scholarly journals N-Nitrosodimethylamine Contamination in the Metformin Finished Products

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5304
Author(s):  
Adam Zmysłowski ◽  
Iza Książek ◽  
Arkadiusz Szterk
Keyword(s):  
Daily Intake ◽  
Active Pharmaceutical Ingredient ◽  
Pharmaceutical Products ◽  
European Medicines Agency ◽  
Acceptable Limit ◽  
Good Linearity

A GC–MS/MS method with EI ionization was developed and validated to detect and quantify N-nitrosodimethylamine (NDMA) and seven other nitrosamines in 105 samples of metformin tablets from 13 different manufactures. Good linearity for each compound was demonstrated over the calibration range of 0.5–9.5 ng/mL. The assay for all substances was accurate and precise. NDMA was not detected in the acquired active pharmaceutical ingredient (API); however, NDMA was detected in 64 (85.3%) and 22 (91.7%) of the finished product and prolonged finished product samples, respectively. European Medicines Agency recommends the maximum allowed limit of 0.032 ppm in the metformin products. Hence, 28 finished products and 7 pronged dosage products were found to exceed the acceptable limit of daily intake of NDMA contamination. The implications of our findings for the testing of pharmaceutical products are discussed.

PP469 From Theory To Practice: Which Value Framework Is Applied For Onco-Hematology Therapies In Italy? A 5-year Retrospective Analysis

2020 ◽  
Vol 36 (S1) ◽  
pp. 37-37
Author(s):  
Americo Cicchetti ◽  
Rossella Di Bidino ◽  
Entela Xoxi ◽  
Irene Luccarini ◽  
Alessia Brigido
Keyword(s):  
Real World ◽  
Ad Hoc ◽  
Grey Literature ◽  
National Level ◽  
Pharmaceutical Products ◽  
European Medicines Agency ◽  
The Real ◽  
R Process ◽  
The One ◽  
The Impact

IntroductionDifferent value frameworks (VFs) have been proposed in order to translate available evidence on risk-benefit profiles of new treatments into Pricing & Reimbursement (P&R) decisions. However limited evidence is available on the impact of their implementation. It's relevant to distinguish among VFs proposed by scientific societies and providers, which usually are applicable to all treatments, and VFs elaborated by regulatory agencies and health technology assessment (HTA), which focused on specific therapeutic areas. Such heterogeneity in VFs has significant implications in terms of value dimension considered and criteria adopted to define or support a price decision.MethodsA literature research was conducted to identify already proposed or adopted VF for onco-hematology treatments. Both scientific and grey literature were investigated. Then, an ad hoc data collection was conducted for multiple myeloma; breast, prostate and urothelial cancer; and Non Small Cell Lung Cancer (NSCLC) therapies. Pharmaceutical products authorized by European Medicines Agency from January 2014 till December 2019 were identified. Primary sources of data were European Public Assessment Reports and P&R decision taken by the Italian Medicines Agency (AIFA) till September 2019.ResultsThe analysis allowed to define a taxonomy to distinguish categories of VF relevant to onco-hematological treatments. We identified the “real-world” VF that emerged given past P&R decisions taken at the Italian level. Data was collected both for clinical and economical outcomes/indicators, as well as decisions taken on innovativeness of therapies. Relevant differences emerge between the real world value framework and the one that should be applied given the normative framework of the Italian Health System.ConclusionsThe value framework that emerged from the analysis addressed issues of specific aspects of onco-hematological treatments which emerged during an ad hoc analysis conducted on treatment authorized in the last 5 years. The perspective adopted to elaborate the VF was the one of an HTA agency responsible for P&R decisions at a national level. Furthermore, comparing a real-world value framework with the one based on the general criteria defined by the national legislation, our analysis allowed identification of the most critical point of the current national P&R process in terms ofsustainability of current and future therapies as advance therapies and agnostic-tumor therapies.

scholarly journals Sustained drug delivery system in fish and the potential for use of PLGA microparticles: a review

2019 ◽  
Vol 64 (No. 7) ◽  
pp. 287-293
Author(s):  
J Matejkova ◽  
P Podhorec
Keyword(s):  
Drug Delivery ◽  
Sustained Release ◽  
Drug Delivery System ◽  
Delivery System ◽  
Hormonal Treatment ◽  
The United States ◽  
Pharmaceutical Products ◽  
European Medicines Agency ◽  
Sustained Drug Delivery ◽  
Plga Microparticles

Many fish species display some form of reproductive disorder in captivity. Captive fish reared in conditions outside the natural spawning environment show a failure of the pituitary to release the maturational gonadotropin luteinizing hormone thus necessitating administration of the hormone to induce spawning. A controlled sustained-release delivery system can conquer the issue of short half-life of gonadotropin releasing hormone (GnRH) in blood and avoid the necessity of using re-injections. Sustained release of GnRHa can induce long-term enhancement in semen production and multiple spawning in species with asynchronous or multiple batch group synchronous ovarian physiology. The most recent development is the incorporation of GnRHa into microparticles of biodegradable polymers that release the drug during a certain period of time ranging from days to weeks. The most attractive polymeric candidate used as a carrier for administering a pharmaceutical products is poly(lactic-co-glycolic acid); (PLGA). PLGA has excellent biodegradability and biocompatibility and is generally recognised as safe by international regulatory agencies including the European Medicines Agency and the United States Food and Drug Administration. This review describes methods of hormonal treatment in fish, highlights the advantage of sustained drug delivery system and discusses the potential of PLGA microparticles as a tool for achieving successful reproduction.

Pharmaceutical Regulation in the European Union

2018 ◽  
Author(s):  
Stuart O. Schweitzer ◽  
Z. John Lu
Keyword(s):  
European Union ◽  
Drug Approval ◽  
Good Clinical Practice ◽  
The United States ◽  
Good Manufacturing Practice ◽  
Pharmaceutical Products ◽  
European Medicines Agency ◽  
Regulatory Regime ◽  
The European Union ◽  
Regulatory Pathways

The main scientific and technical aspects of new drug registration, including pathways to marketing authorization approval, clinical study design and method, and requirement of and specifications for Good Clinical Practice, Good Laboratory Practice, and Good Manufacturing Practice, are all quite similar between Europe and the United States. Differences do exist, however. This chapter provides a closer examination of the drug regulatory regime in the European Union. After providing a brief history of the European Medicines Agency, the chapter examines the agency’s organizational structure and role in ensuring the safety and efficacy of pharmaceutical products for Europe, and discusses the regulatory pathways for generics and biosimilars in the EU. The chapter also looks at recent trends in international drug approval lags.

scholarly journals P59 Assessing medicines for safe use in paediatrics

2020 ◽  
Vol 105 (9) ◽  
pp. e37.1-e37
Author(s):  
Mary Worrall ◽  
Anne Fitzpatrick
Keyword(s):  
European Commission ◽  
Assessment Tool ◽  
New Products ◽  
Daily Intake ◽  
European Medicines Agency ◽  
List Type ◽  
Medicinal Products ◽  
Pharmaceutical Development ◽  
Human Use ◽  
Paediatric Medicines

AimThis service review aimed to reassess and upgrade the ‘New Products Assessment Form’ and to develop an assessment tool in line with European regulations governing paediatric medicines. Many medicinal products routinely used to treat the paediatric population have not been studied or authorised for paediatric use, which means there is widespread unlicensed and ‘off-label’ use of medicines. Medicines deemed safe in adult formulations may not be appropriate for paediatric patients. Medicines must therefore be carefully selected based on agreed criteria including, but not limited to: licensing, excipients, administration, labelling, similarity to other products, safety and handling.MethodA literature review was conducted. Guidance, information, and advice was sought from other healthcare institutions, and European guidelines and directives informing current practise around excipients in paediatric medicines. Pharmacy colleagues were consulted during the development of the tool, and an accessible assessment tool was completed for use in a tertiary paediatric hospital.1–4ResultsThis is the first comprehensive ‘New Products Assessment Form’ in the hospital which complies with the European Medicines Agency (EMA) directives governing excipients in paediatric medicines. The document highlights clearly potential issues and risks associated with product excipients, licensing status, warning label guidance and allows for recording of rationale for the selection of medicines. The ‘New Products Assessment Form’ is intended to highlight potential issues associated with excipients and their associated acceptable daily intake (ADI), but it will also highlight other risks associated with medicines used in paediatrics e.g. inadequate labelling, translation requirements for foreign products, sound-alike/look-alike products, safety and handling, and others.ConclusionThis revised assessment tool has been approved for use in the hospital pharmacy. It will be made available in hospital and community pharmacies on request. Use of the tool should be monitored and audited.ReferencesAnnex to the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’ (SANTE-2017-11668). https://www.ema.europa.eu/en/documents/scientific-guideline/annex-european-commission-guideline-excipients-labelling-package-leaflet-medicinal-products-human_en.pdf. NPPG Neonatal and Paediatric Pharmacists Group Newsletter No 61 Autumn 2016. Excipients in medicines for children. http://nppg.org.uk/wp-content/uploads/2017/04/NPPG-61.pdfQuestions and Answers on Ethanol in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00) https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-ethanol-context-revision-guideline-excipients-label-package-leaflet-medicinal_en.pdfEMA. Guideline on pharmaceutical development of medicines for paediatric use.https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmaceutical-development-medicines-paediatric-use_en.pdf

Werberecht und Absatzförderung/Preisrecht

2019 ◽  
Keyword(s):  
German Law ◽  
Pharmaceutical Products ◽  
Economic Feasibility ◽  
Sales Promotion ◽  
Insurance Companies ◽  
European Medicines Agency ◽  
Regulatory Requirements ◽  
Eu Directive ◽  
Health Insurance Companies ◽  
Advertising Law

The first lecture given at the 21st Marburg debates on pharmaceutical law addressed the criminal consequences of advertising law going hand in hand with sales promotion. It focused on clarifying which forms of cooperation are still desirable, necessary and allowed. In addition to dealing with the regulatory requirements involved in the contractual organisation of digital communication channels and the legal options offered by the information conveyed, among others, by health insurance companies about the economic feasibility of regu-lations on medication, the conference also highlighted the opportunities offered by fiscally optimised sales models for medical products. This main subject of discussion also encompassed upholding the EU directive on the protection of know-how on the publication of registration documentation by the European Medicines Agency. Pricing laws constituted a further main point of discussion at the conference, with issues re-lating to mixed pricing, the possibility of being exempt from factory discounts, the effects of the German law on increasing the provision of pharmaceutical products on forms of treatment with cytostatic agents, and the provision of discounts being addressed. With contributions by Dr. Manja Epping, Dr. Jan-Tobias Häser, Prof. Josef Hecken, Christian Hübner, Dr. Elmar Mand, Dr. Constanze Püschel, Dr. Christoph Ritzer, Dr. Stefan Todt, Peter von Czettritz, Wolfgang Voit

scholarly journals Review of Quality Deficiencies Found in Active Pharmaceutical Ingredient Master Files Submitted to the WHO Prequalification of Medicines Programme

2014 ◽  
Vol 17 (2) ◽  
pp. 169 ◽  
Author(s):  
Isabel Ortega Diego ◽  
Antony Fake ◽  
Matthias Stahl ◽  
Lembit Rägo
Keyword(s):  
Technical Assistance ◽  
Active Pharmaceutical Ingredient ◽  
The United States ◽  
World Health ◽  
European Medicines Agency ◽  
United States Food ◽  
Materials Used ◽  
The Stability ◽  
Health Organization ◽  
Over Time

Purpose. The aim of this work was to determine the number and type of active pharmaceutical ingredient (API) quality deficiencies in API Master Files (APIMFs) as submitted to the World Health Organization (WHO) Prequalification of Medicines Programme (PQP). Methods. We conducted a retrospective review of API quality deficiencies identified following the assessment of new APIMFs for non-sterile APIs during a 6-year period from 1 January 2007 to 31 December 2012. All deficiencies were collected, classified and quantified according to the Common Technical Document (CTD) sections and subsections and as groups of commonly raised questions. Results. There were 5446 deficiencies collected from 159 APIMF deficiency letters by CTD section, by selected CTD subsections and by selected CTD subsections and year. More than 50% of the total number of deficiencies related to the manufacturing sections of the CTD, followed by deficiencies concerning the impurities, the API specification and the stability sections of the CTD.  A pattern of API deficiencies across the different CTD subsections and over time was identified. Conclusions. The most frequent critical deficiencies were related to how the specific manufacturing process and the key materials used, in particular the API starting material, impact the API impurities content. The number and pattern of APIMF deficiencies did not change over time. The results are compared to the findings in similar studies as reported by the United States Food and Drug Administration (USFDA), the European Directorate for the Quality of Medicines (EDQM) and the European Medicines Agency (EMA) and similarities and differences are discussed. Our findings highlight the need for greater guidance and technical assistance for API manufacturers submitting APIMFs to the PQP. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Non-compendial vs compendial analytical tests - a powerful tool for predicting in vitro similarity of highly viscous oral suspension

2019 ◽  
Vol 64 (02) ◽  
pp. 61-72
Author(s):  
Elena Kazandjievska ◽  
Iva Antova ◽  
Slavica Mitrevska ◽  
Aleksandar Dimkovski ◽  
Elena Dimov ◽  
...  
Keyword(s):  
Drug Release ◽  
Negative Impact ◽  
In Vitro Release ◽  
Active Pharmaceutical Ingredient ◽  
Pharmaceutical Products ◽  
Dosage Forms ◽  
Oral Suspension ◽  
In Vitro Dissolution ◽  
Dissolution Profile

In vitro dissolution profiles are increasingly used to evaluate drug release characteristics of pharmaceutical products. The dissolution methods is expected to be an appropriate tool for checking consistency of the pharmaceutical attributes by discriminating similarities and dissimilarities between different drug formulations. Expansion in development of novel “special” dosage forms, due to the manner in which these dosage forms release the active pharmaceutical ingredient, usually requires applying non-compendial dissolution strategy that differs from the traditional compendial recommendations. For demonstrating sameness in the dissolution profile, in vitro drug release comparison between test and reference product of highly viscous oral suspension by applying non-compendial peak vessel against conventional hemispheric vessel was demonstrated in this study. All reference batches exhibited high variability in dissolution data when using hemispheric vessel due to forming mound compact mass at the bottom of the vessel. Different strategies for samples manipulation, before and during dissolution period, were performed in order to eliminate additional variabilities. Modifications of conventional USP 2 apparatus such as using peak vessel provided with more reproducible and reliable result for distinguishing in vitro similarities between different formulations of oral suspensions. Misinterpretation of dissolution data can lead to negative impact on product development. Taking time to observe and evaluate what is happening to the product in the vessel during dissolution is of curtail consideration for proper selection of the dissolution strategy. Keywords: oral suspensions; in-vitro release; hydrodynamic variability; USP apparatus 2/ Paddle apparatus; peak vessel

scholarly journals EVALUATION OF THE PRESENCE OF POLYMORPHIC FORMS AND INFLUENCE ON THE DISSOLUTION PROFILE OF TENOXICAM IN ACTIVE PHARMACEUTICAL INGREDIENT AND FORMULATIONS

2018 ◽  
Vol 2 (2) ◽  
pp. 27-36
Author(s):  
Aline Taís Fries ◽  
Natália Olegário ◽  
Sarah Chagas Campanharo ◽  
Vitor Paulo Pereira ◽  
Martin Steppe
Keyword(s):  
Chemical Properties ◽  
Pharmaceutical Formulations ◽  
Active Pharmaceutical Ingredient ◽  
Xrd Analysis ◽  
Pharmaceutical Products ◽  
In Vitro Dissolution ◽  
Dissolution Profile ◽  
Crystalline Structures ◽  
Polymorphic Forms

Polymorphism is a relatively common phenomenon among pharmaceutical compounds, and one of the main aspects to be considered in the production and development of medications. The investigation of polymorphism associated with oxicams, a group belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs) has increased in recent years and, in the case of tenoxicam, the existence of four polymorphic forms is reported in the literature. The objective of this study was to characterize the presence of different polymorphic forms of tenoxicam in active pharmaceutical ingredient and oral pharmaceutical formulations, as well as to evaluate the influence on in vitro dissolution. The characterization of the three samples of pharmaceutical ingredient of tenoxicam from different suppliers by X-Ray Diffraction (XRD), Infrared (IR) and dissolution profile indicated the presence of a form III crystalline structure, without presenting significant differences between the in vitro dissolution profiles analyzed, and a Dissolution Efficiency (DE%) of 60.30%, 60.70% and 72.34%, respectively. When the four pharmaceutical specialties of tenoxicam were submitted to XRD analysis, they also presented form III crystalline structures. Despite this, the formulations presented different dissolution profiles and a DE% of 75.23%, 83.69%, 78.19% and 90.63%, respectively, without compromising their quality. However, often polymorphism affects physico-chemical properties of drugs, showing the importance of studying this phenomenon, by correlating the presence of crystalline structures to alterations in the quality of active ingredients and pharmaceutical products.

scholarly journals Spectroscopic Analysis of Melatonin in the Terahertz Frequency Range

Sensors ◽  
2018 ◽  
Vol 18 (12) ◽  
pp. 4098 ◽  
Author(s):  
Uroš Puc ◽  
Andreja Abina ◽  
Anton Jeglič ◽  
Aleksander Zidanšek ◽  
Irmantas Kašalynas ◽  
...  
Keyword(s):  
Spectroscopic Analysis ◽  
Active Pharmaceutical Ingredient ◽  
Pharmaceutical Products ◽  
Pharmaceutical Product ◽  
Thz Spectroscopy ◽  
Terahertz Frequency ◽  
Thz Imaging ◽  
Pharmaceutical Ingredients ◽  
Indispensable Tool ◽  
First Time

There is a need for fast and reliable quality and authenticity control tools of pharmaceutical ingredients. Among others, hormone containing drugs and foods are subject to scrutiny. In this study, terahertz (THz) spectroscopy and THz imaging are applied for the first time to analyze melatonin and its pharmaceutical product Circadin. Melatonin is a hormone found naturally in the human body, which is responsible for the regulation of sleep-wake cycles. In the THz frequency region between 1.5 THz and 4.5 THz, characteristic melatonin spectral features at 3.21 THz, and a weaker one at 4.20 THz, are observed allowing for a quantitative analysis within the final products. Spectroscopic THz imaging of different concentrations of Circadin and melatonin as an active pharmaceutical ingredient in prepared pellets is also performed, which permits spatial recognition of these different substances. These results indicate that THz spectroscopy and imaging can be an indispensable tool, complementing Raman and Fourier transform infrared spectroscopies, in order to provide quality control of dietary supplements and other pharmaceutical products.

A Review on Carcinogenic Impurities Found in Marketed Drugs and Strategies for its Determination by Analytical Methods

2021 ◽  
pp. 159-169
Author(s):  
Amitkumar J. Vyas ◽  
Jayshree P. Godhaniya ◽  
Ajay I. Patel ◽  
Ashok B. Patel ◽  
Nilesh K. Patel ◽  
...  
Keyword(s):  
Analytical Methods ◽  
Raw Materials ◽  
Drug Product ◽  
Pharmaceutical Products ◽  
Carcinogenic Risk ◽  
European Medicines Agency ◽  
International Agency ◽  
Angiotensin Ii Receptor Blocker ◽  
Product Recalls ◽  
Angiotensin Ii Receptor

The control of potentially mutagenic and carcinogenic impurities in pharmaceutical products is key importance in evaluating carcinogenic risk to humans. The recent discovery of nitrosamine impurities in some marketed pharmaceuticals has increased the risk of their mutagenic and carcinogenic potential. According to the International Agency for Research on Cancer (IARC), nitrosamine is the chemical classified as a probable human carcinogen. Nitrosamine impurities are known to be mutagenic and carcinogenic, very small exposure of these impurities can lead to cancer. These impurities may be produced and get incorporated into drug substances or drug products by a reagent, catalyst, solvent, or raw materials used in the process of manufacturing. The presence of nitrosamine impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has caused worldwide product recalls. The various regulatory authorities have published the press release or notice regarding the control of these impurities with the interim limit. In 2007, the European medicines agency (EMA) suspended the marketing authorization of Viracept, because of the presence of elevated levels of ethyl methane sulfonate, in the drug product. Validated analytical methods are used to identify and quantify these impurities to the trace level at a given interim limit.

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