The control of pharmaceutical impurities is currently a critical issue to the pharmaceutical industry. 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 receiving important critical attention from regulatory authorities. The different pharmacopoeia such as the British Pharmacopoeia (BP) and the UnitedStates Pharmacopoeia (USP), are slowly incorporating limits to allowable levels of impurities sent in the APIs or formulations.
In order to isolate and identify process-related impurities and degradation products the following methods can be used: 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, 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.
Sources of Impurities in Medicines. Medicines are the formulated forms of active pharmaceutical ingredients. There are 2 types of impurities in medicines: (1) Impurities associated with active pharmaceutical ingredients and (2) Impurities that are created during formulation and or with aging or that are related to the formulated forms
Impurities Associated with APIs.
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:
a) Starting materials or intermediates. These are the most common impurities found in every API unless a proper care is taken in every step involved throughout the multi-step synthesis. 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.
b) 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.
c) Degradation products - Impurities can also be formed by degradation of the end product during manufacturing of bulk drugs.
In general, an individual API may contain all of the above-mentioned types of organic impurities at levels varying from negligible to significant. 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 (i.e. formulators) to take care of these impurities
a) 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
b) 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.
c) Other materials (e.g. filter aids, charcoal)
Residual solvents are in the majority of cases 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.
Impurities Related to Formulation
Apart from bulk drug-related impurities, the formulated form of API may contain impurities that form in various ways.
c) dosage form factors related
Formation of Impurities on Aging
a) Mutual interaction amongst ingredients
Most vitamins are very labile and on aging they pose a problem of instability in different dosage forms, especially in liquid dosage forms.
It has been observed in the pharmacopoeias that there is an impurity limit shown in the specifications of certain raw materials but not given in the case of products made of those raw materials. Although the impurity limit on the drug substances is applicable to the drug products, it would be convenient for the users if the impurity limits were also mentioned in each dosage forms. The limits may vary from orals to injectables. Diclofenac sodium is such an example where an impurity limit is not mentioned in the case of injections.