1. Guideline for Elemental Impurities ICH Q3D(R)

2. 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

3. 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

4. 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

5. 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

6. 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

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

8. 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

9. 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

10. 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

11. 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

12. 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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