Innovative Drug Product Research Articles

Comparative Characterization of Reference Market Product and Generic Product Developed using Reverse Engineering Methodology

The present study is a comparative analysis between the reference market product, Xarelto® 20 mg film-coated tablets, and a generic product developed using reverse engineering methodology, employing low-shear ethanolic granulation. The primary objective in formulating and optimizing this generic product was to attain a formulation that exhibits both physical and chemical stability, closely resembling the innovator or market reference drug product. Both reference and generic products were evaluated using FTIR, TGA, DSC, XRD, SEM, EDX/EDS, Raman mapping, Raman imaging and contact angle measurement studies and were compared. Similar characteristic peaks were observed in the IR spectra of the generic product (RX-LS [AH]) to that of the reference product. Similar crystallinity was detected between reference and generic products. The TG-DSC analysis confirmed the presence of a similar endothermic peak of the generic product to that of the reference product. SEM images showed the presence of deformed granules in both, generic and reference products due to the compression force during tablet production. The specific and major elements present in both samples were C, N, O, Na, Mg, S and Cl. The API and excipient distribution within the reference product and the generic product is closely similar confirmed through the Raman study. Test (θ = 17.3) and reference products (θ = 17.9) showed contact angles around 17 degrees, it indicates that both products have similar wettability capacity, in other words, similar solubility and dissolution behavior. The current study demonstrated the excellent similarity of generic Rivaroxaban 20 mg film-coated tablets with reference products. The exactly similar characteristics of generic products will definitely boost confidence of successful bioequivalence studies and reduce developmental cost and time as there is no a chance of product failure which will lead to redevelopment.

HTA56 Unequal Access of Innovative Drug Products Across Canada

HTA56 Unequal Access of Innovative Drug Products Across Canada

Commercial Low Molecular Weight Heparins - Patent Ecosystem and Technology Paradigm for Quality Characterization.

Heparin is a subject of ever-growing interest for laboratory researchers and pharmaceutical industry. One of the driving factors is its critical life-saving drug status, which during the COVID-19 pandemic has assumed a central role in disease treatment and/or prevention. Apart, heparin is one amongst few drugs enjoying a “demand constant” status. In 2020, heparin market size was valued to US$6.5 bn., and given the ongoing stability in the COVID-19 health crisis, it is expected to reach US$11.43 bn. by 2027 with yearly growth rate momentum (CAGR) of 3.9% during the forecast period (Pepi et al., Mol Cell Proteomics 20:100,025, 2021). As patent is a limited monopoly, every year, many patents on low molecular weight heparin (LMWH; a chemically or enzymatically degraded product of unfractionated heparin) are losing market exclusivity worldwide, inviting the generic/biosimilar drug manufacturers to capture market share with cheaper drug products. By tracking patent expiration, drugs in patent litigation, regulatory setbacks for innovator companies (such as those seeking data exclusivity or patent term extension), or other unexpected events affecting market demand and competition, generics can make investment decisions in manufacturing off-patent LMWH drug products of commercial significance. However, given the US Food and Drug Administration (FDA), European Medicine Agency (EMA), Drug Regulatory Authority of Pakistan (DRAP), and other regulatory authorities scientifically rigorous standards for generic/biosimilar LMWH drug products marketing approval, the market is secured and momentous for drug makers that could demonstrate through scientific and clinical dataset that the generic/biosimilar LMWH drug product is of the same quality and purity as the innovator drug product. This study presents an overview of the patent landscape of commercially available LMWHs and advanced analytical techniques for their structural and biochemical characterization for quality control and quality assurance during manufacturing and post-marketing. The study also covers FDA, EMA, Health Canada, and DRAP’s current approaches to evaluating the generic/biosimilar LMWH drug products for quality, safety including immunogenicity, and efficacy.

Embedding a Sensitive Liquid-Core Waveguide UV Detector into an HPLC-UV System for Simultaneous Quantification of Differently Dosed Active Ingredients during Drug Release.

Individual dosing of pharmaceutics and personalized medicine have become important with regard to therapeutic safety. Dose adjustments, biorelevant drug release and combination of multiple active substances in one dosage form for the reduction in polymedication are essential aspects that increase the safety and acceptance of the patient’s pharmacotherapy. Therefore, not only innovative drug products but also new analytical methods are needed during the drug development phase and for quality control that can simultaneously determine different active ingredients and cover wide concentration ranges. We investigated a liquid-core waveguide UV absorbance flow cell detector coupled to an existing HPLC-UV system. A Teflon AF 2400 capillary tubing of 20 cm length was connected in series to the HPLC flow line and enabled a lower limit of quantification of 1 ng/mL pramipexole (increase in sensitivity by 20 compared to common 0.9 cm flow cells). This allowed the low-concentration of pramipexole and the higher concentrations of levodopa and benserazide occurring during drug release to be determined in a single chromatographic run within 22.5 min.

3D Printing of Pediatric Medication: The End of Bad Tasting Oral Liquids?-A Scoping Review.

3D printing of pediatric-centered drug formulations can provide suitable alternatives to current treatment options, though further research is still warranted for successful clinical implementation of these innovative drug products. Extensive research has been conducted on the compliance of 3D-printed drug products to a pediatric quality target product profile. The 3D-printed tablets were of particular interest in providing superior dosing and release profile similarity compared to conventional drug manipulation and compounding methods, such as oral liquids. In the future, acceptance of 3D-printed tablets in the pediatric patient population might be better than current treatments due to improved palatability. Further research should focus on expanding clinical knowledge, providing regulatory guidance and expansion of the product range, including dosage form possibilities. Moreover, it should enable the use of diverse good manufacturing practice (GMP)-ready 3D printing techniques for the production of various drug products for the pediatric patient population.

Additive manufacturing in drug delivery: Innovative drug product design and opportunities for industrial application.

Additive manufacturing (AM) or 3D printing is enabling new directions in product design. The adoption of AM in various industrial sectors has led to major transformations. Similarly, AM presents new opportunities in the field of drug delivery, opening new avenues for improved patient care. In this review, we discuss AM as an innovative tool for drug product design. We provide a brief overview of the different AM processes and their respective impact on the design of drug delivery systems. We highlight several enabling features of AM, including unconventional release, customization, and miniaturization, and discuss several applications of AM for the fabrication of drug products. This includes products that have been approved or are in development. As the field matures, there are also several new challenges to broad implementation in the pharmaceutical landscape. We discuss several of these from the regulatory and industrial perspectives and provide an outlook for how these issues may be addressed. The introduction of AM into the field of drug delivery is an enabling technology and many new drug products can be created through productive collaboration of engineers, materials scientists, pharmaceutical scientists, and industrial partners.

Generic Drug Product Development in Japan: Regulatory Updates During 2014-2019 and the Future.

The growth of healthcare cost is a serious issue in many countries. Generic drug products play an essential role in reducing healthcare costs because they are less costly than the innovator drug products. The regulatory review of generic drug products in Japan is conducted by the Pharmaceuticals and Medical Devices Agency (PMDA). This report introduces the activities of the PMDA from fiscal years 2014-2019. The number of approvals of new generic drug products and partial changes was trending downward. Alternatively, the PMDA conducted six types of consultation meetings to advise on development and application; the number of consultation meetings was increasing. Moreover, during this period, the Ministry of Health, Labour and Welfare issued two basic principles for ophthalmic dosage forms and dry powder inhaler drug products and revised the guidelines for bioequivalence. Finally, the future of generic drug product development and considerations to improve their regulation were discussed. More efforts will continue to enable a more efficient and rational generic drug product development and shortening of the review period for partial change approval.

Using Filters to Estimate Regional Lung Deposition with Dry Powder Inhalers

To develop an in vitro method to rapidly evaluate regional lung doses delivered by pharmaceutical inhalers. Currently, cascade impactor measurements are used, but these are resource intensive and require significant post processing of in vitro data to arrive at regional deposition estimates. We present a specialized filter apparatus that mimics tracheobronchial (TB) deposition of pharmaceutical aerosols emitted by commercially available dry powder inhalers (DPIs). The filter housing includes an electrostatic neutralizer to eliminate artificial electrostatic filtration effects. Regional deposition (tracheobronchial and alveolar) for four DPIs (Onbrez Breezhaler, Flovent Diskus, Pulmicort Turbuhaler, and Asmanex Twisthaler) was estimated using cascade impactor measurements and an in silico regional deposition model. These estimates were compared to direct measurements of regional deposition as provided by the TB filter mimic and an absolute filter placed downstream of the TB filter housing, representing the alveolar dose. The two methods were shown to provide similar estimates of extrathoracic, tracheobronchial, and alveolar deposition, as well as total recovery of active pharmaceutical ingredients. Because of its design, the TB filter apparatus makes it possible to estimate regional deposition with inhalers directly using variable inhalation profiles without any additional equipment or changes to the experimental configuration. This method may be useful to expedite development of both innovative and generic drug products as it provides regional respiratory tract deposition estimates using fewer resources than exisiting methods.

Formulation and Evaluation of Immediate Release Tablet Dosage Form of Linagliptin and Metformin Hydrochloride

The aim of the current study work was to formulate and assess a fixed dose mixture tablet of instant release oral solid dosage form comprising two anti-diabetic drugs (linagliptin and metformin hydrochloride) for managing of diabetes mellitus type 2.The innovator drug product (Jentadueto Tablet) was evaluated for the various evaluation parameters, which have been taken into consideration during the drug product development. Pre-formulation evaluation was accomplished to safeguard better parameters of formulated drug product. On the result of pre-formulation evaluation and innovator drug product characterization, the model drug product was recognized in various steps. The established formulation was augmented for different excipients. The instant release film covered tablet of linagliptin and metformin HCl was expressed and augmented at laboratory scale. The individual steps (procedures) were improved for the same and the scale-up contemplation have been engaged into account certify the product performance at pilot plant-up to commercial scale-up.
 Keywords: anti-diabetic, linagliptin, metformin

Higher-Order Structure Comparison of a Proposed Biosimilar and the Innovator Biotherapeutic Trastuzumab using Circular Dichroism Coupled with Statistical Analysis

We employ a novel circular dichroism (CD) technology coupled with statistical analysis to assess the higher-order structure (HOS) similarity of commercially available trastuzumab and a proposed biosimilar. This technology shows good potential for enabling the comparison of similarities and differences in secondary and tertiary structures of proteins. Multiple CD spectra in far- and near-UV are obtained reproducibly from a CD spectrometer with fully integrated autosampler and flow cell to eliminate the errors typically associated with sample handling on manual CD spectrometers. The significance of similarities or differences was quantified statistically using three analytical methods (weighted spectral difference, correlation coefficient, and area of overlap). HOS comparison of the secondary structure (far-UV CD spectra) suggested similarity between the innovator drug, trastuzumab (Herceptin®), and biosimilar products. However, the tertiary structure (near-UV CD spectra) suggested statistically significant differences. These differences may be due to changes in tertiary structure or to modifications and degradations during the process of production or storage. The results show that the automated circular dichroism technology coupled with statistical analysis is a robust tool for enabling the comparison of similarities and differences in secondary and tertiary structures of protein products.

The new contraceptive revolution: developing innovative products outside of industry†,‡.

A significant global unmet need for new contraceptive options for both women and men remains due to side effect profiles, medical concerns, and inconvenience of many currently available products. The pharmaceutical industry has largely abandoned early research and development for contraception and will not likely engage to bring new products to the market unless they have been significantly de-risked by showing promise in early phase clinical trials. This lack of interest by big pharma comes at a time when scientific and technological advances in biology and medicine are creating more opportunities than ever for the development of new and innovative drug products. Novel partnerships between the academic sector, small biotechnology companies, foundations, non-government organizations (NGOs), and the federal government could accelerate the development of new contraceptive products. We discuss the challenges and opportunities that we have encountered as an NGO with a mission to develop novel contraceptive products for low- and middle-income countries and how it differs from developing products for higher-income markets. We hope that our experiences and “lessons learned” will be of value to others as they proceed down the product development path, be it for female or male or for hormonal or nonhormonal contraceptives.

Intestinal absorption-modifying excipients: A current update on preclinical in vivo evaluations

Pharmaceutical excipients in drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may increase drug absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the intestinal drug absorption, it is defined as an absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase drug absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo intestinal absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the intestinal absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosal recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect intestinal drug absorption.

FDA's decisions in oncology drug product approvals from 2006 to 2016

ObjectiveUnder the circumstances that several oncology drugs have been approved under expedited programs in the US, this study aimed to analyze the relationship between the expedited programs and characteristics of approvals in the recent decade, and the attitude of the Food and Drug Administration (FDA) toward the development and review of oncology drugs. ResultsOf the 162 approvals that were analyzed, the proportion of orphan drug (OD) designation was higher in accelerated approval (AA) than regular approval (RA). In contrast, no difference was observed in the proportions of priority review (PR) in AA versus RA or in ODs versus non-ODs. In the development time, no difference was observed in any of the expedited programs. Regarding review time, a significant difference was observed in PR versus standard review (SR). In the characteristics of the pivotal study, such as randomization, number of patients, and endpoints, differences were observed in AA versus RA and in ODs versus non-ODs. Conversely, no significant difference was noted in PR versus SR. ConclusionThe overall results of this research validated the attitude of the FDA toward applying each expedited program to facilitate an earlier delivery of innovative oncology drug products to patients with cancer.

Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Biodistribution after Intravenous Dosing in Rats.

Relative biodistribution of FDA-approved innovator and generic sodium ferric gluconate (SFG) drug products was investigated to identify differences in tissue distribution of iron after intravenous dosing to rats. Three equal cohorts of 42 male Sprague-Dawley rats were created with each cohort receiving one of three treatments: (1) the innovator SFG product dosed intravenously at a concentration of 40 mg/kg; (2) the generic SFG product dosed intravenously at a concentration of 40 mg/kg; (3) saline dosed intravenously at equivalent volume to SFG products. Sampling time points were 15 min, 1 h, 8 h, 1 week, two weeks, four weeks, and six weeks post-treatment. Six rats from each group were sacrificed at each time point. Serum, femoral bone marrow, lungs, brain, heart, kidneys, liver, and spleen were harvested and evaluated for total iron concentration by ICP-MS. The ICP-MS analytical method was validated with linearity, range, accuracy, and precision. Results were determined for mean iron concentrations (µg/g) and mean total iron (whole tissue) content (µg/tissue) for each tissue of all groups at each time point. A percent of total distribution to each tissue was calculated for both products. At any given time point, the overall percent iron concentration distribution did not vary between the two SFG drugs by more than 7% in any tissue. Overall, this study demonstrated similar tissue biodistribution for the two SFG products in the examined tissues.

The Breakthrough Hatch Waxman Amendment - A Shared Benefit for Innovations and Subsequent Innovations

Pharmaceutical drug discovery and development is an extensive, investment incurring, and unpredictable process that may take 8-12 years to make a drug reaching to market place. Originator companies generally ensure patent rights over the drug molecules discovered and developed by them at an early drug development stage. This is an effort to inhibit other competitor companies from synthesizing, use in manufacture, or sell these molecules at a later stage. This will also allow the originator company to ensure exclusive profit gains if the drug molecule succeeds to become a blockbuster drug. This security on exclusivity is rationalized to allow the originator company to as recuperate investment and realize benefits as the process of discovery and development of new drug needs a lot of investment in people, efforts, time and financial fronts. Through an Abbreviated new drug application (ANDA) process, applicant may get FDA approval for a generic drug without performing full clinical trials if the proposed drug product is bioequivalent to the innovator drug product. USFDA approves the generic drugs if they demonstrate to have the same quality, purity, strength and stability as that of innovator drugs. A paragraph IV certification is submitted by the generic drug applicant in case they wish to market the generic version of the drug before expiry of the originator’s patent rights. Submitting a Paragraph IV certification would mean that generic applicant claims that it is justified to place generic drug early on the market because its drug does not infringe the patent in question or the patent in question is invalid. In case of successful proceedings over the claims the generic drug applicant is rewarded for a ‘Para IV filing’ by granting a marketing exclusivity for 180 days. Exclusivity means that no company is allowed to launch its product during this period. As a result, there is ‘No Competition’ in the market. As the first mover, this helps the generic manufacturer to have an advantage. It can garner a market share. This is a valuable opportunity for generic drug manufacturer to maximize profit margins without any competition. This provision in the act has promoted healthy competition and helped public health sector with drugs becoming available to public at relatively lower prices. Keywords: ANDA, certification, generic, Hatch Waxman, drug, paragraph, USFDA.

Statistical evaluation of the scaled criterion for drug interchangeability

ABSTRACTAs more and more generic drug products become available in the marketplace, it is a concern whether these generic drug products can be used interchangeably in terms of their quality, safety, and efficacy. The United States Food and Drug Administration (FDA) indicates that an approved generic drug product can serve as a substitute for the innovative drug product. The FDA, however, does not indicate that approved generic drug products can be used interchangeably even if they are bioequivalent to the same innovative drug product. In the past decade, several criteria for assessing interchangeability were proposed in regulatory guidances and/or literature. Chow, Xu, and Endrenyi proposed a scaled criterion for drug interchangeability (SCDI), which takes both intra-subject variability and subject-by-drug variability into consideration. In this paper, the performance of this criterion is statistically evaluated by deriving the upper confidence limit of the test statistic and extrapolating expression of the power to facilitate sample size calculation. The performance of SCDI is also compared with that of the criterion for assessment of individual bioequivalence (IBE) for addressing drug switchability recommended by the FDA, which also takes into account the subject-by-drug variability, under various parameter specifications.

Assessing bioequivalence and drug interchangeability

ABSTRACTAs indicated by the US Food and Drug Administration (FDA), approved generic drug products can be used as substitutes for their respective innovative drug products. The FDA, however, does not indicate that two generic copies of the same innovative drug can be used interchangeably, even though they have been shown to be bioequivalent to the same innovative drug product. As more and more generic drug products become available in the market place, it is a concern whether these approved generic drug products have the same quality and safety/efficacy and hence can be used interchangeably. To address the issue of drug interchangeability, several criteria such as individual bioequivalence criterion, a criterion based on the variability due to subject-by-drug interaction, and a scaled criterion for drug interchangeability (SCDI) have been proposed in the literature. In this article, the performances of these criteria, including a newly proposed reversed average bioequivalence criterion, are studied under a 2x4 replicated crossover design in terms of the percentage of passing at the best and worst possible scenarios of similarity. The goal of this paper is to investigate the interchangeability in terms of switchability between a generic (test) drug product and an originator (reference) drug product.

On safety margin for drug interchangeability

ABSTRACTAs more and more generic (or biosimilar) drug products become available in the market place, it is a concern whether the approved generic (or biosimilar) drug products are safe and efficacious and hence can be used interchangeably. According to current regulation, most regulatory agencies such as the United States Food and Drug Administration (FDA) indicate an approved generic (or biosimilar) drug product can serve as a substitute for the innovative drug product. Bioequivalence (biosimilarity) assessment for regulatory approval among generic copies (or biosimilars) of the innovative drug product are not required. In practice, approved generic (or biosimilar) drugs are commonly used interchangeably without any mechanism of safety monitoring. In this article, current bioequivalence (or biosimilarity) limit is adjusted according to the observed geometric mean ratio and corresponding variability for development of safety margins for monitoring of drug interchangeability by minimizing the relative change in response with and without the switching.

Key Technical Aspects Influencing the Accuracy of Tablet Subdivision.

Tablet subdivision is a common practice used mainly for dose adjustment. The aim of this study was to investigate how the technical aspects of production as well as the method of tablets subdivision (employing a tablet splitter or a kitchen knife) influence the accuracy of this practice. Five drugs commonly used as subdivided tablets were selected. For each drug, the innovator drug product, a scored-generic and a non-scored generic were investigated totalizing fifteen drug products. Mechanical and physical tests, including image analysis, were performed. Additionally, comparisons were made between tablet subdivision method, score, shape, diluent composition and coating. Image analysis based on surface area was a useful tool as an alternative assay to evaluate the accuracy of tablet subdivision. The tablet splitter demonstrates an advantage relative to a knife as it showed better results in weight loss and friability tests. Oblong, coated and scored tablets had better results after subdivision than round, uncoated and non-scored tablets. The presence of elastic diluents such as starch and dibasic phosphate dehydrate conferred a more appropriate behaviour for the subdivision process than plastic materials such as microcrystalline cellulose and lactose. Finally, differences were observed between generics and their innovator products in all selected drugs with regard the quality control assays in divided tablet, which highlights the necessity of health regulations to consider subdivision performance at least in marketing authorization of generic products.

Content Related to Older Adults in Canadian Innovator–Drug Product Monographs: An Exploratory Analysis

Background Drug product monographs are an important source of information for drug inquiries. There has been little investigation of the content of product monographs for geriatric data.