Challenges and Opportunities of Implementing Data Fusion in Process Analytical Technology-A Review.

The release of the FDA's guidance on Process Analytical Technology has motivated and supported the pharmaceutical industry to deliver consistent quality medicine by acquiring a deeper understanding of the product performance and process interplay. The technical opportunities to reach this high-level control have considerably evolved since 2004 due to the development of advanced analytical sensors and chemometric tools. However, their transfer to the highly regulated pharmaceutical sector has been limited. To this respect, data fusion strategies have been extensively applied in different sectors, such as food or chemical, to provide a more robust performance of the analytical platforms. This survey evaluates the challenges and opportunities of implementing data fusion within the PAT concept by identifying transfer opportunities from other sectors. Special attention is given to the data types available from pharmaceutical manufacturing and their compatibility with data fusion strategies. Furthermore, the integration into Pharma 4.0 is discussed.

Challenges and Opportunities While Developing a Group A Meningococcal Conjugate Vaccine Within a Product Development Partnership: A Manufacturer's Perspective From the Serum Institute of India.

BACKGROUND: In 2002, the Meningitis Vaccine Project (MVP) chose the Serum Institute of India, Ltd (SIIL), as its manufacturing partner to establish a product development partnership (PDP) with the Meningitis Vaccine Project (MVP). MVP was a collaboration between PATH and the World Health Organization (WHO) to develop meningococcal conjugate vaccines for sub-Saharan Africa. METHOD: From the outset, SIIL recognized that a partnership with MVP carried some risk but also offered important opportunities for accessing new conjugate vaccine technology and know-how. Over 3 years, SIIL successfully accepted technology transfer for the group A meningococcal polysaccharide from SynCo Bio Partners and a conjugation method from the US Food and Drug Administration. RESULTS: SIIL successfully scaled up production of a group A meningococcal conjugate vaccine that used SIIL tetanus toxoid as the carrier protein. Phase 1 studies began in India in 2005, followed by phase 2/3 studies in Africa and India. A regulatory dossier was submitted to the Indian authorities in April 2009 and WHO in September 2009. Export license was granted in December 2009, and WHO prequalification was obtained in June 2010. Vaccine was introduced at public scale in Burkina Faso that December. The group A meningococcal conjugate vaccine was named MenAfriVac, and is the first internationally qualified vaccine developed outside of big pharma. CONCLUSIONS: The project proved to be a sound investment for SIIL and is a concrete example of the potential for PDPs to provide needed products for resource-poor countries.

The Evolution of the Meningitis Vaccine Project.

BACKGROUND: In 2001, the Meningitis Vaccine Project (MVP) was tasked to develop, test, license, and introduce a group A meningococcal (MenA) conjugate vaccine for sub-Saharan Africa. African public health officials emphasized that a vaccine price of less than US$0.50 per dose was necessary to ensure introduction and sustained use of this new vaccine. METHODS: Initially, MVP envisioned partnering with a multinational vaccine manufacturer, but the target price and opportunity costs were problematic and formal negotiations ended in 2002. MVP chose to become a "virtual vaccine company," and over the next decade managed a network of public-private and public-public partnerships for pharmaceutical development, clinical development, and regulatory submission. MVP supported the transfer of key know-how for the production of group A polysaccharide and a new conjugation method to the Serum Institute of India, Ltd, based in Pune, India. A robust staff structure supported by technical consultants and overseen by advisory groups in Europe and Africa ensured that the MenA conjugate vaccine would meet all international standards. RESULTS: A robust project structure including a team of technical consultants and 3 advisory groups in Europe and Africa ensured that the MenA conjugate vaccine (PsA-TT, MenAfriVac) was licensed by the Drug Controller General of India and prequalified by the World Health Organization in June 2010. The vaccine was introduced in Burkina Faso, Mali, and Niger in December 2010. CONCLUSIONS: The development, through a public-private partnership, of a safe, effective, and affordable vaccine for sub-Saharan Africa, PsA-TT, offers a new paradigm for the development of vaccines specifically targeting populations in resource-poor countries.

Emergence of biopharmaceutical innovators in China, India, Brazil, and South Africa as global competitors and collaborators.

Biopharmaceutical innovation has had a profound health and economic impact globally. Developed countries have traditionally been the source of most innovations as well as the destination for the resulting economic and health benefits. As a result, most prior research on this sector has focused on developed countries. This paper seeks to fill the gap in research on emerging markets by analyzing factors that influence innovative activity in the indigenous biopharmaceutical sectors of China, India, Brazil, and South Africa. Using qualitative research methodologies, this paper a) shows how biopharmaceutical innovation is taking place within the entrepreneurial sectors of these emerging markets, b) identifies common challenges that indigenous entrepreneurs face, c) highlights the key role played by the state, and d) reveals that the transition to innovation by companies in the emerging markets is characterized by increased global integration. It suggests that biopharmaceutical innovators in emerging markets are capitalizing on opportunities to participate in the drug development value chain and thus developing capabilities and relationships for competing globally both with and against established companies headquartered in developed countries.

Nomenclature and guideline to express the amount of a membrane protein synthesized in animal cells in view of bioprocess optimization and production monitoring.

Studies of a bioprocess optimization and monitoring for protein synthesis in animal cells face a challenge on how to express in quantitative terms the system performance. It is possible to have a panel of calculated variables that fits more or less appropriately the intended goal. Each mathematical expression approach translates different quantitative aspects. We can basically separate them into two categories: those used for the evaluation of cell physiology in terms of product synthesis, which can be for bioprocess improvement or optimization, and those used for production unit sizing and for bioprocess operation. With these perspectives and based on our own data of kinetic S2 cells growth and metabolism, as well as on their synthesis of the transmembrane recombinant rabies virus glycoprotein, here indicated as P, we show and discuss the main characteristics of calculated variables and their recommended use. Mainly applied to a bioprocess improvement/optimization and that mainly used for operation definition and to design the production unit, we expect these definitions/recommendations would improve the quality of data produced in this field and lead to more standardized procedures. In turn, it would allow a better and easier comprehension of scientific and technological communications for specialized readers.

Developing Vaccines for SARS-CoV-2 and Future Epidemics and Pandemics: Applying Lessons from Past Outbreaks.

The COVID-19 pandemic is a stark reminder of the heavy toll that emerging infectious diseases (EIDs) with epidemic and pandemic potential can inflict. Vaccine development, scale-up, and commercialization is a long, expensive, and risky enterprise that requires substantial upfront planning and offers no guarantee of success. EIDs are a particularly challenging target for global health preparedness, including for vaccine development. Insufficient attention has been given to challenges, lessons learned, and potential solutions to support and sustain vaccine industry engagement in vaccine development for EIDs. Drawing from lessons from the most recent Ebola epidemic in the Democratic Republic of the Congo, as well as the 2009 H1N1 influenza, 2014-2016 Ebola, and 2015-16 Zika outbreaks preceding it, we offer our perspective on challenges facing EID vaccine development and recommend additional solutions to prioritize in the near term. The 6 recommendations focus on reducing vaccine development timelines and increasing business certainty to reduce risks for companies. The global health security community has an opportunity to build on the current momentum to design a sustainable model for EID vaccines.

[Introducing the Academy of Pharmaceutical Science and Technology, Japan].

The Academy of Pharmaceutical Science and Technology, Japan (APSTJ) has contributed to advances in pharmaceutical sciences and progress in formulation technologies. The APSTJ has some 2000 individual members including pharmacists, researchers, technologists, and representatives of regulatory authorities. Remarkably, more than 800 individual members are from the industry. The APSTJ holds an annual meeting and several conferences or seminars on pharmaceutical technologies and skills. It has also set up 13 focus groups (FGs), including some working energetically on medical pharmacy research. For example, the FG on "personalized formulations" aims to develop a suitable dosage form for each individual patient to confirm the concept of personalized medication. To provide opportunities to hear the voices of patients and understand their medical needs, another FG has started a hospital-based internship program for industrial researchers. Furthermore, as an activity of the Japan Agency for Medical Research and Development, an industry-university joint consortium for "pediatric drug formulations" was organized within an FG to develop suitable formulations for pediatric use. The mission of the APSTJ is to provide safe, effective, user-friendly drug products based on pharmaceutical science and technology and cooperation with clinical researchers and medical staff.

Oligotrophic Media Compared with a Tryptic Soy Agar or Broth for the Recovery of Burkholderia cepacia Complex from Different Storage Temperatures and Culture Conditions.

The Burkholderia cepacia complex (BCC) is capable of remaining viable in low-nutrient environments and harsh conditions, posing a contamination risk in non-sterile pharmaceutical products as well as a challenge for detection. To develop optimal recovery methods to detect BCC, three oligotrophic media were evaluated and compared with nutrient media for the recovery of BCC from autoclaved distilled water or antiseptic solutions. Serial dilutions (10-1 to 10-12 CFU/ml) of 20 BCC strains were inoculated into autoclaved distilled water and stored at 6°C, 23°C and 42°C for 42 days. Six suspensions of Burkholderia cenocepacia were used to inoculate aqueous solutions containing 5 µg/ml and 50 µg/ml chlorhexidine gluconate (CHX) and 10 µg/ml benzalkonium chloride (BZK), and stored at 23°C for a further 199 days. Nutrient media such as Tryptic Soy Agar (TSA) or Tryptic Soy Broth (TSB), oligotrophic media (1/10 strength TSA or TSB, Reasoner's 2nd Agar [R2A] or Reasoner's 2nd Broth [R2AB], and 1/3 strength R2A or R2AB) were compared by inoculating these media with BCC from autoclaved distilled water and from antiseptic samples. The recovery of BCC in water or antiseptics was higher in culture broth than on solid media. Oligotrophic medium showed a higher recovery efficiency than TSA or TSB for the detection of 20 BCC samples. Results from multiple comparisons allowed us to directly identify significant differences between TSA or TSB and oligotrophic media. An oligotrophic medium pre-enrichment resuscitation step is offered for the United States Pharmacopeia (USP) proposed compendial test method for BCC detection.

Helping science to succeed: improving processes in R&D.

Bringing drugs to the market remains a costly and, until now, often unpredictable challenge. Although understanding the underlying science is key to further progress, our imperfect knowledge of disease and complex biological systems leaves excellence in execution as the most tangible lever to sustain our serendipitous approach to drug discovery. The problems encountered in pharmaceutical R&D are not unique, but to learn from other industries it is important to recognise similarity, rather than differences, and to advance industrialisation of R&D beyond technology and automation. Tools like Lean and Six Sigma, already applied to increase business excellence across diverse organisations, can equally be introduced to pharmaceutical R&D and offer the potential to transform operations without large-scale investment.

Scientific workflows as productivity tools for drug discovery.

Large pharmaceutical companies annually invest tens to hundreds of millions of US dollars in research informatics to support their early drug discovery processes. Traditionally, most of these investments are designed to increase the efficiency of drug discovery. The introduction of do-it-yourself scientific workflow platforms has enabled research informatics organizations to shift their efforts toward scientific innovation, ultimately resulting in a possible increase in return on their investments. Unlike the handling of most scientific data and application integration approaches, researchers apply scientific workflows to in silico experimentation and exploration, leading to scientific discoveries that lie beyond automation and integration. This review highlights some key requirements for scientific workflow environments in the pharmaceutical industry that are necessary for increasing research productivity. Examples of the application of scientific workflows in research and a summary of recent platform advances are also provided.

Handing over the baton: connecting medicinal chemistry with process R&D.

The pharmaceutical industry, as virtually any other industry, is continuously striving to become more effective and efficient. This demand for improving business processes is focused on all parts of the organization-from R&D and manufacturing to marketing and sales. Specifically from an R&D perspective, there are two areas that stand out as having caught more attention than others: attrition and timelines. While the former, so far, has seen relatively small changes for the better, the latter has reached clear targets in reducing the overall time required for the various activities conducted during drug discovery and development phases. For process R&D-the unit accountable for the design and optimization of small-molecule synthetic routes as well as delivery of active substance (API) for clinical and toxicological testing-the key contribution in this respect has been the shortening of lead times for supply of the first batch of material on scale. Thus, applying a work model based on balanced frontloading has shown that this crucial task can be taken off the critical path, and instead of delivering required API amounts several months post candidate drug nomination, the availability can now be guaranteed at or even ahead of reaching this milestone. The paradigm shift that has been necessary in order to reach this goal is the subject of this article.

Creating a learning organization to help meet the needs of multihospital health systems.

PURPOSE: The considerations that leaders of multihospital health systems must take into account in developing and implementing initiatives to build and maintain an exceptional pharmacy workforce are described. SUMMARY: Significant changes that require constant individual and organizational learning are occurring throughout healthcare and within the profession of pharmacy. These considerations include understanding why it is important to have a succession plan and determining what types of education and training are important to support that plan. Other considerations include strategies for leveraging learners, dealing with a large geographic footprint, adjusting training opportunities to accommodate the ever-evolving demands on pharmacy staffs in terms of skill mix, and determining ways to either budget for or internally develop content for staff development. All of these methods are critically important to ensuring an optimized workforce. Especially for large health systems operating multiple sites across large distances, the use of technology-enabled solutions to provide effective delivery of programming to multiple sites is critical. Commonly used tools include live webinars, live "telepresence" programs, prerecorded programming that is available through an on-demand repository, and computer-based training modules. A learning management system is helpful to assign and document completion of educational requirements, especially those related to regulatory requirements (e.g., controlled substances management, sterile and nonsterile compounding, competency assessment). CONCLUSION: Creating and sustaining an environment where all pharmacy caregivers feel invested in and connected to ongoing learning is a powerful motivator for performance, engagement, and retention.

Assessment tool for establishing local pharmaceutical manufacturing in low- and middle-income countries.

OBJECTIVE: In many low- and middle-income countries (LMICs), limited availability, substandard quality and high prices of pharmaceutical products lead to lack of access to essential medicines and poor health outcomes. Manufacturing pharmaceuticals in LMICs may improve access for patients while increasing the market size for manufacturers. METHODS: We present a tool for assessment of local manufacturing feasibility of pharmaceuticals, intended for use among key stakeholders during the business development process. The tool consists of five domains: product selection and capacity, market sizing, market entry, funding and quality assurance. KEY FINDINGS: The tool is intended to identify barriers and facilitators for local manufacturing and provide a roadmap for decision-making across multiple stakeholders. A case study in Namibia identified key barriers and facilitators to successful manufacturing in that county. CONCLUSIONS: Careful consideration of feasibility and potential for success may lead to improved health for the populations of LMIC as well as significant market potential for pharmaceutical manufacturers.

Development and innovation of system resources to optimize patient care.

PURPOSE: Various incremental and disruptive healthcare innovations that are occurring or may occur are discussed, with insights on how multihospital health systems can prepare for the future and optimize the continuity of patient care provided. SUMMARY: Innovation in patient care is occurring at an ever-increasing rate, and this is especially true relative to the transition of patients through the care continuum. Health systems must leverage their ability to standardize and develop electronic health record (EHR) systems and other infrastructure necessary to support patient care and optimize outcomes; examples include 3D printing of patient-specific medication dosage forms to enhance precision medicine, the use of drones for medication delivery, and the expansion of telehealth capabilities to improve patient access to the services of pharmacists and other healthcare team members. Disruptive innovations in pharmacy services and delivery will alter how medications are prescribed and delivered to patients now and in the future. Further, technology may also fundamentally alter how and where pharmacists and pharmacy technicians care for patients. This article explores the various innovations that are occurring and that will likely occur in the future, particularly as they apply to multihospital health systems and patient continuity of care. CONCLUSION: Pharmacy departments that anticipate and are prepared to adapt to incremental and disruptive innovations can demonstrate value in the multihospital health system through strategies such as optimizing the EHR, identifying telehealth opportunities, supporting infrastructure, and integrating services.

Industry Perspective on Biomarker Development and Qualification.

Pharmaceutical and biotechnology companies routinely use biomarkers to obtain quantitative metrics for drug exposure, efficacy, and safety and to inform clinical trial design with regard to patient selection, treatments, and outcomes. Biomarker science has the unique capability to catalyze precompetitive collaborations between academia, industry, regulatory agencies, and other stakeholders with the ultimate goal of accelerating the delivery of safe and effective medicines to patients, particularly in areas of high unmet need.

In vitro evaluation of the biological activities of IgG in seven Chinese intravenous immunoglobulin preparations.

The IgG activities of antigen recognition, Fc-mediated complement activation and cellular Fcγ-receptors (FcγRs) binding are critical for intravenous immunoglobulin (IVIg) immunotherapy in a variety of immune deficiency diseases. Further, these activities could be influenced by different plasma sources and the IVIg manufacturing processes of different manufacturers. This study evaluated and compared the biological activities of IgG in 7 IVIg preparations produced by different Chinese manufacturers. By using ELISA and two-dimensional immunoblotting, the binding capacity and antibody repertoire of IVIg against typical pathogenic antigens were investigated. Further, Fc-mediated complement activation and receptor binding activities were measured by the haemolysis method and flow-cytometric assay respectively. The results showed that all of the preparations tested have a broad spectrum of antibodies against the E. coli O157:H7 proteome, and each IVIg has its own distinct antibody repertoire. Compared to the European Pharmacopoeia IgG standard, the mean indices of the pathogenic antigen binding capacity, complement activation activity and FcγRs binding activity in Chinese preparations were 152%, 143% and 87%. The biological activities varied widely among the 7 IVIg preparations, and no significant differences were observed between the different batches of most IVIgs from the same manufacturer. This study will contribute to the improvement of the IVIg product quality evaluation system and an increased understanding of the variety of IgG biological activities in Chinese IVIg preparations.

[The application of new technologies to hospital pharmacy in Spain]. / Aplicación de las nuevas tecnologías a la farmacia hospitalaria en España.

OBJECTIVE: To describe the degree of introduction of new technologies in the medication use process in pharmacy services in Spain. METHOD: A descriptive study via a survey into the degree of introduction of computer systems for: management, computerized physician order entry (CPOE), automated unit dose drug dispensing, preparation of parenteral nutrition solutions, recording drug administration, pharmaceutical care and foreseen improvements. The survey was sent by electronic mail to the heads of the pharmacy services of 207 hospitals throughout Spain. RESULTS: Response index: 82 hospitals (38.6%). 29 hospitals (36.7%) have a modular management system, 24 (30.4%) an integrated one and 34 (44.9%) a modular-integrated one. CPOE is utilised in 17 (22.4%). According to the size of the hospital, between 17.9 and 26.7% of unit dose dispensing is done online with a management software; between 5.1 and 33.3% of unit dose dispensing is automated. Automation of unit dose dispensing centred in the pharmacy service varies between 10 and 33.3%. Between 13.2 and 35.7% of automated in-ward dispensing systems are utilised. Administration records are kept manually on a computerised sheet at 23 (31.5%) of the hospitals; at 4 (5.4%) on CPOE and 7 (9.5%) online on the integral management programme and 4 (5.4%) on specific nursing softwares. Sixty-three per cent foresee the implementation of improvements in the short to medium term. CONCLUSIONS: The introduction of new technologies is being developed in Spain aiming to improve the safety and management of drugs, and there is a trend towards increasing their deployment in the near future. It is hoped that their fomentation could help to bring about process reengineering within pharmacy services in order to increase the time available for devotion to pharmaceutical care.

The strategic relevance of manufacturing technology: An overall quality concept to promote innovation preventing drug shortage.

Manufacturing is the bridge between research and patient: without product, there is no clinical outcome. Shortage has a variety of causes, in this paper we analyse only causes related to manufacturing technology and we use shortage as a paradigm highliting the relevance of Pharmaceutical Technology. Product and process complexity and capacity issues are the main challenge for the Pharmaceutical Industry Supply chain. Manufacturing Technology should be acknowledged as a R&D step and as a very important matter during University degree in Pharmacy and related disciplines, promoting collaboration between Academia and Industry, measured during HTA step and rewarded in terms of price and reimbursement. The above elements are not yet properly recognised, and manufacturing technology is taken in to consideration only when a shortage is in place. In a previous work, Panzitta et al. proposed to perform a full technology assessment at the Health Technological Assessment stage, evaluating three main technical aspects of a medicine: manufacturing process, physicochemical properties, and formulation characteristics. In this paper, we develop the concept of manufacturing appraisal, providing a technical overview of upcoming challenges, a risk based approach and an economic picture of shortage costs. We develop also an overall quality concept, not limited to GMP factors but broaden to all elements leading to a robust supply and promoting technical innovation.