Abstract and include residual starting materials, reagents and

Abstract This review aims to concisely summarise the issue of impurities in drug substance materials with specific focus on the regulatory requirements associated with impurities and the analytical techniques used to detect and quantify them. The review will also look at impurity management in Fluoxetine production as an example of a case study for the reader.IntroductionAn impurity is defined by the International Conference on Harmonisation as “any component of the drug substance that is not the chemical entity defined as the drug substance”.1 The safety profile of a drug substance is dependent not only on the pharmacological effects of the drug substance but also of the impurities and the levels at which these impurities are present. Impurities must therefore be regulated and controlled in the pharmaceutical industry for reasons of safety and efficacy. The International Conference on Harmonisation (ICH) was set up in an attempt to achieve worldwide harmonisation on the regulation of the pharmaceutical industry in order to bring down cost of manufacturing and increase patient access to medications. The ICH releases guidelines on all aspects of pharmaceutical manufacturing which if followed will allow for a registration application for a new drug substance within the three regions of Europe, Japan and the the U.S.A. The ICH has issued 4 guidelines relating to impurities in drug substances which will be summarised in this review. RegulationsThe ICH has classified impurities into organic impurities, inorganic impurities and residual solvents.1 Organic impurities can arise from the manufacturing and/or storage of the new drug substance and include residual starting materials, reagents and intermediates as well as degradation products and by-products. Inorganic impurities result from the manufacturing process and include reagents, ligands and catalysts as well as heavy metals, inorganic salts and other materials like filter aids or charcoal. Solvents are volatile liquids used in the manufacturing of a drug substance that can be organic or inorganic. All these impurities must be controlled to certain limits and regulated accordingly to ensure safety and efficacy of the drug substance. When applying for a marketing authorisation for a drug substance or product the impurities most likely to occur must be accounted for in the application. The application should include each identified impurity, each unidentified impurity, total impurities, residual solvents and inorganic solvents.  With regard to organic impurities the applicant should theorise the impurities most likely to occur during the synthesis, purification and storage of the drug substance. This evaluation should be performed taking into account the chemical reactions involved in the synthesis as well as the impurities associated with the raw materials used in the manufacture of the drug substance. Evaluating chemical reactions to determine the most likely impurities will be further discussed in the Fluoxetine case study. The applicant should also summarise the laboratory studies conducted to detect impurities during the development process as well as from batches from the proposed commercial process and from stress testing. The guideline defines the identification threshold of an impurity as “a limit above which an impurity should be identified” and states that the structure of any impurity present above this threshold should be characterised. In addition to this any degradation product observed in stability studies at recommended storage conditions at levels greater than the identification threshold should also be identified. If the identification of an impurity is not feasible, a report on the unsuccessful laboratory studies should be included in the application.1 Identification of organic impurities which are present in levels below the identification threshold is usually not necessary unless these impurities are expected to be unusually toxic such as genotoxic impurities like alkyl halides or sulfonates.4  If impurities below the identification threshold have been identified it is also recommended to include these in the application.The ICH has also issued guidelines to recommend acceptable amounts of residual solvents in pharmaceuticals. Solvents are often a critical parameter in the manufacture of a pharmaceutical in terms of crystal formation, purity and solubility and so appropriate selection of a suitable solvent should be undertaken to enhance the yield of the drug substance. The guideline outlines two simple principles when dealing with residual solvents, firstly that solvents of the lowest possible toxicity should be used and secondly that solvents offer no therapeutic effect and should be removed from drug products as much as is practicable. The Q3C(R6) guideline classifies the most commonly used solvents into 1 of 3 classes according to their possible risk to humans with class 1 being the most toxic and class 3 the least. Class 1 solvents like methylchloroform should, according to the guideline, be avoided in the production of drug substances, excipients or drug products unless their use can be strongly justified on a benefit to risk basis.5 Class 2 solvents such as hexane and methanol should be limited to protect patients from potential adverse effects. Ideally class 3 solvents such as Acetone or Butanol should be used where possible.5 The guideline uses the term “Permitted Daily Exposure (PDE)” to describe the acceptable intake of residual solvents and gives limits for solvent levels in drug products in mg/day for example it states the permitted daily exposure to acetonitrile is 4.1mg/day regardless of dose.5 There are two options available when calculating whether or not a drug product is within these specified limits. Option 1 calculates the concentration of residual solvent in each constituent of a drug product and if all fall below the limit in ppm then the product is within the limit. Option 2 is used when one or more of the constituents of a drug are above the limit so the drug product as a whole is analysed to check if it is within the limit.5 Residual solvents are usually analysed and quantified using chromatographic techniques such as gas chromatography however this may not be necessary for class 3 solvents in which case a non-specific method of loss on drying may be used instead.5 Analysis of all batches used for clinical, safety and stability testing should be recorded in the application for a new drug substance. A visible record of the chromatographic analysis of batches should be included in the application to represent the impurity profile of the batches.1 Quantitative levels of the impurities present should be presented numerically.1 An impurity present at a level below 1.0% should be recorded to 2 decimal places while levels above 1% should be recorded to 1 decimal place.1 A spreadsheet of the data collected should be included in the application for the new drug substance. Higher reporting thresholds are sometimes proposed for some impurities meaning the impurity can be present at a higher level before its reported, these should be justified in the application.1 Every impurity must also be qualified in terms of its biological safety and the acceptance criteria for an impurity should take into account its biological safety profile. Qualification of an impurity will depend on many factors such as the patient populations, daily dose and route and duration of administration.1 A lower qualification threshold of an impurity could be used if there is evidence that the impurity has been previously linked to toxic effects in patients. As well as this a higher qualification threshold could be used if there is less risk than usual associated with either the patient population, drug class or for other clinical considerations.1 When thresholds of impurities are exceeded there are a number of steps the manufacturer can take such as decreasing the level of the impurity to below the threshold or by providing more safety data on the impurity.