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BY- Kalyani jog Pallavi Shirsat INTRODUCTION : Impurities in pharmaceuticals are the unwanted chemicals that remain with the active pharmaceutical ingredients (APIs), or develop during formulation, or upon aging of both API and formulated APIs to medicines. The presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the pharmaceutical products. Impurity profiling (i.e., the identity as well as the quantity of impurity in the pharmaceuticals), is now getting receiving important critical attention from regulatory authorities. The different pharmacopoeias, such as the British Pharmacopoeia (BP) and the United States Pharmacopoeia (USP), are slowly incorporating limits to allowable levels of impurities present in the APIs or formulations. INTRODUCTION Tests to detect impurities.. : Tests to detect impurities.. Slide 4: A number of recent articles6-8 have described a designed approach and guidance for isolating and identifying process-related impurities and degradation products using mass spectrometry, Nuclear Magnetic Resonance (NMR), high-performance liquid chromatography (HPLC), Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS), and tandem mass spectrometry for pharmaceutical substances. In general, according to ICH guidelines on impurities in new drug products,2 identification of impurities below the 0.1% level is not considered to be necessary unless the potential impurities are expected to be unusually potent or toxic. In all cases, impurities should be qualified. If data are not available to qualify the proposed specification level of an impurity, studies to obtain such data may be needed (when the usual qualification threshold limits given below are exceeded). According to ICH, the maximum daily dose qualification threshold is considered as follows: This paper reviews the impurities found in the pharmaceuticals-identifying different sources, as well as providing examples and demonstrating possible measures to take care of the impurities in the pharmaceuticals Sources Of Impurities in Medicines : Impurities associated in with APIsOrganic impuritiesInorganic impuritiesSolvent residuesImpurities related to formulationImpurity forms during formulationFormation of impurities on aging Medicines are the formulated forms of active pharmaceutical ingredients. There are 2 types of impurities in medicines:(1) Impurities associated in with active pharmaceutical ingredients and (2) Impurities that form are created during formulation and or with aging or that are related to the formulated forms. According to ICH guidelines,1 impurities associated with APIs are classified into the following categories: Organic impurities (Process and Drug-related) Inorganic impurities Residual solvents Organic impurities may arise during the manufacturing process and/or storage of the drug substance. They may be identified or unidentified, volatile or non-volatile, and include the following: Starting materials or intermediates- These are the most common impurities found in every API unless a proper care is taken in every step involved inthroughout the multi-step synthesis. Sources Of Impurities in Medicines Slide 6: Although the end products are always washed with solvents, there are always chances of having the residual unreacted starting materials may remain unless the manufacturers are very careful about the impurities. In paracetamol bulk, there is a limit test for p-aminophenol, which could be a starting material for some one manufacturer or be an intermediate for the othersanother.By-products- In synthetic organic chemistry, getting a single end product with 100% yield is very rare; there is always a chance of having by-products. In the case of paracetamol bulk, diacetylated paracetamol Figure 1) may form as a by-product. Degradation products- Impurities can also be formed by degradation of the end product during manufacturing of bulk drugs. However, degradation products resulting from storage or formulation to different dosage forms or aging are common impurities in the medicines. The degradation of penicillins and cephalosporins is a well-known example of degradation products. The presence of a ß-lactam ring as well as that of an a-amino group in the C6/C7 side chain plays a critical role in their degradation.9 dioxide from the carboxyl group when heated. Decarboxylation also occurred in the case of photoreaction of rufloxacin. Slide 7: Reagents, ligands, and catalysts- These chemicals are less commonly found in APIs; however, in some cases they may pose a problem as impurities. In general, an individual API may contain all of the above-mentioned types of organic impurities at levels varying from negligible to significant. A detailed investigation of impurities in semi-synthetic penicillin was performed both by the manufacturers and the different research groups. A review paper on penicillins and cephalosporins9 describes methods of isolation, detection, and quantification of degradation products, and antigenic polymeric by-products. Studies show the presence of traces of ampicillin polymers and hydrolyzed products in the API.10 It has also been found that the presence of certain chemicals such as triethylamine has a degradative effect on the product. Ampicillin trihydrate samples having triethylamine content of 2000 ppm to 4000 ppm (determined by visual color method developed by Gist- Brocades, Delft, Holland)10 were found to be stable under accelerated stability testing. However, the product showed appreciable degradation when triethylamine content became 7000 ppm. Recent pharmacopoeia11 included the limit tests for the traces of impurities present in ampicillin and amoxycillin bulk raw materials. The residual solvents associated with these APIs have also been determined.10 Slide 8: As the organic impurities are the most common product- as well as process-related impurities, it is the responsibility of both the manufacturers of APIs and the users (ie, formulators) to take care of these impurities according to ICH guidelines or compendia. In addition, for an optically active single isomer drug there could be enantiomeric impurities present in the API. Enantiomeric impurities- The single enantiomeric form of a chiral drug is now considered as an improved chemical entity that may offer a better pharmacological profile and an increased therapeutic index with a more favorable adverse reaction profile.12 However, the pharmacokinetic profile of levofloxacin (S-isomeric form) and ofloxacin (R-isomeric form) are comparable, suggesting the lack of advantages of single isomer in this regard.12 In any case, cost benefits as well as the patient’s compliance need to be considered in selecting drugs. For the manufacturers of single enantiomeric drug (eutomer), the undesirable stereoisomers in drug control are considered in the same manner as other organic impurities. The prominent single isomer drugs, which are being marketed, include levofloxacin (S-ofloxacin), levalbuterol (R-albuterol), esomeprazole (S-omeprazole). Slide 9: impurities may also derive from the manufacturing processes used for bulk drugs. They are normally known and identified and include the following: Reagents, ligands, and catalysts- The chances of having these impurities are rare: however, in some processes, these could create a problem unless the manufacturers take proper care during production. Heavy metals- The main sources of heavy metals are the water used in the processes and the reactors (if stainless steel reactors are used), where acidification or acid hydrolysis takes place. These impurities of heavy metals can easily be avoided using demineralized water and glass-lined reactors. Other materials (eg, filter aids, charcoal)- The filters or filtering aids such as centrifuge bags are routinely used in the bulk drugs manufacturing plants, and, in many cases, activated carbon is also used. The regular monitoring of fibers and black particles in the bulk drugs is essential to avoid these contaminations. Slide 10: Residual solvents are organic volatile chemicals used during the manufacturing process or generated during the production. It is very difficult to remove these solvents completely by the work-up process; however, efforts should be taken to the extent possible to meet the safety data. Some solvents that are known to cause toxicity should be avoided in the production of bulk drugs. Depending on the possible risk to human health, residual solvents are divided into 3 classes.3 Solvents such as benzene (Class I, 2 ppm limit) and carbon tetrachloride (Class I, 4 ppm limit) are to be avoided. On the other hand, the most commonly used solvents such as methylene chloride (600 ppm), methanol (3000 ppm), pyridine (200 ppm), toluene (890 ppm), N,N-dimethylformamide (880 ppm), and acetonitrile (410 ppm) are of Class II. Class III solvents (acetic acid, acetone, isopropyl alcohol, butanol, ethanol, and ethyl acetate) have permitted daily exposures of 50 mg or less per day. In this regard, ICH guidelines3 for limits should be strictly followed. Slide 11: Apart from bulk drug-related impurities, the formulated form of API may contain impurities that form in various ways. a) method related A known impurity, 1-(2,6-diclorophenyl)indolin-2-one is formed in the production of a parenteral dosage form of diclofenac sodium if it is terminally sterilized by autoclave.13 It was the condition of the autoclave method (ie, 123 + 2°C) that enforced the intramolecular cyclic reaction of diclofenac sodium forming the indolinone derivative and sodium hydroxide. The formation of this impurity has been found to depend on the initial pH of the formulation. The concentration of the impurity in the resultant product in the ampoule exceeds the limit of the raw material in the BP. b) environmental related The primary environmental factors that can reduce stability include the following: Slide 12: Exposures to adverse temperatures- There are many APIs that are labile to heat or tropical temperatures. For example, vitamins as drug substances are very heat-sensitive and degradation frequently leads to loss of potency in vitamin products, especially in liquid formulations.Light-especially UV light- Several studies have reported that ergometrine as well as methyl ergometrine injection is unstable under tropical conditions such as light and heat, and a very low level of active ingredient was found in many field samples.In only 50% of the marketed samples of ergometrine injections tested did the level of active ingredient comply with the BP/USP limit of 90% to 110% of the stated content. The custom-made injection of ergometrine (0.2 mg/mL) showed almost complete degradation when kept 42 hours in direct sunlight.Humidity- For hygroscopic products, humidity is considered detrimental to both bulk powder and formulated solid dosage forms. Aspirin and ranitidine are classical examples. Slide 13: c) dosage form factors related Although the pharmaceutical companies perform pre-formulation studies, including a stability study, before marketing the products, sometimes the dosage form factors that influence drug stability force the company to recall the product. In general, liquid dosage forms are very much susceptible to both degradation and microbiological contamination. In this regard, water content, pH of the solution/suspension, compatibility of anions and cations, mutual interactions of ingredients, and the primary container are critical factors. Microbiological growth resulting from the growth of bacteria, fungi, and yeast in a humid and warm environment may result in oral liquid products that are unusable for human consumption. Microbial contaminations may occur during the shelf life and subsequent consumer-use of a multiple-dose product due to inappropriate use of certain preservatives in the preparations, or because of the semi-permeable nature of primary containers. You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.