As preventive quality control management has now become a focus area for large, medium and small pharma in the country, metal detection in pharmaceuticals covering bulk drugs excipients and finished formulations is now gaining ground in India. This had led to a profusion of advanced multi-spectrum detection technologies allowing total fool-proof automatic detection of impurities making the process mandatory and vital for end-users to check the same with the metal detector manufacturers.
The metal impurities are organic, inorganic impurities and residual solvents. The metal contaminants are through water and manufacturing vessels corrosion which contaminates tablets, capsules, dry powders and liquids.
The impurities are presence of chemicals that remain with active pharmaceutical ingredients (API) or drug formulations. It occurs in the drug substances during synthesis or could be derived from raw material sources like intermediates, reagents, solvents, catalysts, and reaction by-products.
The process of metal detection is undertaken prior to the process of final packaging. The types of metal detectors are external sensors and use of magnets at the rejection chutes of the sifters. The leading manufacturers of detectors are Techno Four, Metler Toledo, Thermo Fisher to name a few.
However Indian pharma companies invest in metal detectors manufactured in the country which are embedded with advanced technology. These are a wide range of metal detectors incorporating electromagnetic induction measurement, multi-frequency transmission and receiving and radio frequency signals. There are off line and online metal detectors. The online detectors priced from Rs. 7 lakh to Rs. 15 lakh are advanced equipment attached to the manufacturing equipment. The offline detectors are inspection tables are ideal for small scale pharma operations.
Pharma equipment operates at high speed and therefore fractions of movable metal parts getting dislodged are possible occurrences. There is every possibility of metal contamination in pharma manufacturing which happens either as a foreign particles through raw material or by accidental means through machinery. These metal contaminants are classified as ferrous, non -ferrous or stainless steel contaminants. In the backdrop of 483 warning letters being issued to various companies by the USFDA, there is need for an implementation of a robust mechanism to ensure that all the final finished formulations are free from metal contaminants,” pointed out YA Chowdary, executive vice president, Medreich Ltd., India.
There is a significant advancement in the metal detection technologies. There are machineries available which scans for the metal contaminants in each and every tablet/capsule during a manufacturing process with a production capacity of up to 10,000 tablets per minute. Eddy current principle is adopted in these detectors to detect the metal contaminants. In this method, a stable electromagnetic field is created which gets imbalanced when ever a metal contaminant passes though it. And the disturbance in the electromagnetic field signals the presence of metal contaminants. The tablet or capsule which undergoes the metal detection process ejects if it contains a metal contaminant. In the case of iron formulation drugs , due to the presence of the iron molecule these detectors can give a false signals which needs to be eliminated by adjusting the magnitude of the signals in the detectors, so that the product signals will not interfere with the contaminant signals. added Chowdary.
The most crucial feature of a metal detector is the sensitivity because its primary task is to reject actual contaminants. The aperture sizes of the detectors are designed based on the speed of production lines and the sensitivity required. A metal contaminant size of 0.25 mm diameter can be detected which could be a wire or metal content of ferrous and non ferrous nature, noted Chowdary.
During drug product development, impurities may be formed as a result of the inherent instability of drug substances, or due to incompatibility with added excipients, or may appear as results of interactions with packaging materials. The amount of various impurities found in drug substances will determine the ultimate safety of the final pharmaceutical product. Therefore, the identification, quantization, qualification, and control of impurities are now a critical part of the drug development process, according to Agilent which is known for its range of analytical technologies for impurity profiling in pharmaceutical development.
The global regulatory authorities focusing on impurities control are International Conference on Harmonization (ICH), the United States Food and Drug Administration (USFDA), the European Medicines Agency (EMA), the Canadian Drug and Health Agency, the Japanese Pharmaceutical and Medical Devices Agency (PMDA), and the Australian Department of Health and Ageing Therapeutic Goods. In addition, a number of official compendia, like the British Pharmacopoeia (BP), United States Pharmacopoeia (USP), Japanese Pharmacopoeia (JP), and European Pharmacopoeia (EP) have clearly defined the impurity content limits present in APIs and formulations. But the Indian drug regulatory is yet to come out with dedicated guidelines for the same.
The metal impurities are seen as a threat to the patients and this has led pharma companies to invest in advanced metal detection technologies. The control of impurities has always been a critical issue for the pharmaceutical industry, said P Krishnamurthy, executive vice president, corporate quality control, Medreich Ltd.
The metal detection technologies have improved by leaps and bounds and so have the new regulations been enforced. In 2012, it was the European Commission which has now called to detect 30 metals out of 103 elements of periodic tables using Atomic Absorption methods. The USP has now replaced section 231 with 232 and 233. ICH has mandated Q3D. European Commission has stated that for drug formulation purity tests, companies should test for 14 elements, USP has 15 elements and ICH 24 metal identification and estimation. Further, European Commission has classified Class I A, I B and I C metals of significant metal safety concern. Under Class II category, it has listed the metals of low safety concern. In Class II is has minimal safety metals list including iron and zinc content. However Indian Pharmacopoeia is silent on this, said Krishnamurthy.
Metallic impurities is great concern for both drug product and drug substance manufacturing. This was part of specification as heavy metals from the beginning. With growing knowledge and technology there is an increasing need for detection and quantification of specific metals. The more toxic metals being lead, mercury, arsenic, cadmium etc. Potential sources of metallic impurities are drug substance and excipients with metal catalyst residues etc. The other sources of metallic impurities are manufacturing equipments, container closure system and water.
Visible trends in metal detection
Metal detection in pharmaceutical manufacturing cannot be ignored. Manufacturers must eliminate such contaminants. This has led the pharma companies to invest in metal detectors which are highly precise and reject every metal particle if at all they present. The latest advances in metal detection are electronic based systems, said Chowdary.
Challenges in metal detection
The challenges for the industry is to check the compatibility of manufacturing equipment with the product. With reference to metal catalyst residues API manufacture should identify these metals and test for their residues, fix the limit as per PDE ( permitted daily exposure) the testing to be done at the time of development so that proper process changes are made to eliminate these residues. This can than be either part of development report confirming its absence or part of specification either all batches or can be skip test. Advanced method such as ICP-OES ( Inductively Coupled Plasma - Optical Emission Spectroscopy) can be used for this analysis, A.G.Raghu, managing director, Santhana Gopala Consultants and technical director, Gland Chemicals Pvt. Limited, Bengaluru.
If water is treated ( DM water, Purified Water &Water for Injection), the risk of metallic impurities can be avoided. However it is better to have check on source water periodically on metallic impurities as this will reflect on treatment cost, he added.
According to Chowdary, if a drug is detected for a metal contamination, the entire business of the company will be at stake. Therefore no company can take a risk. Going by the state of the art metal detection technology available, strategic investments need to be made. While many pharma companies including Medreich had the foresight to gone in for metal detectors, it is a challenge for small and medium pharma companies to invest.
With India having a large presence of small and medium pharma manufacturers, investments into metal detection machines increases project cost .
Another issue is the access to trained manpower to handle these detectors. There is a need for an increased number of engineering diploma holders having the PLC(programmer logic controller ) know-how.
Metallic impurities will not add any therapeutic value to the patient and if it is more than PDE, it may harm the patient. Hence it is important we have to test for these impurities in our drug substance and drug product. We have new ICH guide line ICH Q3D, also USP 37 chapter 232 which it is official from May, 2014, gives more information on this subject, said Raghu.
According to Sunil Mundra, managing director, Natural Capsules, the big threat of metal contamination is chromium content in gelatin capsules which are imported by pharma suppliers and manufacturers of formulations. The chromium content is carcinogenic and government of India has failed to take note of this. This is a serious threat for the pharma exporters as gelatin products going from India need to obtain special permission from regulators in the US and EU.