Generic Drug Industry Research Articles

The Viability of Emerging Public and Private Generic Drug Infrastructure in India: An in-vitro Case Study Using Statins as Model Drug

The healthcare system has been fundamentally altered by the introduction of generic medications, and their market share continues to rise because these are genuine, dependable, secure, affordable, and accessible to all the needy and poor in society. In this regard, the generic drug industry, which strives for authenticity, affordability, and accessibility, plays a significant role. Using HMG CoA reductase inhibitors (Atorvastatin and Rosuvastatin) as model drugs, the study aimed to determine the viability of the emerging public and private generic drug infrastructure in India, which included Janaushadhi, Dava India, and other assorted companies. The organoleptic properties and official and non-official quality control tests were evaluated. According to the in-vitro dissolution profiles, the Mankind brand of atorvastatin has shown the highest dissolution profile (75.29%), and the Dava India brand of rosuvastatin has the maximum drug release (97.26%) in one hour release. The Peppas model best explained the drug release model, which inferred the release profile to be diffusion-specific. The compatibility analysis of the tablet formulation has been shown through FTIR studies. These results concluded that public generic drugs are as effective as private generic drugs, and patients can easily take the cost-effective brand of medication.

Experience Learned and Perspectives on Using Model-Integrated Evidence in the Regulatory Context for Generic Drug Products-a Meeting Report.

This report summarizes relevant insights and discussions from a 2022 FDA public workshop titled Best Practices for Utilizing Modeling Approaches to Support Generic Product Development which illustrated how model-integrated evidence has been used and can be leveraged further to inform generic drug product development and regulatory decisions during the assessment of generic drug applications submitted to the FDA. The workshop attendees discussed that model-integrated evidence (MIE) approaches for generics are being applied in the space of long-acting injectable (LAI) products to develop shorter and more cost-effective alternative study designs for LAI products. Modeling and simulation approaches are utilized to support virtual BE assessments at the site of action for locally acting drug products and to assess the impact of food on BE assessments for oral dosage forms. The factors contributing to the success of the model-informed drug development program under PDUFA VI were discussed. The generic drug industry shared that decisions on formulation candidate/formulation variant selection, on pilot in vivo bioavailability studies, and on alternative study designs for BE assessment are informed by modeling and simulation approaches. There was agreement that interactions between the regulatory agencies and the industry are desirable because they improve the industry's understanding of scientific and other regulatory considerations on implementing modeling and simulation approaches in drug development and regulatory submissions.

Integration of artificial neural network and physiologically based biopharmaceutic models in the development of sustained-release formulations.

Model-informed drug development is an important area recognized by regulatory authorities and is gaining increasing interest from the generic drug industry. Physiologically based biopharmaceutics modeling (PBBM) is a valuable tool to support drug development and bioequivalence assessments. This study aimed to utilize an artificial neural network (ANN) with a multilayer perceptron (MLP) model to develop a sustained-release matrix tablet of metformin HCl 500mg, and to test the likelihood of the prototype formulation being bioequivalent to Glucophage® XR, using PBBM modeling and virtual bioequivalence (vBE). The ANN with MLP model was used to simultaneously optimize 735 formulations to determine the optimal formulation for Glucophage® XR release. The optimized formulation was evaluated and compared to Glucophage® XR using PBBM modeling and vBE. The optimized formulation consisted of 228mg of hydroxypropyl methylcellulose (HPMC) and 151mg of PVP, and exhibited an observed release rate of 42% at 1h, 47% at 2h, 55% at 4h, and 58% at 8h. The PBBM modeling was effective in assessing the bioequivalence of two formulations of metformin, and the vBE evaluation demonstrated the utility and relevance of translational modeling for bioequivalence assessments. The study demonstrated the effectiveness of using PBBM modeling and model-informed drug development methodologies, such as ANN and MLP, to optimize drug formulations and evaluate bioequivalence. These tools can be utilized by the generic drug industry to support drug development and biopharmaceutics assessments.

Increasing impact of quantitative methods and modeling in establishment of bioequivalence and characterization of drug delivery.

Increasing impact of quantitative methods and modeling in establishment of bioequivalence and characterization of drug delivery.

Regulatory utility of mechanistic modeling to support alternative bioequivalence approaches: A workshop overview.

On September 30 and October 1, 2021, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics cosponsored a live virtual workshop titled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches." The overall aims of the workshop included (i) engaging the generic drug industry and other involved stakeholders regarding how mechanistic modeling and simulation can support their product development and regulatory submissions; (ii) sharing the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (iii) establishing a consensus on best practices for using mechanistic modeling approaches, such as physiologically based pharmacokinetic modeling and computational fluid dynamics modeling, for BE assessment; and (iv) introducing the concept of a Model Master File to improve model sharing between model developers, industry, and the FDA. More than 1500 people registered for the workshop. Based on a postworkshop survey, the majority of participants reported that their fundamental scientific understanding of mechanistic models was enhanced, there was greater consensus on model validation and verification, and regulatory expectations for mechanistic modeling submitted in abbreviated new drug applications were clarified by the workshop.

Regulatory utility of physiologically-based pharmacokinetic modeling to support alternative bioequivalence approaches and risk assessment: A workshop summary report.

This report summarizes the proceedings for day 2 sessions 1 and 3 of the 2-day public workshop entitled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches," a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG). The aims of this workshop were: (1) to discuss how mechanistic modeling, including physiologically-based pharmacokinetic (PBPK) modeling and simulation, can support product development, and regulatory submissions; (2) to share the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (3) to establish a consensus on best practices for using PBPK modeling for BE assessment to help drive further investment by the generic drug industry into mechanistic modeling and simulation; and (4) to introduce the concept of a Model Master File to improve model-sharing. The theme of day 2 covered PBPK absorption model for oral products as an alternative BE approach and a tool for supporting risk assessment and biowaiver (session 1), oral PBPK for evaluating the impact of food on BE (session 2), successful cases, and challenges for oral PBPK (session 3). This report summarizes the topics of the presentations of day 2 sessions 1 and session 3 from FDA, academia, and pharmaceutical industry, including the current status of oral PBPK, case examples as well as the challenges and opportunities in this area. In addition, panel discussions on the utility of oral PBPK in both new drugs and generic drugs from regulatory and industry perspective are also summarized.

Collusion in the US generic drug industry

We study cartels that operated in the US generic drug industry, leveraging quarterly Medicaid data for the period 2011–2018 and a difference-in-differences approach comparing the evolution of prices of allegedly collusive drugs with a group of competitive control drugs. Our analysis highlights (i) the difficulty of establishing a suitable control group when collusion is pervasive, (ii) the importance of accounting for market structure changes when defining the control period, and (iii) the existence of across- and within-drug heterogeneity. We focus on six drug markets that that were part of the expanded initial complaint and where there was no entry in the same class during the collusive period, permitting a clean measure of the causal impact of collusion on prices. Our most conservative estimates suggest that collusion led to price increases of between 0 and 166% for each of the six drugs, and damages of between $0 and $3 million for the Medicaid market.

The history of a transdermal product: From innovation to generic

The development, registration and successful launch of a novel, innovative transdermal pharmaceutical product requires an idea, structured planning and a highly skilled, specialist team. It is not often that the opportunity arises to document this activity. This paper demonstrates the multidisciplinary effort required to take such a product (Axiron®, a transdermal testosterone product) from innovation to market and also describes its ultimate fate after the generic drug industry took an interest in its commercial success. Although many understand various aspects of this drug development process this understanding is often, by necessity, limited to the specialities of each of the individuals involved. It is hoped that this paper will provide an interesting overview of the entire process from beginning (innovation) to end (genericization).

Processing-Structure-Performance Relationships of Microporous Metal-Organic Polymers for Size-Selective Separations.

Small-molecule impurities, such as N-nitrosodimethylamine (NDMA), have infiltrated the generic drug industry, leading to recalls in commonly prescribed blood pressure and stomach drugs in over 43 countries since 2018 and directly affecting tens of millions of patients. One promising strategy to remove small-molecule impurities like NDMA from drug molecules is by size exclusion, in which the contaminant is removed by selective adsorption onto a (micro)porous material due to its smaller size. However, current solution-phase size-exclusion separations are primarily limited by the throughput-selectivity trade-off. Here, we report a bioinspired solution to conquer these critical challenges by leveraging the assembly of atomically precise building blocks into hierarchically porous structures. We introduce a bottom-up approach to form micropores, mesopores, and macroscopic superstructures simultaneously using functionalized oxozirconium clusters as building blocks. Further, we leverage recent advances in photopolymerization to design macroscopic flow structures to mitigate backpressure. Based on these multiscale design principles, we engineer simple, inexpensive devices that are able to separate NDMA from contaminated drugs. Beyond this urgent model system, we expect this design strategy to open up hitherto unexplored avenues of nanomaterial superstructure fabrication for a range of size-exclusion purification strategies.

Quality and corruption in the generic drug industry

Quality and corruption in the generic drug industry

The Competitive Advantage of the Vertically Integrated Business Model in Generic Drug Industry

The Competitive Advantage of the Vertically Integrated Business Model in Generic Drug Industry

Do mergers and acquisitions improve firms' financial performance? The case of the U.S. generic drug industry

This paper examines the financial performance of all mergers and acquisitions (M&A) involving publicly traded companies that occurred in the U.S. generic drug industry from 1996 to 2017. The control group was chosen using a nearest neighbor matching procedure. Our empirical strategy controls for unobservable firm‐specific fixed effects as well M&A fixed effects. Our findings suggest that profit levels do not change significantly following M&As, but total revenues decline after M&As. Firms undergoing an M&A cut operating expenses but not through reduction in labor expenses or number of employees.

Assessment of comparative bioavailability of Itraconazole capsule 100 mg under fasting conditions by average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE) approaches

The assessment of interchangeability (prescribability and switchability) is one of the debatable topics in the generic drug industry. Currently, the question is whether we have an adequate assessment system for the evaluation of generic drug products. The objective of the study is to assess the comparative oral bioavailability of Itraconazole capsule 100mg after administering single dose to adult, healthy, human subjects in fasted state by different bioequivalence approaches like average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE) and to monitor the safety of study subjects. An open-label, balanced, randomized, two-treatment, two-sequence, four-period, crossover, single-dose comparative oral bioavailability study was conducted in sixteen healthy, adult, human subjects in a fasted state. Test formulation, Itraconazole capsule 100mg, and reference formulation, SPORANOX® (Itraconazole) capsule 100mg, were administered in a fasted state. The test formulation, Itraconazole capsule 100mg, showed bio-inequivalent against reference SPORANOX® (Itraconazole) capsule 100mg in study subjects under a fasted state. Also, the test formulation exhibited a similar safety and tolerability profile compared to the reference formulation. There was no report of serious adverse events (SAEs) and deaths in the study. The test formulation was found to be bio-inequivalent to reference formulation in the study subjects under a fasted state by estimating different bioequivalence approaches like average bioequivalence, population bioequivalence, and individual bioequivalence.

Decision Science for Generic Drug Development and Review.

Decision Science for Generic Drug Development and Review.

Application of Lean methodologies in the reduction of setup times in the pharmaceutical industry

Introduction: The strong international competitiveness motivated by globalization with the purpose of reaching an increasingly demanding public, makes cost reduction and quality increase a primary need across all sectors. The generic drug industry where price is the primary weapon in consumer reach is no exception and creates a strong need in the application of Lean methodologies to optimize the production. Objectives: Reduce of changeover times by the application of lean methodologies structured by a proposed model. Methods: This study started with a review of the bibliography of the Lean’s origin and the several methodologies ending with the application of a proposed application model. The implementation was based on a detailed study of the setups resulting in a set of solution proposals dedicated to the main problems applying several lean tools. Results: Reduction of change times by 20% and waiting times by 24.5% within 3 months. Conclusions: The application of Lean methodologies revealed a great utility in the identification of causes and in the creation of solutions. The implementation of this model, although in an initial phase, allowed not only reduction of the times of changes, but also other improvements such as the reduction of the number of waits. However, this application, due to being inserted in the pharmaceutical industry, is limited by some procedures that cannot be changed.

The More Monitoring, the Better Quality? Empirical Evidence from the Generic Drug Industry

In response to the growing concern on drug safety issues, the U.S. Food and Drug Administration (FDA) has implemented major moves in its inspection regime to ensure that the agency allocates more inspection resources to the low-quality manufacturing facilities. The actions of the government agency implicitly assume that the frequent inspections at low-quality facilities could reduce the drug safety concerns. However, whether more monitoring guarantees better quality remains unclear. In this study, we directly examine the validity of this assumption in the generic drug industry and test the impact of inspection frequency on the manufacturing quality. We first perform a recurrent-event cox proportional hazards model with instrumental variables to investigate the impact of inspection frequency on the gap time between successive recall events. We observe a significant increase in the recall hazard rate for those facilities experiencing decreases in the inspection frequency; on the contrary, there is no significant change in the recall hazard for facilities experiencing more frequent quality monitoring. We then exploit a shift of inspection resources from domestic to foreign facilities and compare the recall rate before and after the resource shift. The consistent results reassure our findings. Overall, we do not find evidence that supports the link between more frequent inspections and fewer recall events, suggesting that the current risk-based inspection model alone might not help bring down the quality failures in drug products. We propose two explanations for the results -- the organizational culture and the inherent quality levels -- and discuss the potential actions the FDA and the relevant regulators could take to augment the inspection regime.

The Generic Drug Industry Embraces a Faster, Cheaper Pathway for Challenging Patents.

Most new brand-name drugs are protected by patents from generic competition, but these patents are occasionally granted in error. Invalidating such patents has traditionally been accomplished via court litigation by generic manufacturers, which is expensive and time consuming. In 2011, Congress created an administrative alternative to court litigation of patents, called inter partes review, intended to be much faster and less expensive. To evaluate the use of inter partes review to challenge pharmaceutical patents, including the number of challenges, the number of associated drug products, and the extent to which challengers have been successful. We obtained data pertaining to inter partes review proceedings, including identity of patent challenger, duration of proceedings, and outcome, from September 16, 2012 through April 24, 2017 from UnifiedPatents.com, and combined it with information about drug products and their associated patents, including patent type, contained in the US Food and Drug Administration's Orange Book. Generic drug manufacturers have embraced the new inter partes review process, succeeding in overturning all challenged claims in 43% of the patents they have targeted since 2011, and some challenged claims in an additional 8%. Inter partes review for drug patents has consistently been completed within 12months, as required by statute. Successful challenges have been brought most frequently against drug patents covering new formulations or methods of use, rather than drug patents covering active ingredients. In the pharmaceutical market, the inter partes review process can meaningfully contribute to ensuring that invalid patents do not block timely availability of generic drugs.

Cambrex to enter finished-dose drug business

Departing from its focus on producing active pharmaceutical ingredients (APIs) for drug industry customers, Cambrex has signed an agreement to acquire Halo Pharma, a contract manufacturer of finished-dose drugs, for about $425 million. Halo produces solids, liquids, creams, and ointments for about 70 customers at facilities in Whippany, N.J., and Montreal. It will generate sales this year of more than $100 million, Cambrex says. A former Abbott Laboratories business, Halo is currently owned by the private investment firm SK Capital Partners. Cambrex had sales last year of $526 million, mostly of small-molecule APIs for innovator and generic drug industry customers. It is one of only a handful of large, U.S.-based contract development and manufacturing organizations (CDMOs) that focus on APIs. “With the acquisition of Halo, we are entering a new market within the overall CDMO space,” Cambrex CEO Steve Klosk said in a conference call with stock analysts. “Not unlike

Pharmaceutical industry–physician interaction compliance guidelines: Analysis of contagion wealth effects on large generic firms

Background This study examines the contagion effect on shareholders’ wealth of large generic firms to the issuance of guidelines by the Office of Inspector General “to efficiently monitor adherence to applicable statutes, regulations and program requirements” of the branded pharmaceutical companies. These guidelines prod pharmaceutical manufacturers to employ internal controls and self-regulation while marketing to the physicians. Methods We use a standard event-study methodology to measure the effect on the value of nine large generic firms around four events including the final guidance issued by Office of Inspector General. Results The results show that there is a contagion effect with an overall loss in net wealth of large generic firms’ shareholders. The US government’s policy guidance necessitated pharmaceutical industry to reexamine and refine for the better, its marketing practices. The government achieved this change in pharmaceutical industry’s behaviour without actually introducing any regulation suggesting the efficacy of self-regulation. Conclusions Our findings suggest that there is a contagion effect of Office of Inspector General guidelines on generic drug industry due to facilitated self-regulation by branded pharmaceutical industry. Thus, the direct implication is that any regulatory event that is meant for one firm or a group of firms in the health sector could adversely impact peer firms in the same industry (pharmaceutical) or related industries such as biotechnology or generic industries. In other words, the study shows that government’s public policy initiatives that effect the value of the targeted firms could change not only the firms’/industry’s behavior but also let government achieve its objectives without contemplating additional regulations. This in turn, may accrue significant cost savings for the government in avoiding the regulation and its related measures. Our results also support an argument that a mechanism that combines industry self-regulation with government monitoring, lends the greatest opportunity for the overall welfare of the society.

Merger mania: mergers and acquisitions in the generic drug sector from 1995 to 2016

BackgroundDrug shortages and increasing generic drug prices are associated with low levels of competition. Mergers and acquisitions impact the level of competition. Record merger and acquisition activity was reported for the pharmaceutical sector in 2014/15, yet information on mergers and acquisitions in the generic drug sector are absent from the literature. This information is necessary to understand if and how such mergers and acquisitions can be a factor in drug shortages and increasing prices.MethodsData on completed merger and acquisition deals that had a generic drug company being taken over (i.e. ‘target’) were extracted from Bloomberg Finance L.P. The number and announced value of deals are presented globally, for the United States, and globally excluding the United States annually from 1995 to 2016 in United States dollars.ResultsGeneric drug companies comprised 9.3% of the value of all deals with pharmaceutical targets occurring from 1995 to 2016. Globally, in 1995 there were no deals, in 2014 there were 22 deals worth $1.86 billion, in 2015 there were 34 deals totalling $33.56 billion, and in 2016 there were 42 deals worth in excess of $44 billion. This substantial increase was partially attributed to Teva’s 2016 acquisition of Allergan’s generic drug business. The surge in mergers and acquisitions for 2015/16 was driven by deals in the United States, where they represented 89.7% of the dollar value of deals in those years.ConclusionsThe recent blitz in mergers and acquisitions signals that the generic drug industry is undergoing a transformation, especially in the United States. This restructuring can negatively affect the level of competition that might impact prices and shortages for some products, emphasizing the importance of updating regulations and procurement policies.