Physiologically Based Biopharmaceutics Modeling (PBBM): Best Practices for Drug Product Quality, Regulatory and Industry Perspectives: 2023 Workshop Summary Report.

Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are based on the integration of physiological, pharmacological, and pharmaceutical data to simulate and predict drug behavior in vivo. Effective utilization of PBBM requires a consistent approach to model development, verification, validation, and application. Currently, only one country has a draft guidance document for PBBM, whereas other major regulatory authorities have had limited experience with the review of PBBM. To address this gap, industry submitted confidential PBBM case studies to be reviewed by the regulatory agencies; software companies committed to training. PBBM cases were independently and collaboratively discussed by regulators, and academic colleagues participated in some of the discussions. Successful bioequivalence "safe space" industry case examples are also presented. Overall, six regulatory agencies were involved in the case study exercises, including ANVISA, FDA, Health Canada, MHRA, PMDA, and EMA (experts from Belgium, Germany, Norway, Portugal, Spain, and Sweden), and we believe this is the first time such a collaboration has taken place. The outcomes were presented at this workshop, together with a participant survey on the utility and experience with PBBM submissions, to discuss the best scientific practices for developing, validating, and applying PBBMs. The PBBM case studies enabled industry to receive constructive feedback from global regulators and highlighted clear direction for future PBBM submissions for regulatory consideration.

Question-based review for pharmaceutical development: An enhanced quality approach.

Over the last years, the pharmaceutical industry has faced real challenges regarding quality assurance. In this context, the establishment of more holistic approaches to the pharmaceutical development has been encouraged. The emergence of the Quality by Design (QbD) paradigm as systematic, scientific and risk-based methodology introduced a new concept of pharmaceutical quality. In essence, QbD can be interpreted as a strategy to maximize time and cost savings. An in-depth understanding of the formulation and manufacturing process is demanded to optimize the safety, efficacy and quality of a drug product at all stages of development. This innovative approach streamlines the pharmaceutical Research and Development (R&D) process, provides greater manufacturing flexibility and reduces regulatory burden. To assist in QbD implementation, International Conference on Harmonisation (ICH), U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) organized and launched QbD principles in their guidance for industry, identifying key concepts and tools to design and develop a high-quality drug product. Despite the undeniable advantages of the QbD approach, and the widespread information on QbD regulatory expectations, its full implementation in the pharmaceutical field is still limited. The present review aims to establish a crosswise overview on the current application status of QbD within the framework of the ICH guidelines (ICH Q8(R2) - Q14 and ICH Q2(R2)). Moreover, it outlines the way information gathered from the QbD methodology is being harmonized in Marketing Authorization Applications (MAAs) for European market approval. This work also highlights the challenges that hinder the deployment of the QbD strategy as a standard practice.

Quality by design (QbD) approach in marketing authorization procedures of Non-Biological Complex Drugs: A critical evaluation.

The emergence of innovator-driven complex drug products, such as Non-Biological Complex Drugs (NBCDs), has provided disruptive advances in the Nanotechnology and Biotechnology fields. However, the design and development of NBCDs can be particularly challenging due to some unresolved scientific and regulatory challenges associated with the pharmaceutical quality assessment. The application of a more holistic, systematic, integrated science and risk-based approach, such as Quality by Design (QbD), is essential to address key scientific, technological, and regulatory constraints in the research and development of the NBCDs. The deeper product and process understanding derived from the implementation of the QbD approach ensures consistent, reliable, and high-quality pharmaceutical products. Furthermore, this approach promotes innovation and continuous improvement in the entire product lifecycle. Regulatory authorities highly recommend QbD-based submissions to successfully translate NBCDs from laboratory-scale research to the pharmaceutical market with the required quality, safety, and efficacy standards. The main aim of this article is to obtain a comprehensive and in-depth investigation into the state of implementation of the QbD approach in the pharmaceutical development and marketing authorization of NBCDs in Europe and the United States, through the analysis of the available data from their regulatory dossiers. In addition, it aims to understand and discuss how the QbD approach is used and implemented for complex drug products in the pharmaceutical industry, highlighting the gaps and challenges involved with its implementation. An analysis is held regarding QbD's advantages in terms of knowledge growth, regulatory flexibility, and the speed of development based on big data science, along with the reduction of regulatory failures and market withdrawals.

Increasing the Reuse of Protein Non-Naïve Nonhuman Primates in Pharmaceutical Drug Discovery and Development: An Overview and Industry Position on the Challenges and Benefits.

The IQ Consortium NHP Reuse Working Group (WG) comprises members from 15 pharmaceutical and biotechnology companies. In 2020, the WG developed and distributed a detailed questionnaire on protein non-naïve NHP reuse to the WG member companies. The WG received responses from key stakeholders including principal investigators, facility managers, animal welfare officers and research scientists. This paper's content reflects the consolidated opinion of the WG members and the questionnaire responses on the subject of NHP reuse within nonclinical programs at all stages of research and development. Many of the pharmaceutical companies represented in the working group or participating in the questionnaire have already achieved some level of NHP reuse in their nonclinical programs, but the survey results suggested that there is significant potential to increase NHP reuse further and a need to understand the considerations involved in reuse more clearly. The WG has also focused carefully on the inherent concerns and risks of implementing protein non-naive NHP reuse and has evaluated the best methods of risk assessment and decision-making. This paper presents a discussion on the challenges and opportunities surrounding protein non-naïve NHP reuse and aims to stimulate further industry dialogue on the subject and provide guidance for pharmaceutical companies to establish roadmaps and decision trees enabling increased protein non-naïve NHP reuse. In addition, this paper represents a solid basis for collaborative engagement between pharmaceutical and biotechnology companies with contract research organizations (CROs) to discuss how the availability of protein non-naïve NHP within CROs can be better leveraged for their use within nonclinical studies.

Phycocyanin, a super functional ingredient from algae; properties, purification characterization, and applications.

Phycocyanins (PCYs) are a group of luxuriant bioactive compounds found in blue-green algae with an estimated global market of about US$250 million within this decade. The multifarious markets of PCYs noted by form (e.g. powder or aqueous forms), by grade (e.g. analytical, cosmetic, or food grades), and by application (such as biomedical, diagnostics, beverages, foods, nutraceuticals and pharmaceuticals), show that the importance of PCYs cannot be undermined. In this comprehensive study, an overview on PCY, its structure, and health-promoting features are diligently discussed. Methods of purification including chromatography, ammonium sulfate precipitation and membrane filtration, as well as characterization and measurement of PCYs are described. PCYs could have many applications in food colorants, fluorescent markers, nanotechnology, nutraceutical and pharmaceutical industries. It is concluded that PCYs offer significant potentials, although more investigations regarding its purity and safety are encouraged.

Current Trends of Practices in Nonclinical Toxicology: An Industry Survey.

The growth in drug development over the past years reflects significant advancements in basic sciences and a greater understanding of molecular pathways of disease. Benchmarking industry practices has been important to enable a critical reflection on the path to evolve pharmaceutical testing, and the outcome of past industry surveys has had some impact on best practices in testing. A survey was provided to members of SPS, ACT, and STP. The survey consisted of 37 questions and was provided to 2550 participants with a response rate of 24%. Most respondents (∼75%) came from the US and Europe. The survey encompassed multiple topics encountered in nonclinical testing of pharmaceuticals. The most frequent target indications were oncology (69%), inflammation (55%), neurology/psychiatry/pain (46%), cardiovascular (44%), and metabolic diseases (39%). The most frequent drug-induced toxicology issues confronted were hepatic, hematopoietic, and gastrointestinal. Toxicological effects that impacted the no observed adverse effect level (NOAEL) were most frequently based on histopathology findings. The survey comprised topics encountered in the use of biomarkers in nonclinical safety assessment, most commonly those used to assess inflammation, cardiac/vascular, renal, and hepatic toxicity as well as common practices related to the assessment of endocrine effects, carcinogenicity, genotoxicity, juvenile and male-mediated developmental and female reproductive toxicity. The survey explored the impact of regulatory meetings on program design, application of the 3 Rs, and reasons for program delays. Overall, the survey results provide a broad perspective of current practices based on the experience of the scientific community engaged in nonclinical safety assessment.

Species selection for nonclinical safety assessment of drug candidates: Examples of current industry practice.

In drug development, nonclinical safety assessment is pivotal for human risk assessment and support of clinical development. Selecting the relevant/appropriate animal species for toxicity testing increases the likelihood of detecting potential effects in humans, and although recent regulatory guidelines state the need to justify or dis-qualify animal species for toxicity testing, individual companies have developed decision-processes most appropriate for their molecules, experience and 3Rs policies. These generally revolve around similarity of metabolic profiles between toxicology species/humans and relevant pharmacological activity in at least one species for New Chemical Entities (NCEs), whilst for large molecules (biologics) the key aspect is similarity/presence of the intended human target epitope. To explore current industry practice, a questionnaire was developed to capture relevant information around process, documentation and tools/factors used for species selection. Collated results from 14 companies (Contract Research Organisations and pharmaceutical companies) are presented, along with some case-examples or over-riding principles from individual companies. As the process and justification of species selection is expected to be a topic for continued emphasis, this information could be adapted towards a harmonized approach or best practice for industry consideration.

Inherent Safety Assessment of Industrial-Scale Production of Chitosan Microbeads Modified with TiO2 Nanoparticles.

In this study, the inherent safety analysis of large-scale production of chitosan microbeads modified with TiO2 nanoparticles was developed using the Inherent Safety Index (ISI) methodology. This topology was structured based on two main stages: (i) Green-based synthesis of TiO2 nanoparticles based on lemongrass oil extraction and titanium isopropoxide (TTIP) hydrolysis, and (ii) Chitosan gelation and modification with nanoparticles. Stage (i) is divided into two subprocesses for accomplishing TiO2 synthesis, lemongrass oil extraction and TiO2 production. The plant was designed to produce 2033 t/year of chitosan microbeads, taking crude chitosan, lemongrass, and TTIP as the primary raw materials. The process was evaluated through the ISI methodology to identify improvement opportunity areas based on a diagnosis of process risks. This work used industrial-scale process inventory data of the analyzed production process from mass and energy balances and the process operating conditions. The ISI method comprises the Chemical Inherent Safety Index (CSI) and Process Inherent Safety Index (PSI) to assess a whole chemical process from a holistic perspective, and for this process, it reflected a global score of 28. Specifically, CSI and PSI delivered scores of 16 and 12, respectively. The analysis showed that the most significant risks are related to TTIP handling and its physical-chemical properties due to its toxicity and flammability. Insights about this process's safety performance were obtained, indicating higher risks than those from recommended standards.

The use of emerging safety biomarkers in nonclinical and clinical safety assessment - The current and future state: An IQ DruSafe industry survey.

Pharmaceutical and biotechnology companies rarely disclose their use of translational emerging safety biomarkers (ESBs) during drug development, and the impact of ESB use on the speed of drug development remains unclear. A cross-industry survey of 20 companies of varying size was conducted to understand current trends in ESB use and future use prospects. The objectives were to: (1) determine current ESB use in nonclinical and clinical drug development and impact on asset advancement; (2) identify opportunities, gaps, and challenges to greater ESB implementation; and (3) benchmark perspectives on regulatory acceptance. Although ESBs were employed in only 5-50% of studies/programs, most companies used ESBs to some extent, with larger companies demonstrating greater nonclinical use. Inclusion of ESBs in investigational new drug applications (INDs) was similar across all companies; however, differences in clinical trial usage could vary among the prevailing health authority (HA). Broader implementation of ESBs requires resource support, cross-industry partnerships, and collaboration with HAs. This includes generating sufficient foundational data, demonstrating nonclinical to clinical translatability and practical utility, and clearly written criteria by HAs to enable qualification. If achieved, ESBs will play a critical role in the development of next-generation, translationally-tailored standard laboratory tests for drug development.

Model predictive control in pharmaceutical continuous manufacturing: A review from a user's perspective.

Pharmaceutical continuous manufacturing is considered as an emerging technology by the regulatory agencies, which have defined a framework guided by an effective quality risk management. With the understanding of process dynamics and the appropriate control strategy, pharmaceutical continuous manufacturing is able to tackle the Quality-by-Design paradigm that paves the way to the future smart manufacturing described by Quality-by-Control. The introduction of soft sensors seems to be a helpful tool to reach smart manufacturing. In fact, soft sensors have the ability to keep the quality attributes of the final drug product as close as possible to their references set by regulatory agencies and to mitigate the undesired events by potentially discard out of specification products. Within this review, challenges related to implementing these technologies are discussed. Then, automation control strategies for pharmaceutical continuous manufacturing are presented and discussed: current control tools such as the proportional integral derivative controllers are compared to advanced control techniques like model predictive control, which holds promise to be an advanced automation concept for pharmaceutical continuous manufacturing. Finally, industrial applications of model predictive control in pharmaceutical continuous manufacturing are outlined. Simulations studies as well as real implementation on pharmaceutical plant are gathered from the control of one single operation unit such as the tablet press to the control of a full direct compaction line. Model predictive control is a key to enable the industrial revolution or Industry 4.0.

Scientific diligence for oncology drugs: a pharmacology, translational medicine and clinical perspective.

Increasingly, new drug development by major pharmaceutical companies relies on in-licensing of innovative therapies. Often there are limited data accompanying these novel entities. By focusing on scientific principles and generating key preclinical and clinical data, discovery companies can improve their valuations. From the lens of a large pharmaceutical company, we highlight key scientific aspects that are assessed to mitigate risk in valuations and deal terms. Our focus is on clinical development aspects for oncology drugs by stage of development. However, these lessons apply equally to other therapeutic areas.

Tg.rasH2 Mouse Model for Assessing Carcinogenic Potential of Pharmaceuticals: Industry Survey of Current Practices.

The Tg.rasH2 mouse was developed as an alternative model to the traditional 2-year mouse bioassay for pharmaceutical carcinogenicity testing. This model has found extensive use in support of pharmaceutical drug development over the last few decades. It has the potential to improve quality and timeliness, reduce animal usage, and in some instances allow expedient decision-making regarding the human carcinogenicity potential of a drug candidate. Despite the increased use of the Tg.rasH2 model, there has been no systematic survey of current practices in the design, interpretation of results from the bioassay, and global health authority perspectives. Therefore, the aim of this work was to poll the pharmaceutical industry on study design practices used in the dose range finding and definitive 6-month studies and on results relative to the ongoing negotiations to revise The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S1 Guidance. Twenty-two member companies of International Consortium for Innovation and Quality in Pharmaceutical Development DruSafe Leadership Group participated in the survey, sharing experiences from studies conducted with 55 test compounds between 2010 and 2018. The survey results provide very useful insights into study design and interpretation. Importantly, the results identified several key opportunities for reducing animal use and increasing the value of testing for potential human carcinogenicity using this model. Recommended changes to study designs that would reduce animal usage include eliminating the requirement to include positive control groups in every study, use of nontransgenic wild-type littermates in the dose range finding study, and use of microsampling to reduce or eliminate satellite groups for toxicokinetics.

Benchmarking biopharmaceutical process development and manufacturing cost contributions to R&D.

This study aims to benchmark and analyze the process development and manufacturing costs across the biopharmaceutical drug development cycle and their contribution to overall research and development (R&D) costs. This was achieved with a biopharmaceutical drug development lifecycle cost model that captured the costs, durations, risks and interdependencies of the clinical, process development and manufacturing activities. The budgets needed for process development and manufacturing at each phase of development to ensure a market success each year were estimated. The impact of different clinical success rate profiles on the process development and manufacturing costs at each stage was investigated, with a particular focus on monoclonal antibodies. To ensure a market success each year with an overall clinical success rate (Phase I to approval) of ~12%, the model predicted that a biopharmaceutical company needs to allocate process development and manufacturing budgets in the order of ~$60 M for pre-clinical to Phase II material preparation and ~$70 M for Phase III to regulatory review material preparation. For lower overall clinical success rates of ~4%, which are more indicative of diseases such as Alzheimer's, these values increase to ~$190 M for early-phase and ~$140 Mfor late-phase material preparation; hence, the costs increase 2.5 fold. The costs for process development and manufacturing per market success were predicted to represent 13-17% of the R&D budget from pre-clinical trials to approval. The results of this quantitative structured cost study can be used to aid decision-making during portfolio management and budget planning procedures in biopharmaceutical development.

An industrial approach towards solid dosage development for first-in-human studies: Application of predictive science and lean principles.

Tablet development is challenging during early clinical phases of drug discovery because of dose uncertainty, limited active pharmaceutical ingredient availability, and short lead times. Here, we introduce a new framework to expedite product development using a suite of in-house and commercially available predictive tools developed through the integration of computer modelling and material-sparing characterisation methods. The strategy underpins the use of dry granulation for formulation development with guidance on scale-up and manufacturability to achieve 'First Time Right'. We present an analytical strategy based on predictive science with a focus on stability, and shelf-life related attributes to assure product quality. Thus, we provide a holistic approach towards robust, scientific product development through integrated project knowledge and risk-based approaches, delivering significant savings in both material and resources.

Therapy for the individual: Towards patient integration into the manufacturing and provision of pharmaceuticals.

Individualized therapy with pharmaceutical products aims to elicit predictable and optimized treatment responses from specific patients. Doing so requires production platforms and technology capable of tailoring products to individual patient needs. However, despite recent manufacturing innovations and key technologies on the rise, e.g. continuous manufacturing and additive manufacturing (3D printing), the prevailing production paradigm employed in the pharmaceutical industry is mass production. Although mass production is efficient and cost-effective, it is typically based on a 'one-size-fits-all' product concept and lacks the flexibility and agility required to fully meet the needs of the individual patient. Indeed, we present data that confirm a suspected major imbalance between the recent medical evolution underpinning personalized/precision medicine and the recent advances in the associated manufacturing technologies. In this context we target the needs of the individual as a main driver for pharmaceutical products which support individualized therapy. We particularly address that a wider integration of critical patient dimensions into the manufacture and provision of pharmaceutical products is pivotal for enabling a patient-centric and efficient mass customization-based production paradigm. Here, we present a critical review of the area and its inherent challenges which aims to clarify key design requirements for establishing mass customization opportunities. Through primary sources of scientific information for individualized therapies, patient needs are captured, analysed, and conceptualized. This summarized set of key drivers provides the basis for a proposed patient-centric framework of requirements for use in design of product and production platforms for mass customization. The extent to which emerging pharmaceutical manufacturing technologies satisfy key individual patient needs is explored through a high-level assessment against the proposed patient-centric framework, with special attention paid to oral dosage forms. Altogether this holistic review and position paper, with its constituent steps, reveals major gaps in the evolution of Product-Process-Production approaches and solutions required for producing affordable individualized/personalized pharmaceuticals that respond to the needs and demands of the individual patient. Lastly, in a brief commentary and outlook, we suggest key research directions for closing gaps and addressing manufacturing technology challenges. We also articulate the importance of tackling them in a holistic, integrated way, together with challenges in product individualization and personalization.

Vitamin D microencapsulation and fortification: Trends and technologies.

Today, as per the latest medical reports available, majority of the population throughout globe is facing vitamin D (Vit D) deficiency. Even in sub-tropical countries like India and many others Vit D deficiency is highly prevalent despite the exuberant available sunshine (a major source of Vit D) throughtout the year. The reason could be attributed to an array of factors including socioeconomical, cultural and religious. Further, other than the sunlight, there are very limited sources of Vit D to fulfil the recommended dietary allowance of Vit D (RDA: 400-800 IU per day). A large proportion of Vit D is lost during food processing and storage due to environmental stress conditions such as temperature, pH, salt, oxygen and light. Vita D, an important micronutrient, is essentially required for the prevention of disorders such as neurodegenerative diseases, cardiovascular diseases, cancer etc. in addition to its traditional role in bone metabolism. Therefore, in order to meet the daily requirements of Vit D for human body, WHO has recognized fortification as the most efficient and safest method to address malnutrition. But there are innumerable chellenges involved during food fortification using Vit D as fortificants such as homogeneity into the food matrix, physico-chemical/photochemical degradation, loss during processing and storage, interactions with other components of food matrix resulting into change in taste, texture and appearance thus affecting acceptability, palatability and marketability. Fortification of Vit D into food products especially the ones which have an aqueous portion, is not simple for food technologist. Recent advances in nanotechnology offer various microencapsulation techniques such as liposome, solid-lipid particles, nanostructured lipid carriers, emulsion, spray drying etc. which have been used to design efficient nanomaterials with desired functionality and have great potential for fortification of fortificants like Vit D. The present review is an undate on Vit D, in light of its fortification level, RDA, factors affecting its bioavailability and various microencapsulation techniques adopted to develop Vit D-nanomaterials and their fate in food fortification.

Near-infrared spectroscopic applications in pharmaceutical particle technology.

Near-infrared spectroscopy (NIRS) is nowadays an established analytical technique in the pharmaceutical industry. The aim of this review is to present the progress of NIRS in providing useful information for pharmaceutical particle technology. NIR methods are now developed to characterize a wide variety of materials (active pharmaceutical ingredients, excipients, co-processed powders, and physical mixtures) and pharmaceutical dosage forms (conventional, modified drug release technologies, and phytomedicines). This review also provides a number of spectra to illustrate the fundamental understanding of NIRS which has been gained. The sampling that must occur prior to the acquisition of near-infrared spectra is also discussed, as well as developments in monitoring mixing, tableting, and coating. This review will be valuable for product formulation and process engineering specialists.

Response of safety pharmacologists to challenges arising from the rapidly evolving changes in the pharmaceutical industry.

This commentary highlights and expands upon the thoughts conveyed in the lecture by Dr. Alan S. Bass, recipient of the 2017 Distinguished Service Award from the Safety Pharmacology Society, given on 27 September 2017 in Berlin, Germany. The lecture discussed the societal, scientific, technological, regulatory and economic events that dramatically impacted the pharmaceutical industry and ultimately led to significant changes in the strategic operations and practices of safety pharmacology. It focused on the emerging challenges and opportunities, and considered the lessons learned from drug failures and the influences of world events, including the financial crisis that ultimately led to a collapse of the world economies from which we are now recovering. Events such as these, which continue to today, challenge the assumptions that form the foundation of our discipline and dramatically affect the way that safety pharmacology is practiced. These include the latest scientific and technological developments contributing to the design and advancement of safe medicines. More broadly, they reflect the philosophical mission of safety pharmacology and the roles and responsibilities served by safety pharmacologists. As the discipline of Safety Pharmacology continues to evolve, develop and mature, the reader is invited to reflect on past experiences as a framework towards a vision of the future of the field.

The West coast regional safety pharmacology society meeting update: Filling translational gaps in safety assessment.

The Safety Pharmacology Society (SPS) held a West Coast Regional Meeting in Foster City, CA on November 14, 2018 at the Gilead Sciences Inc. site. The meeting was attended by scientists from the pharmaceutical and biotechnology industry, contract research organizations (CROs) and academia. A variety of scientific topics were presented by speakers, covering a broad variety of topics in the fields of safety risk assessment; from pro-arrhythmia and contractility risk evaluation, to models of heart failure and seizure in-a-dish; and discovery sciences; from stem cells and precision medicine, to models of inherited cardiomyopathy and precision cut tissue slices. The present review summarizes the highlights of the presentations and provides an overview of the high level of innovation currently underlying many frontiers in safety pharmacology.