When the most recent guidelines for control of elemental impurities went into effect, 24 elemental impurities were listed as being of concern. If found in drug substances, these impurities could pose health risks without providing any therapeutic benefit to patients. According to ICH Q3D(R1) guidelines, they fall into 3 classes:
- Class 1: Elements considered highly toxic and have limited or no use in the manufacture of pharmaceuticals: As, Cd, Hg and Pb
- Class 2: Toxicity based on route of administration:
- 2A: Elements with high probability of occurrence in the drug product: Co, Ni and V
- 2B: Low abundance elements with a reduced probability of occurrence, which may be excluded from risk assessment unless they are intentionally added during manufacture of drug substances: Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl
- Class 3: These elements require risk assessment for inhalation and parenteral routes of administration, but have relatively low toxicity by the oral route: Ba, Cr, Cu, Li, Mo, Sb and Sn
Due to their potential toxicity, regulators, including the FDA, have issued guidelines for controlling these elemental impurities in order to keep them within acceptable permittable µg/day limits. The limits vary with route of administration. For example, Pd has a permitted daily limit of 100 µg/day for the oral route, a 10 µg/day limit for the parenteral route, and a limit of just 1 µg/day for the inhalation route.
The FDA recommends that for drug products marketed in the U.S., manufacturers establish procedures for identifying and controlling elemental impurities in accordance with ICH Q3D recommendations.
As with ICH M7(R1) guidance regarding genotoxic impurities, the FDA’s recommendations for control of elemental impurities is intended for CDMOs and sponsors to incorporate into their safety and risk management protocols. The guidelines do not establish legally enforceable responsibilities—unless specific regulatory or statutory requirements are cited. If there are no such citations, the documents are intended to describe recommendations based on the latest thinking about this topic.
Sources of elemental impurities
Elemental impurities arise from two main sources. One is the equipment itself. In aggressive chemistry, some metal contamination can occur as a result of leaching out from the equipment if proper materials aren’t used.
The second common source of elemental impurities comes from raw materials, causing contamination. Pd, Pt and Ru could be introduced with the use of catalysts, for example.
10 strategies for assuring elemental impurities remain within specifications
We have found in our many years of experience that the following strategies help us assure the chemistry remains within regulatory specifications throughout the project:
- Evaluate the chemistry’s compatibility with the equipment that will be used—avoid putting something into the line that’s aggressive or corrosive.
- Maintain and monitor the equipment regularly to avoid equipment failure that may cause contamination.
- Be cognizant of, and anticipate, where in the process elemental impurities could be introduced.
- Establish protocols for testing, and if impurities are found to be out of spec, have protocols in place for eliminating or reducing them to acceptable levels.
- Make comprehensive purification of the drug substance part of process development.
- Utilize inductively coupled plasma (ICP) testing in a clean room to detect trace metals during process development to determine the following:
- Where metals are coming into the process.
- Where in the process they are accumulating.
- Where in the process they are being removed.
- Where they are coming in with raw materials, to determine if the raw materials are properly purified.
- Conduct ICP testing on a final sample of material.
- Focus not only on metals–control all impurities.
- If risk assessment shows the elemental impurity level to be consistently above the control threshold, additional controls should be established to ensure that the elemental impurity level does not exceed the permitted daily exposure (PDE) for the specific dosage form. These additional controls could be included as in-process controls or in the specifications of the API.
- As part of a raw materials quality initiative, begin elemental impurities risk management by requesting and scrutinizing information from suppliers, such as the Certificate of Analysis, to determine whether raw materials were tested for elemental impurities.
ICH and regulatory agencies recommend that API manufacturers conduct product risk assessments by first identifying known and potential sources of elemental impurities and developing in-process controls to ensure the elemental impurity level does not exceed the PDE for the specific dosage form for which the API is intended. These recommendations, spelled out in guidance documents such as ICH Q3D, describe sources of elemental impurities. These include elements intentionally added, elements potentially present in the raw materials and catalysts used to prepare the drug substance, and elements potentially introduced by leaching from equipment that is incompatible with the chemistry. Forethought, protocols, controls and appropriate testing assure that elemental impurities remain within specifications.
For other articles that look at impurities and ICH guidelines, check out ” For other articles that look at impurities and ICH guidelines, check out “Best practices in following ICH guidelines for APIs,” “Identifying Impurities in APIs,” and “Setting Comprehensive Specifications in API Manufacturing.” Please call us if you have questions at (978) 462-5555.