In various manufacturing processes of pharmaceutical products, different metals and metal ions are used. For example, oxidation and reduction reactions in pharmaceutical formulations are often initiated by the action of heat, light and traces of metal powders or ions. In catalytic reactions, various metals viz, platinum, rhodium etc. either in powder form or supported on a suitable media are used. Due to their ability to form complexes with heavy metal ions, aliphatic polyesters are added to skin-protective ointments. However, the maximum permissible limit of the concentration of heavy metals in any oral drug is about 10 ppm, in most of the cases.

Various heavy metals have been evaluated for their potential risk to human health and have been categorized into three basic classes as follows:

• Class 1 Metals: Metals of significant safety concern, known or suspect human carcinogens or possible causative agents of other significant toxicity. Examples: As, Cd, Hg and Pb
• Class 2 metals: Metals with low safety concern, with lower toxic potential to man. Examples: Cu, Cr, Ir, Mo, Ni, Os, Pd, Pt, Rh, Ru and V. They are generally well tolerated up to exposures that are relevant to the context of this guideline. They may be trace metals required for nutritional purposes or they are often present in food stuffs or readily available nutritional supplements.
• Class 3 metals: Metals with minimal safety concern, with no significant toxicity. Their safety profile is well established. Examples: Sb, Ba, Li, Cr, Cu, Sn and Ni.

Class 1 is subdivided into two subclasses. Platinoids are in class 1A and class 1B. For the platinoids in subclass 1B a conservative approach has been adopted, because there are very limited toxicity data. Thus the indicated limit for Class 1B is the limit for the total amount of those platinoids that, based on the used synthesis procedures, are anticipated to be present.

Effects of some of the heavy metals and their permissible limits are discussed below.

Platinum (Pt): Pt is the most important of the six heaviest of the group VIII elements, collectively called the “platinum group metals” or “platinoids”. Metallic Pt is often used as catalyst in many formulation reactions viz., oxidation-reduction and decomposition reactions in pharmaceutical industries.

Pt complexes exhibiting a range of oxidation states are known, although the principal valences are Pt II and IV. Pt II forms a tetra-coordinate aqua ion [Pt (H2O)4]2+. A variety of amine complexes such as the anti-tumour compound cis-PtCl2(NH3)2 (cis-platin) are also known. The most important Pt IV compounds are salts of the red hexachloroplatinate ion PtCl62-.

Gastrointestinal absorption of Pt salts is extremely low (<5% of oral dose). Excretion of most of the absorbed fraction is normally via the faeces. The acute toxicity of Pt salts is dependent on water solubility (the more soluble salts being more toxic) and speciation. A range of Pt IV salts are reported to have rodent oral LD50 values from 10 to >1100 mg/kg. Pt and its compounds have a wide spectrum of toxicity ranging from relatively low toxicity of Pt metal to genotoxic/cytotoxic effects (e.g. cis-platin) and sensitisation reactions associated with some Pt salts and complexes.

Palladium (Pd): Palladium resembles and occurs together with the other platinum group metals and nickel. It is present at very low concentrations (<1 µg/kg) in the earth’s crust. Palladium alloys are widely used in dentistry (e.g., for crowns and bridges), thus representing the most frequent cause of constant palladium exposure.

Palladium levels detected in food ranged from 0.3 (milk and poultry) to 15µg/kg fresh weight (honey sample collected from a polluted area). In general the amounts of palladium exceeded those of platinum found in diverse food groups. The human average dietary intake of palladium appears to be up to 2 µg/day.

Palladium ions are poorly absorbed from the digestive tract (< 0.5 % of the initial dose in adult rats). After intravenous administration the highest concentration of palladium was found in kidney, liver, spleen, lymph nodes, adrenal gland, lung and bone. Palladium ions were found to be eliminated in faeces and urine. Urinary excretion rates of intravenously dosed rats and rabbits ranged from 6.4 to 76 %. Following oral administration > 95 % of palladium was eliminated in faeces of rats due to non-absorption.

Most of the case reports refer to palladium sensitivity associated with exposure to palladium-containing dental restorations, symptoms being contact dermatitis, stomatitis or mucositis. Side–effects noted from other medical or experimental uses of palladium preparations include fever, haemolysis, discoloration or necrosis at injection sites after subcutaneous injections and erythema and oedema following topical application.

Nickel (Ni): Ni is a Group VIIIB element of the first transition series. Although it can exhibit valences of 0, I, II and III, its main oxidation state is +2. Estimates of the presumed human Ni requirement range from 5-50 µg/day (Department of Health, USA 1991).

Rhodium (Rh): Rh is a platinum group VIII element of the second transition series. Its principal oxidation states are I, II and III, though Rh III is the most common state, especially in terms of aqua ion formation. Rh catalysts (Rh-Pt metal alloy; Rh CO complexes) are widely used.

Molybdenum (Mo): Mo is a Group VIB element of the second transition series. Its main oxidation states are IV and VI, the most common forms of which are oxyanions. The predominant form of Mo occurring in soils and natural waters is the molybdate ion, MoO42- which forms soluble compounds with a variety of cations including K+, NH4+ and Ca2+. MoO2 and MoS2 are insoluble in water.

Detection and analysis
The standard methods for the qualitative and quantitative analysis of the heavy metals in drugs and medicines required instruments viz.Inductively Coupled Plasma (ICP), and Inductively Coupled Plasma Mass Spectrometry (ICP-MS), Quadrupole ICP-MS etc. Geochemical analysis labs were early adopters of ICP-MS technology because of its superior detection capabilities, particularly for the rare-earth elements (REEs). ICP-MS has many advantages over other elemental analysis techniques such as atomic absorption and optical emission spectrometry, including ICP Atomic Emission Spectroscopy (ICP-AES).Descriptions and tests can be found in the norms and standards of the ISO; these have been established in collaboration with manufacturers. Requirements are not given in pharmacopoeias; the suitability of a particular material for a container is normally established by conducting stability studies in which the material is in contact with the drug in question.

The presence of beyond permissible limit metals/metal ions not only degrades the product quality but also their presence may be dangerous as they can damage expensive equipment. Thus, the pharmaceutical industry like other industries viz., food, chemical, coal, ceramic, aggregates, mineral processing, plastic and rubber and packaging needs highly accurate metal detection device to meet the requirements of demanding consumers and stringent legislation. There are different types of metal detectors; some are suitable for self-monitoring online metal detection.

Normally, the metal detectors are designed for the compliance with GMPs, with multiple aperture sizes and the ability to detect 0.2 mm or even less metal spheres and come with easy-to-use suitable size VGA touch screen interface with advanced digital signal processing to provide detailed analysis and reporting for process applications including pharmaceutical, food, chemical, coal, ceramic, aggregate, mineral, plastics and packaging industries.