Preface
It’s the duty and responsibility of a manufacturer to ensure that a pharmaceutical product consists of the right dose of lifesaving drug and is free from any form of unwanted and harmful contaminants. Health agencies like FDA regulate pharmaceutical market’s by issuing guidelines for identity, strength, quality and purity of drug products and their ingredients through USP.
Elemental impurities in Pharmaceutical products can be rooted from A. source of the ingredients used in preparation (e.g. Herbs), B. process of drug compound synthesis (e.g. Catalysts) or
C. manufacturing process (e.g. molding, packaging). Although there have been no known health related incidents from elemental contamination in pharma products, but it has been scientifically established that elements like Arsenic, Mercury, Cadmium, Lead are of potential toxic nature.
USP <231>
Prior to implementation of USP <232>, <233>& <2232> elemental impurity analysis is carried out by USP <231>, which is a calorimetric analysis based on element reaction with thioacetamide to produce a precipitate of metallic sulfide, which is then compared with a lead standard solution visually.
However, this approach of elemental determination has several drawbacks like loss of volatile elements (As, Hg) during sample preparation, Matrix & standard inconsistency, and variability in interpretation of results among analysts. Advancements in elemental scientific instrumentation have created a more simple and accurate measurement possible and so from Jan 2018, USP has implemented the new guidelines of USP <232>, <233>.
USP <232>, <233>, <2232> & ICH
USP <232> specifies limits for the amounts of elemental impurities in drug products, drug substances, active ingredients and excipients, USP <233> describes the analytical procedure (ICP-OES and ICP-MS) for the evaluation of the levels of the elemental impurities. USP <2232> describes elemental analysis in dietary supplements & ICH Q3D categorizes the elements in four classes for the risk assessment process and defines a more harmonized approach for drug assessment.
USP <232>
Toxicology limits in PDE (Permissible Daily Exposure) μg/day of Fifteen elements have been defined in this chapter based on their route of administration. These limits are as shown in the following table.
Table 1: Elemental Impurities for Drug Products
USP <233>
This chapter deals with analytical procedure for elemental impurity evaluation like sample preparation, Instrumental methods, protocol for method validation with instrumental procedures like ICP-OES & ICP-MS. It also specifies that an alternate procedure can also be used, provided that it meets the validation requirements.
Sample preparation states that “The selection of the appropriate sample preparation depends on the material under test and is the responsibility of the analyst. When a sample preparation is not indicated in the monograph, an analyst may use any of the following appropriately validated preparation procedures”. These procedures are Neat, Direct aqueous solution, Direct organic solution, Indirect solution (microwave digestion, leachate extraction).
Instrumental methodology states that “System standardization and suitability evaluation using applicable reference materials should be performed on the day of analysis”. This requires Matrix matched blank, Standard solution 1 (1.5J of target element), Standard solution 2 (0.5J of target element) and Sample solution diluted NMT 1.5J with an appropriate diluent.
“J value” is the concentration (PDE) of the element of interest, appropriately diluted to the working range of the instrument, after the sample preparation process. Calculation for “J value” is as follows.
J value= PDE (μg/day) / (Max daily dose x dilution factor)
System suitability is checked by running standard solution 1 (1.5J) before and after sample solution, and the drift should not be more than 20% for each target element. USP <233> doesn’t define any specific instrument conditions, instead states that the sample be analyzed according to the manufacture suggestions for program and wavelength, m/z.
Suitability of the technique and analytical procedure is to be established by validation/ verification protocols (USP <1225> <1224>) with various parameters like-
1. Detectability 2.Reputability, 3. Specificity 4. Accuracy, 5. Precision, 6. Limit of Quantification & 7. Linearity & range.
USP <2232>
This chapter defines the elemental contaminants in dietary supplements. It focuses on four elements As, Pb, Cd & Hg. Their limits are as defined in the following table.
Table 2: Elemental Impurities for Dietary Supplements
ICH Q3D
ICH Q3D defines the guidelines for elemental impurities in drug products. It has three parts in it.
1. Evaluation of the toxicity data for potential elemental impurities,
2. Establishment of a Permitted Daily Exposure (PDE) for each element of toxicological concern
3. Application of a risk-based approach to control elemental impurities in drug products. This guideline has classified elemental impurities into three classes based on their toxicity (PDE) and likelihood of occurrence in the drug product.
Table 3: PDE for Elemental Impurities as per ICH Q3D
How to comply with USP?
With these updates in Pharma guidelines there are lot of questions the minds of analysts, like:
Which technique is suitable for the analyst’s products?
What is the procedure for sample preparation?
How do the analyst interpret the data?
Let us look at these instrumentation and sample preparation approach for a better idea about how to treat samples and which instrumentation technique is suitable for specific analysis.
Sample Preparation
Some of the pharmaceutical products are water soluble, so a simple dilution with a suitable solvent can do the job but for complex and insoluble products, different approaches like “Microwave digestion” has to be employed. This a simple technique where a sample is digested in acidic medium under high pressure and temperature environment is created inside the Microwave digestion vessel, whose parameters are controlled by dedicated pressure and temperature sensors. This approach gives a clear sample solution which can be analyzed by any of the two instrumentation techniques defined in the guidelines. For speciation and oxidation state analysis different approaches have to employed.
ICP-OES
Inductively Coupled Plasma – Optical Emission Spectroscopy (ICP-OES/ICP-AES) is a plasma spectroscopy technique where a liquid sample is aspirated into plasma through a suitable sample introduction system where specific element emits light. This emitted light consists of spectra of respective elements present in the sample which is further resolved by an optical system and then detected by a detector. This instrumentation technique generally has two viewing positions- Axial (for ppb to ppm rage) and Radial (for ppm to % range). This technique is suitable for high dynamic linearity range. Selection of elements is based on wavelengths and analytical interference are caused by spectral overlaps between elements.
ICP-MS
Inductively Coupled Plasma – Mass Spectroscopy (ICP-MS) is also a plasma spectroscopy technique which analyses elemental impurities in a sample based on the element’s mass to charge (m/z) ratio. It consists of a sample introduction system, which aspirates the sample into plasma, which then ionizes the elements present in samples. This ionized elements then travel through a collision or reaction cell which removes the interferences and then separated based on their m/z ratio by a quadrupole system and then detected by a detector. It has a single view position and analyses samples in the concentration range of ppt to ppm or sub % levels. Analytical interferences are caused by isotopic interferences of elements. Speciation analysis can be carried out by coupling with HPLC or IC units where the species separation is carried out by the chromatography technique and quantification of the species is done by ICP-MS.
Note: This document is intended for personal education use only and it is not a substituent to any guidelines or methods.
