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Dr Orna Dreazen, CEO of Nextar and former General Director of the Israeli Laboratory Accreditation Authority (ISRAC), gave a webinar presentation on medicinal formulation development essentials. Dr Dreazen focused on the proper planning of the development process while keeping the end in mind, by performing risk management for the various stages of the drug life cycle, from drug development to commercial production. Thanks to all the participants in the webinar. Watch the webinar (in Hebrew) or download the pdf presentation (in English): Formulation Development Essentials Presentation:

Recently, Nextar's subsidiary (Nextage Therapeutics, TASE:NXTG) announced that they had completed the development of a unique formulation which allows targeted delivery of CBD and other cannabinoids to the brain. This formulation is an adaptation of the technology developed by Nextar and provides a solution for the main challenge in treating brain-diseases: efficient delivery of drugs through the Blood-Brain Barrier (BBB). Okay ... but we know that CBD reaches the brain without the utilization of special technologies. So why fix something that is not broken? The main challenge is targeting Cannabinoids treatment only to the brain The use of cannabinoids for medical purposes has become increasingly common in recent years, and patients can choose between different routes of administration based on the required medical treatment and their personal needs. There are a few routes for administration of cannabinoids into the body, each has its pros and cons. Most of them (all but topical administration) result in systemic exposure. This none-specific exposure poses several challenges: 1. Unwanted side effects The endocannabinoid system is an endogenous system. The endocannabinoid receptors are the most abundant receptors in the human body. Hence, APIs from cannabis and/or cannabis-based treatments will be non- specifically bound to the relevant receptors in the body in addition to the brain. While at times, this type of interaction can be beneficial, it may also cause undesired side-effects when targeting the brain. 2. Administration of excessive cannabinoids dosages The blood-brain barrier is a protective layer which prevents the entry of chemicals and pathogens to the most vital and sensitive organ in the body. It is a known fact that cannabinoids can cross the blood-brain barrier and thereby reach the brain. The challenge arises when cannabinoids are exposed systemically, as only a small part of the administered dosage finds its way into the brain while the rest gets systemically dispersed. With the capability of specifically targeting the brain, it is possible to reach therapeutic levels at the brain using lower cannabinoids concentrations. This will result in minimizing unwanted side effect, prolonging the effect in the brain, minimize possible organ damage, and possibly reduce the product cost. 3. Cannabinoids accumulation in tissues and organs Although the use of cannabinoids is considered safe, during research done by GW Pharmaceuticals on patients treated with Epidiolex® (Cannabidiol) it was noted that a significant percentage of the patients (16%) had shown an increase in liver enzymes. This observation indicates that although their product is designed to affect the brain in the treatment of Lennox-Gastaut syndrome or Dravet syndrome, it still might cause undesired liver activity and possible damage. Another example of unwanted accumulation of cannabinoids in body tissues is in mother's milk. Studies have shown residues of THC at least six days after administration. Thus, mothers in need of medical cannabinoids treatment are facing two choices: avoid breastfeeding or discontinue the treatment. Accumulation of cannabinoids in the body might also affect the endocannabinoids tone and enhance malfunctions. Therefore, by using a targeted brain delivery technology, these types of accumulation of cannabinoids in tissues and organs are reduced, and possible damage to body organs minimized. Although the endocannabinoid system challenge is unique to cannabinoids, the latter two challenges exist for most drugs designed to treat brain-related diseases. The apparent need for the improvement of therapies for brain-diseases treatment led Nextar and Nextage to invest and further develop unique technology for targeted treatment of the brain-related diseases. This technology provides a solution for the main challenge in treating brain-diseases: efficient delivery of drugs through the Blood-Brain Barrier (BBB). Want to learn more about our drug delivery system and how it works? The second part of this article will be published soon. Subscribe here for updates on new blog posts.

During many years of experience with clients, we have encountered confusion between the terms GMP (Good Manufacturing Practice) and GLP (Good Laboratory Practice). For example, we are asked to manufacture clinical trial materials in compliance with GLP, or that bioanalysis for animal tissues will be performed under GMP conditions. Quite a few people have asked us: is there really a difference between those two? In general, it can be said that the purpose of both GMP and GLP requirements is to protect the patients that will be using the product. To better understand the difference, let's overview briefly each of the concepts. GMP in a nutshell Good Manufacturing Practice (GMP) is a set of regulatory requirements that ensures consistency and safety during the manufacturing of products for human and animal consumption (drugs, medical devices, food and beverage, cosmetics, and food supplements). Although the requirements vary between industries and geographies, the purpose of GMP is the same: keeping the safety of the consumer. The GMP system applies to all aspects of manufacturing, testing, and quality assurance of the product- from raw materials quality to manufacturing procedures and QC testing. Dozens of regulatory requirements must be embedded by the production facility in order to achieve a quality product, including a strong quality management approach, proper production facilities, well-trained personnel, proper documentation and archiving, controlled storage environment, and more. The GMP requirements also apply to the post-production phase, and the manufacturer must be obligated to monitor the product in the clinical trial/market and provide a strong recall system (pharmacovigilance). GLP in a nutshell Good Laboratory Practice (GLP) quality system is the set of regulatory binding principles. These principles are used to guarantee the validity of the safety data generated during the non-clinical phases. Unlike GMP, GLP applies not only to products for human and animal consumption but also to environmental chemistry such as pesticides and other non-pharmaceutical products. The GLP system requires that all procedures and testing will be extensively documented in a very accurate manner, so that the quality and reliability of the data is ensured. GMP vs. GLP There are two main differences between GMP and GLP quality systems. The first difference is that they both refer to different stages and processes in the developmental path of products. While the GLP principles refer to laboratories engaged with preclinical testing, including in-vitro and animal testing, bioanalytical methods. etc.. The GMP requirements apply to all products manufactured for human patients, from first-in-man trials to mass production. The second main difference is the definition of the QA role between the two systems. The role of the QA team according to the GLP principles is to serve as the extension or long arm of the regulator. This means that the QA is not expected to interfere in the planning of the various processes, but only to audit them. If issues that require further reference arise during the audit, the QA is not entitled to suggest corrective actions. In processes carried out under the GMP requirements, the QA is an integral part of the team, from planning the activities and proposing preventing actions, through responding to questions as they arise, to reviewing the processes and proposing corrective actions if needed. Did you know? The campaign for the OECD-GLP recognition in the Israeli-GLP was led by Dr. Orna Dreazen, former General Director of the Israel Laboratory Accreditation Authority (ISRAC). This campaign was a great success, and in 2002 ISRAC was recognized as a full member of the OECD-GLP working group, long before the State of Israel became a member of the OECD. Dr. Dreazen currently serves as the CEO of Nextar's Chempharma Solutions. Additional reading 1. World Health Organization (WHO) GMP Questions and Answers: https://www.who.int/medicines/areas/quality_safety/quality_assurance/gmp/en/ 2. World Health Organization (WHO) Good Laboratory Practice (GLP) Handbook: https://www.who.int/tdr/publications/documents/glp-handbook.pdf Want to to get email notifications on new posts? Subscribe here for updates on new blog posts.

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formulation Development anlaytical Development test Articles Preparation Preclinical trials Bioanalytical testing manufacturing scale up Analytical method validation manufacturing Stability testing clinical trials Bioanalytical Testing The term "bioanalysis" refers to the quantitative measurement of analytes (i.e., drugs and their metabolites) and biomarkers in biological matrices such as serum, urine, and different body tissues. In other words, bioanalysis refers to the analytical procedures performed in a laboratory environment on biological samples. ​ Bioanalysis of the drug begins at the preclinical stage, when the drug is being tested for its efficacy, toxicity, and pharmacokinetics (how the body affects the drug). During this stage, tests should be performed under Good Laboratory Practice (GLP) requirements in order to protect the integrity of the data. Bioanalytical testing for clinical trials is performed under cGMP requirements. ​ The development of bioanalytical methods raises some unique challenges. Two of these challenges are the low limit of detection (the lowest concentration for which the analyte can be distinguished) and the low limit of quantitation (the lowest concentration for which the analyte concentration can be quantified). This challenge is even greater in small animals, where the initial dose is significantly lower. Bioanalytical studies should be performed in compliance with GMP or GLP according to the developmental stage. In order to save time and money, it is recommended that bioanalytical method development, validation, and testing will be performed by the same laboratory. Choosing a supplier that holds both GLP and GMP credentials will help you to avoid a technology transfer. Tip from our scientists Previous stage Next stage Services for you of bioanalytical methods for quantitation of active drugs, natural compounds, and metabolites. Development and validation ​ Testing of and such as plasma, serum, urine, vitreous fluid, CSF, and cerebral fluid. tissues body fluids ​ testing and documentation. GLP ​ Preparation of for pre-clinical efficacy/toxicity studies. test articles ​ Contact Us

formulation Development anlaytical Development test Articles Preparation Preclinical trials Bioanalytical testing manufacturing scale up Analytical method validation manufacturing Stability testing clinical trials GMP Manufacturing GMP production of clinical trial material (CTM) is usually the last developmental milestone before introducing your drug into clinical trials. Assuming that your drug development process was continuous and without significant challenges, this milestone is usually achieved 9-12 months after begins. formulation development ​ Clinical Trial production is very different from mass production. At the commercial stage, the drug is already well defined, and the production process is carried out by line operators dedicated to specific products. However, in the early stages of development, the product is still evolving, hence the production process is subjected to changes. As challenges might arise during manufacturing, it is necessary to provide real-time solutions that will meet the regulatory requirements. Therefore, CTM production is usually performed by development scientists with vast knowledge and experience in different production processes. ​ Tip from our scientists The primary package (i.e., tubes, bottles, vials, etc.) affects not only the filling and closure procedures for your products but also has a great effect on product stability. It is recommended to choose the primary packaging components during formulation development in order to gain as much information as possible on packaging compatibility with the product. Short term stability study at this stage may provide some information about leaking, change of color, and other characteristics that might be affected by the package. Previous stage Next stage Services for you Drug and medical device studies in a GMP certified facility, according to FDA and EMEA requirements. manufacturing for Phase I-III ​ of sterile products in ISO 5 (class 100) cleanrooms (suitable for parenteral and ophthalmic solutions, topical creams for open wounds treatment, etc.) Aseptic manufacturing Manufacturing of such as suspensions, emulsions, topical creams, foams, polymers, etc. formulations liquid and semi-solid and for the finished product. Analytical stability testing Full QA/QC support and . QP services ​ and packaging. Clinical labeling ​ Planning and executing processes for formulations developed by the client or by us (including Technology transfer to and from Nextar). scale-up Development and manufacturing of special drug delivery systems such as liposomes. ​ Preparation of Chemistry, Manufacturing, and Controls ( ) supporting documentation for submission to regulatory agencies. CMC ​ ​ Contact Us