Elemental impurities in Pharmaceutical Materials according to new ICH Guidelines and USP Chapters 232 and 233 Application Note · PlasmaQuant MS

Introduction

Although the risk factors for heavy metal impurities in pharmaceutical materials have changed dramatically, standard methods for their testing and control have not changed much for more than 100 years. As a result, heavy metal limits have had little basis in toxicology. For that reason, one of the most significant standards introduced by the United States Pharmacopeia (USP) in the past decade has been new methodology for determining elemental impurities and contaminants in drug products and dietary supplements

These new methods have been going through a review and approval process for a number of years, and a recent announcement by the USP (1) has indicated that these new chapters will be implemented on January 1, 2018, to coincide with the full approval of the International Conference on Harmonization (ICH) Q3D Step 4 guidelines (2), which is expected to be December 16, 2017, for existing pharmaceutical products. The new methods will address the limitations of the current method, extending the list of analytes, reducing the maximum permitted exposure limits and taking into account the route of exposure. The use of closed vessel sample digestion and modern instrumental techniques is also introduced to ensure the accurate recovery and determination of individual analyte concentrations.

Chapter and ICH Q3D Chapter and ICH Q3D specify maximum limits for the amount of elemental impurities permitted in drug products, drug substances, active ingredients and excipients. These impurities may be present naturally, derived from the production catalysts or introduced inadvertently through the manufacturing process, or they could be environmental contaminants in the pharmaceutical raw materials. When elemental impurities have the potential to be present, compliance to the specified levels is a requirement. Table 1 shows a total of 24 elemental impurities together with their toxicity limits, defined as the maximum permitted daily exposure (PDE) level in micrograms per day for oral, parenteral and inhalation drug delivery categories. The PDE levels are based on an arbitrary adult human body weight of 50kg (110lb) and a suggested dosage of 10g of supplement per day. The PDE limits represent the updated levels as proposed in the most recent revision of USP , published for public comment on Mar-Apr 2016 in Pharmacopeial Forum 42(2) (3) and aligned with ICH Q3D Step 4 dated 16 December 2014 (2).

Element Classification The new Elemental Impurities chapters subdivide the metals desired for testing into several groups. The first group or Class 1 elements consist of the toxic elements Arsenic, Cadmium, Lead and Mercury. These elements will be tested for in all drug products and constitute the minimum requirement for testing. Class 2 elements are to be tested for based on risk of exposure due to components (excipients or drug substances), manufacturing process, or route of exposure. Subclass 2A elements must also be included in all assessments, due to their ubiquity and relative toxicity. Subclass 2B elements only need be evaluated if they are intentionally added to the processes used to generate the product. Class 3 elemental impurities have relatively low toxicity by oral administration, but require assessment if delivered through the parenteral or inhalational routes.

Elemental Speciation Chapter also addresses elemental speciation, although it does not specify an analytical procedure. Each elemental impurity has the potential to be present in different oxidation states or species. Arsenic and mercury are of particular concern because of the highly variable toxicity of their inorganic and organic forms. The arsenic limits are based on the inorganic form, which is the most toxic. The mercury limits are based on the inorganic form because methyl mercury, the most toxic form, is rarely an issue for pharmaceuticals. However, if there is a known potential for the material to contain methyl mercury, such as those derived from fish or kelp, and appropriate speciation procedure is required.

Chapter Chapter (4) deals with the analytical procedure, including the sample preparation procedure, instrumental method, and validation protocols for measuring the elemental impurities using one of two plasma-based spectrochemical techniques — ICP-OES and ICP-MS, or alternatively any other trace-element technique such as Flame Atomic Absorption or Graphite Furnace Atomic Absorption, as long as it meets the data quality objectives of the method defined in the validation protocol section. In addition, before any technique is used, the overall analytical procedure must be confirmed to be appropriate for the instrument being used and the samples being analyzed by meeting the Alternative Procedure Validation protocol. The chapter also recommends reading USP General Chapter on plasma spectrochemistry for further guidance.

Validation Protocol Meeting the validation protocol described in Chapter is critical for this application as all aspects of the analytical procedures, including the instrumental technique and sample dissolution process, must be validated and shown to be acceptable. This is dependent on the procedure used as to whether it is a limit procedure or a quantitative procedure. Limit procedures must confirm detectability, repeatability and specificity of the measurement, while quantitative procedures must demonstrate accuracy, precision (repeatability and ruggedness) and specificity. Meeting the performance requirements defined in these tests must be demonstrated experimentally using an appropriate system suitability procedure and reference material. The suitability of the method must be determined by conducting studies with the material under test, supplemented or spiked with known concentrations of each target element of interest at the appropriate acceptance limit concentration. It should also be emphasized that the materials under test must be spiked before any sample preparation steps are performed.