Guideline for Elemental Impurities ICH Q3D(R)

Q3D comprises safety-based permitted daily exposures for 24 elementals and recommendations for a risk-based and science-based approach to control of those elements in pharmaceutical products It applies to new finished drug products and new drug products containing existing drug substance The intent of Q3D is to develop PDEs and a mechanism to control for elemental impurities

Why does Q3D, if it is possible to control of residual catalysts and heavy metal impurities? certain metals can be introduced into a drug product from impurities in raw materials or from processing equipment, which are not satisfactorily controlled by a test for heavy metals the characteristic that is relevant to patient safety is the total daily mass of an elemental impurity delivered to the patient because the toxicological risk depends only on the total exposure Q3D emphasizes a holistic, risk-based approach to control of elemental impurities, and provides a rational assessment mechanism that is appropriate for all elemental impurities

ICH Q3D classifies 24 elements based on toxicity and likelihood of occurrence in final drug products Class 1 Elements are considered a significant risk and may end up in final drug products due to their use in common materials Class 2A Elements are considered toxic and are relatively likely to appear in final drug products due to their presence in stainless steel equipment Class 2 Elements are less likely to be incorporated into final drug products, but must be assessed when intentionally added Class 2B Class 3 Elements are considered non-toxic and must only be evaluated when administered by certain routes other Not addressed in Q3D, but in other regional guidelines and due quality considerations

Potential Sources of Elemental Impurities Residual impurities resulting from elements intentionally added (e.g., catalysts) in the formation of the drug substance, excipients or other drug product components Elemental impurities that are not intentionally added and are potentially present in the drug substance, water or excipients used in the preparation of the drug product Elemental impurities that are potentially introduced into the drug substance and/or drug product from manufacturing equipment Elemental impurities that have the potential to be leached into the drug substance and drug product from container closure systems

Potential Sources of Elemental Impurities Manufacturing equipment stainless steel: Drug Substance catalysts and inorganic reagents Elemental Impurities in drug Product Excipients magnesium stearate alginate calcium silicate, Sunset yellow FCF titanium dioxide ferric oxides colorants or coatings of undefined structure or composition Container Closure System glass syringes Water

Summary of risk assessment Identification Evaluation Summary of risk assessment Control strategy

Control of Elemental Impurities Modification of the steps in the manufacturing process that result in the reduction of elemental impurities below the control threshold through specific or non-specific purification steps Implementation of in-process or upstream controls, designed to limit the concentration of the elemental impurity below the control threshold in the drug product Establishment of specification limits for excipients or materials (e.g., synthetic intermediates) Establishment of specification limits for the drug substance Establishment of specification limits for the drug product Selection of appropriate container closure systems

There are three basic options for determining elemental impurity content The drug product analysis represents the analyses of elemental impurities in the final product form, where the typical dosage unit is scaled to a maximum daily dose The summation option characterizes elemental impurity concentrations in specific ingredients in their dosage form, and then sums these contributions, which must be less than the PDE The individual component option is simply a subset of the summation approach and may be useful for suppliers of specific drug product components

Lifecycle Management Science-based and risk-based approaches at each lifecycle stage Improving process understanding and process performance Re-evaluation of the risk assessment in case of changes: synthetic routes, excipient suppliers, raw materials, processes, equipment, CCI or facilities

Special Considerations for Biotechnologically-Derived Products The risks of presence of elemental impurities at the drug substance are considered low: elements are not typically used as catalysts or reagents in the manufacturing of biotech products elements are added at trace levels in media feeds during cell culture processes, without accumulation and with significant dilution/removal during further processing typical purification schemes used in biotech manufacturing such as extraction, chromatography steps and dialysis or Ultrafiltration-Diafiltration (UF/DF) have the capacity to clear elements introduced in cell culture/fermentation steps or from contact with manufacturing equipment to negligible levels

Special Considerations for Biotechnologically-Derived Products In cases where the biotechnology-derived drug substance contains synthetic structures (such as antibody-drug conjugates), appropriate controls on the small molecule component for elemental impurities should be evaluated Potential elemental impurity sources included in drug product manufacturing (e.g., excipients) and other environmental sources should be considered for biotechnologically derived drug products. The contribution of these sources to the finished product should be assessed because they are typically introduced in the drug product manufacture at a step in the process where subsequent elemental impurity removal is not generally performed Risk factors that should be considered in this assessment should include the type of excipients used, the processing conditions and their susceptibility to contamination by environmental factors (e.g., controlled areas for sterile manufacturing and use of purified water) and overall dosing frequency

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