Excipients risk assessment

From a regulatory standpoint, the FDA s concern regarding safety involves the toxicity, degradants, and impurities of excipients, as discussed in other chapters in this book. In addition, other chapters of this book address types of toxicity concerns, toxicity testing strategies, and exposure and risk assessment of excipients. 

Consequently, the environmental risk assessment (ERA) of medicinal products has to be evaluated and appropriate legislation and regulatory guidance has been issued in the European Union (EU). Recently, Directive 2001/83/EC [12], as amended by Directive 2004/27/EC [13], requires an evaluation of the potential environmental risks to be performed for every application for each active ingredi-ent/excipients from every medicinal product to be authorized. However, the... 

Labelling should state clearly the excipient composition of the medicine so that predictable harmful effects can be avoided, especially in very young patients. For the formulator, the choice of excipients should be guided by a thorough risk assessment of the excipients, the route of administration and the patient susceptibility. It is highly recommended to refer to manuals such as authorities guidelines, pharmacopoeias, a handbook of excipients and the latest literature available. 

The Guideline recommends acceptable amounts of RS in pharmaceuticals which are safe for the patient. Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used or produced in the manufacture of active substances or excipients, or in the preparation of medicinal products. It is stated that medicinal products should contain no higher levels of residual solvents than can be supported by safety data. Three classes of solvents have been defined based on risk assessment. 

Preparations differ in size and complexity. The scale may range from a tailor-made preparation for one patient to a (semi-)industrial production for thousands of patients. The complexity may range from the reconstitution of an authorised medicine to complex preparations from active substances and excipients. In this chapter we focus mainly on stock preparatiOTis. The principles described are equally applicable to simpler preparations such as extemporaneous preparations and even for reconstitution [4]. However, the extent of quality control and validation should be justified by risk assessment [5, 6 and Chap. 21]. 

C. Carlsson, A.-K. Johansson, G. Alvan, K. Bergman and T. Kiihler, Are pharmaceuticals potent environmental pollutants Part II. Environmental risk assessments of selected pharmaceutical excipients, Sci. Total Environ., 2006, 364, 88-95. 

Appendices This section is most likely to contain additional data associated with biological-based products. It should contain information as regards the facilities and equipment used for the manufacture of biotech products. Assessment of the risk of contamination from adventitious agents such as transmissible spongiform encephalopathy agents (TSEs), bacteria, mycoplasma, fungi or viruses should also be provided. Additional information on novel excipients that have not been used before should also be included in this section. 

An important outcome of the JECFA evaluation is the establishment of an ADI for a food additive. The ADI is based on the available toxicological data and the no adverse effect level in the relevant species. JECFA defines the ADI as an estimate of the amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk (8). JECFA utilizes animal data to determine the ADI based on the highest no-observed-adverse-effect level (NOAEL), and a safety factor is applied to the NOAEL to provide a margin of safety when extrapolating animal data to humans. JECFA typically uses safety factors of 50, 100, or 200 in the determination of an ADI. The NOAEL is divided by the safety factor to calculate the ADI. The food additive is considered safe for its intended use if the human exposure does not exceed the ADI on a chronic basis. This type of information may potentially be used to help assess the safety of a pharmaceutical excipient that is also used as a food additive, based on a comparison of the ADI to the estimated daily intake of the excipient. 

The information presented therefore provides a kind of flow chart to assess the risk of using a particular excipient. In increasing order, these would seem to he ... 

Process technology selection for the manufacture of amorphous solid dispersions requires consideration of the particular complexities of the drug and excipients. HME offers the possibility to manufacture drug products in a continuous, cost-effective manner, yet it presents unique challenges that must be tackled. Noting the significant interplay between formulation and process, a risk-based classification system has been developed to aid in the early assessment of dispersion success using melt extrusion. 

Excipients are inert pharmaceutical ingredients that are used in product formulations. Excipients may perform a variety of functional roles in the pharmaceutical product. In the vast majority of cases, excipients have limited (if any) pharmacological activity, unlike the API. Because of this difference in the expected biological activity and the risk/benefit relationship between excipients and active drug substances, the approaches for the safety assessment of excipients and API will differ. ... 

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