Dosage issues

The dossier requires that the process foundation— chemistry, engineering, scale-up, bulk drug chemical and physicochemical attributes, environmental impact, process controls, preparative and developmental history, and bulk/ dosage issues— be readily available and well organized for the assembly of the various individual submissions. Increas-... 

The preclinical trials are performed in in vitro and animal studies to assess the biological activity of the new compound. In phase 1 of the clinical trials the safety of a new drug is examined and the dosage is determined by administering the compound to about 20 to 100 healthy volunteers. The focus in phase II is directed onto the issues of safety, evaluation of efficacy, and investigation of side effects in 100 to 300 patient volimteers. More than 1000 patient volunteers are treated with the new drug in phase 111 to prove its efficacy and safety over long-term use. 

Good Manufacturing Practice. The GMPs were issued by the U.S. FDA in 1978 to provide minimum quahty standards in the production of pharmaceuticals (qv) for the finished dosage form as well as their ingredients. The standard has been updated periodically. 

Comprehensive physicochemical characterization of any raw material is a crucial and multi-phased requirement for the selection and validation of that matter as a constituent of a product or part of the product development process (Morris et al., 1998). Such demand is especially important in the pharmaceutical industry because of the presence of several compounds assembled in a formulation, such as active substances and excipients, which highlights the importance of compatibility among them. Besides, variations in raw materials due to different sources, periods of extraction and various environmental factors may lead to failures in production and/or in the dosage form performance (Morris et al., 1998). Additionally, economic issues are also related to the need for investigating the physicochemical characteristics of raw materials since those features may determine the most adequate and low-cost material for specific procedures and dosage forms. 

Approximately one-third of patients with MDD do not respond satisfactorily to their first antidepressant medication.37 In such cases, the clinician must evaluate the adequacy of antidepressant therapy, including dosage, duration, and patient compliance.17 Treatment reappraisal also should include verification of the patient s diagnosis and reconsideration of clinical factors that could be impeding successful therapy, such as concurrent medical conditions (e.g., thyroid disorder), comorbid psychiatric conditions (e.g., alcohol abuse), and psychosocial issues (e.g., marital stress).16... 

Another category of potential confounding variables includes dosing issues. Caffeine researchers have administered a wide variety of experimental dosages, an issue related obviously to physiological effects but also of interest to those concerned with caffeine doping. The timing of the... 

Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms based on a biopharmaceutics classification system. Center for Drug Evaluation and Research, Food and Drug Administration, issued 8/2000, posted 8/31/2000. http //www.fda.gov/cder/guidance/ index, htm... 

The development pharmaceutics discussion for liquid and semi-liquid dosage forms may need to pay particular attention to the following points or issues as well as the general points listed above. 

Issues relating to chemical incompatibility and instability may be less significant for solid dosage forms compared with liquid and semi-solid preparations. 

Issues similar to those discussed above for other dosage form types arise from the active ingredients and excipients proposed for use. 

The availability of unpreserved and preserved dosage forms is considered. Mention is made of formulation changes necessitated by multidose products. The need for adequate antimicrobial preservative efficacy can be discussed if this was an issue during product development. 

CPMP/QWP/2570/98 Concept paper on the development of a CPMP note for guidance on in-use stability testing of non-sterile human medicinal products (November 1998) CPMP/QWP/2934/99 draft Note for guidance on in-use stability testing of human medicinal products (released for comment December 1999) CPMP/QWP/598/99 draft Note for guidance on process validation (released for comment September 1999, also issued under CVMP reference EMEA/CVMP/598/99 draft) CPMP/QWP/486/95 Note for guidance on manufacture of the finished dosage form (reissued April 1996)... 

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