variedad de inventario, dado por la complejidad de mantener dos procesos que tienen efecto en la gestión de inventarios, relacionados con la investigación y desarrollo, y producción. La complejidad de estos procesos exige de un sistema logístico con capacidad y flexibilidad suficiente para adaptarse a las distintas regulaciones existentes y la variación en los planes de ventas, además de un sistema informático que permita integrar las partes del sistema. El presente artículo tiene el propósito de evaluar la situación de la Gestión de Inventarios en el Centro de Inmunología Molecular a partir de la implementación de los conceptos de Insumo Proyecto e Insumo Proceso. Para el desarrollo de la investigación se emplearon diferentes métodos y herramientas como: análisis bibliográfico, entrevistas a expertos, consultas de registros, tormenta de ideas, entre otros. Entre las herramientas utilizadas se encuentran: Modelo de Referencia para la Evaluación de la Gestión de Inventarios, Microsoft Excel y Diagrama Causa-Efecto. Los resultados demuestran el impacto positivo alcanzado por la diferenciación entre los insumos utilizados en procesos productivos e investigación, por el alcance dado en distintos procesos de la Gestión de Inventarios en el orden organizativo y financiero, logrando la mejora de indicadores como rotación de inventarios, ciclo de importación y satisfacción del cliente(AU)

The emergence of the biotechnological sector started a revolution in the traditional competitive basis of the pharmaceutical industries, in terms of development and manufacture of products, especially those aimed at human health. Inventory management in this industry is very complex, with varied, high-volume inventories, given the complexity of executing two processes that have an effect on inventory management: production, and R&D. The complexity of these processes demands a logistical system with the capacity and flexibility to adapt to the many different regulations in existence and changes in sales plans, and an informatics solution that allows integration of the different parts of the system. The current article aims to evaluate the situation of Inventory Management at the Molecular Immunology Center from the implementation of the concepts of Project Input and Process Input. The research was carried out through diverse methods and tools including bibliographic analysis, expert interviews, record querying, and brainstorming. The tools used included: Reference Model for Inventory Management Evaluation, Microsoft Excel, and cause-effect diagrams. The results show a positive impact achieved by differentiating inputs used for production and inputs used for R&D, and its reach into the process of Inventory Management at the organization level, improving indicators like inventory rotation, importing cycle, and client satisfaction(AU)

Inequalities in access to biological treatments for psoriasis: results from the Italian Psocare registry.

BACKGROUND: Limited evidence is available on the impact of socioeconomic factors on drug prescriptions for psoriasis. OBJECTIVES: To investigate factors influencing prescription of conventional vs. biological treatment for patients with psoriasis, based on the Italian Psocare registry, with a special focus on socioeconomic factors. METHODS: This was a cross-sectional study evaluating the baseline data of patients included in the Psocare registry. All of the consecutive adult patients with a diagnosis of chronic plaque psoriasis or psoriatic arthritis who were prescribed a systemic treatment for psoriasis at participating centres were included in this study. Univariate and multivariate analyses of the baseline factors associated with a biologics prescription were performed. RESULTS: From September 2005 to September 2009, 12 838 patients were identified. A multivariate analysis revealed that, among other factors, completing a level of education higher than lower secondary school and being employed as a manager or a professional were independent factors associated with a biologics prescription at entry in the registry. Additional analyses on the association between these two variables and a severe psoriasis condition [Psoriasis Area Severity Index (PASI) score > 20] revealed a significantly increasing trend of severe disease towards lower educational attainment, while unemployed patients were more likely to have a more severe condition compared with the other categories of workers. CONCLUSIONS: We documented inequalities of drug prescriptions for psoriasis in Italy, with a trend towards a higher frequency of prescription for more expensive biologics in higher socioeconomic sectors of the population.

Approaches to Quality Risk Management When Using Single-Use Systems in the Manufacture of Biologics.

Biologics manufacturing technology has made great progress in the last decade. One of the most promising new technologies is the single-use system, which has improved the efficiency of biologics manufacturing processes. To ensure safety of biologics when employing such single-use systems in the manufacturing process, various issues need to be considered including possible extractables/leachables and particles arising from the components used in single-use systems. Japanese pharmaceutical manufacturers, together with single-use suppliers, members of the academia and regulatory authorities have discussed the risks of using single-use systems and established control strategies for the quality assurance of biologics. In this study, we describe approaches for quality risk management when employing single-use systems in the manufacturing of biologics. We consider the potential impact of impurities related to single-use components on drug safety and the potential impact of the single-use system on other critical quality attributes as well as the stable supply of biologics. We also suggest a risk-mitigating strategy combining multiple control methods which includes the selection of appropriate single-use components, their inspections upon receipt and before releasing for use and qualification of single-use systems. Communication between suppliers of single-use systems and the users, as well as change controls in the facilities both of suppliers and users, are also important in risk-mitigating strategies. Implementing these control strategies can mitigate the risks attributed to the use of single-use systems. This study will be useful in promoting the development of biologics as well as in ensuring their safety, quality and stable supply.

Access to Care for Multiple Sclerosis in Times of Economic Crisis in Greece--the HOPE II Study.

BACKGROUND: While there is currently no cure for multiple sclerosis (MS), treatment with biologic disease-modifying drugs (bDMDs) can reduce the impact of the condition on the lives of patients. In Greece, the regulatory change in the distribution system of bDMDs, limited their administration through the designated pharmacies of the National Organization for Healthcare Services Provision (EOPYY) or the National Health System (ESY) hospitals, thus potentially impacting access to MS treatment. In this context, the aim of this paper was to assess the barriers to bDMDs, by recording MS patients' experiences. METHODS: A survey research was conducted between January and February 2014 in Athens and 5 other major Greek cities with the methods of personal and telephone interview. A structured questionnaire was used to elicit socio-economic and medical information, information related to obstacles in accessing bDMDs and medical treatment, from MS patients that visited EOPYY pharmacies during the study period. RESULTS: During the last year 69% of 179 participants reported that the distribution system of bDMDs has improved. Thirteen percent of participants encountered problems in accessing their medication, and 16.9% of participants in accessing their physician, with the obstacles being more pronounced for non-Athens residents. Frequent obstacles to bDMDs were the distance from EOPYY pharmacies and difficulties in obtaining a diagnosis from an EOPYY/ESY physician, while obstacles to medical care were delays in appointment booking and travel difficulties. CONCLUSION: Even though the major weaknesses of the distribution system of bDMDs have improved, further amelioration of the system could be achieved through the home delivery of medicines to patients living in remote areas, and through the development of a national MS registry.

Drift, evolution, and divergence in biologics and biosimilars manufacturing.

Biological medicines (biologics) are produced in living cells and purified in complex, multi-step processes. Compared with chemically synthesized small-molecule drugs, biologics are more sensitive to changes in manufacturing conditions. Process and product consistency should be founded on rigorous design and control of manufacturing processes, but consistency is ultimately ensured through robust quality systems. Even a minor change in any component of a quality system could lead to product drift, evolution, and divergence, which may impact the quality, safety, efficacy, and/or interchangeability of biologics. Unintended or unexplained deviations in manufacturing processes can lead to excursions in product attributes (i.e., drift). Well-managed quality systems can help detect and mitigate drift. Occasionally, quality attributes could shift outside of established acceptable ranges as the result of a known manufacturing change (defined here as evolution). Such changes should be studied extensively for effects on product safety and efficacy. With the advent of biosimilars, similar biologics will be produced by multiple manufacturers with different quality systems. Different patterns of product drift and evolution could contribute, over time, to clinically meaningful differences among biologics, including among originator products across regions and among originator products and biosimilar products, a process defined here as divergence. Manufacturers and policymakers can minimize the potential impact of divergence by establishing robust pharmacovigilance systems; requiring distinguishable names for all biologics, including both originator products and biosimilars; adhering to high standards for designations of interchangeability; and ensuring that patient medical records accurately reflect the specific biologic dispensed, especially if the biologic could be sourced from multiple manufacturers.

Strategic plan aims to curb drug shortages.

The U.S. Food and Drug Administration has released a strategic plan to strengthen its response to imminent and existing drug shortages, as well as a proposed rule requiring manufacturers of drugs and biologics to alert the agency to the impending discontinuation of any products or interruptions in manufacturing that could deplete supply.

Preventing shortages of biologic medicines.

Shortages of small-molecule injectable drugs have captured the attention of patients, healthcare providers, regulators and policy makers in recent years. While these shortages have several causes, non-compliance with current good manufacturing practice and subsequent shutdowns of manufacturing facilities have played a central role. Sterile injectable drugs are particularly susceptible to manufacturing quality disruptions because of their sensitivity to contamination. Biologics are subject to the same fill-finish contamination risk as sterile injectables, but their active ingredients are also sensitive to subtle changes in the manufacturing process and to storage and handling of their final dosage forms. Originator biologics will lose market exclusivity in the years ahead as patents expire and as competitors develop biosimilar products. The availability of therapeutic alternatives may provide opportunities to reduce costs and increase patient access, but this should not come at the expense of critical investments in the manufacturing of these complex and sensitive products.

Barriers to accessing biologic treatment for rheumatoid arthritis in Greece: the unseen impact of the fiscal crisis--the Health Outcomes Patient Environment (HOPE) study.

The latest regulatory change in the distribution system of biologic disease-modifying, antirheumatic drugs limited their sale only through the designated pharmacies of the National Organization for Healthcare Services Provision (EOPYY) or the National Health System (NHS) hospitals, adding to the complexity of access to effective treatment for rheumatoid arthritis (RA) in Greece. The aim of this paper was to assess the barriers to access RA treatment, by recording patients', rheumatologists' and EOPYY pharmacists' experiences. One twenty-three patients, 12 rheumatologists and 27 pharmacists from Athens and other urban areas in Greece participated in the study. Three types of standardized questionnaires were used to elicit information from each group of respondents using the method of personal interview for patients and the method of postal survey for doctors and pharmacists. During the last year, 26% of patients encountered problems in accessing their rheumatologist and 49% of patients experienced difficulties in accessing their medication. Ninety-two percent of rheumatologists and 96% of pharmacists confirmed that patients experience difficulties in accessing RA medication. The most commonly reported reasons for reduced access to medical treatment were travel difficulties and long distance from doctor's clinic, as well as delays in booking an appointment. The most frequently reported barriers to access pharmaceutical treatment were difficulties in the prescription process, distance from EOPYY pharmacies and medicine shortages in NHS hospitals. The study showed that RA patients are facing increased barriers to access timely and effective treatment. Redesign of the current system of distribution ensuring the operation of additional points of sale is deemed necessary.

Mammalian cell culture capacity for biopharmaceutical manufacturing.

: With worldwide sales of biopharmaceuticals increasing each year and continuing growth on the horizon, the manufacture of mammalian biopharmaceuticals has become a major global enterprise. We describe the current and future industry wide supply of manufacturing capacity with regard to capacity type, distribution, and geographic location. Bioreactor capacity and the use of single-use products for biomanufacturing are also profiled. An analysis of the use of this capacity is performed, including a discussion of current trends that will influence capacity growth, availability, and utilization in the coming years.

Mammalian cell cultures for biologics manufacturing.

Biopharmaceuticals represent a growing sector of the pharmaceutical industry, and are used for a wide range of indications, including oncology and rheumatology. Cultured mammalian cells have become the predominant expression system for their production, partly due to their ability to complete the posttranslational modifications required for drug safety and efficacy. Over the past decade, the productivity of mammalian cell culture production processes has growth dramatically through improvements in both volumetric and specific productivities. This article presents an overview of the biologics market, including analysis of sales and approvals; as well as a review of industrial production cell lines and cell culture operations.