ICH Q3D Implementation Working Group (IWG)—Training Modules
ICH Q3D is a complex guideline. The overall requirement in terms of control is clear—there are defined limits for some 24 elements, and levels of the elements described must be controlled within these limits in the final drug product. Simple. The complexity comes when defining how this is achieved. The guideline provides a series of options to evaluate risk and effect control, ranging from control in each individual component based on a fixed dose for the product of 10 g (Option 1) to simply testing the final product (Option 3). A detailed description of the options and when/how these are applied as part of a risk assessment is beyond the scope of this review; the point is that there are significant challenges in applying the guideline practically solely using the guideline for that purpose. This was recognized by the ICH Expert Working Group responsible for the guideline, resulting in the establishment immediately after step 4 of an Implementation Working Group. A key objective of the IWG was to develop training materials to assist implementation.
In February ICH finally published the long awaited training modules.(2) These modules, produced by the ICH Q3D implementation working group, cover both safety and quality aspects, the areas covered are listed below:
This provides an overview of the modules. Included within this is a very useful flow diagram,Figure 1, highlighting the anticipated overall process from the risk assessment through to definition of control strategy.
Modules 1–3 Cover Toxicology Aspects
Module 1—Different Routes of Administration
Module 2—Justification of Levels Greater than Permissible Daily Exposure Limits
Module 3—Non ICH Elements
Modules 4–7 Cover Chemistry (Quality) Aspects
Module 4—Large Volume Parenterals
Module 5—Risk Assessment
Module 7—Calculation Options
Highlighting some key points, module 5, relating to risk assessments, discusses the key role of GMP in assessing risk—this is an important and a helpful point relating to API manufacture. It emphasizes the importance of:
Design and qualification;
However, it also focuses on the risk arising from manufacturing equipment, making a relatively generic statement over the often more chemically aggressive nature of API manufacturing procedures compared to drug product manufacturing. It even suggests monitoring the drug substance for potential impurities arising from manufacturing equipment (e.g., stainless steel—Cr, Mn, Mo, V, Ni). It is a pity that this risk is highlighted without also making the point that it would be expected that such risk would be addressed as part of GMP and form part of the process accommodation procedure rather than rely on screening to verify.
Rightly the module makes the point that a significant potential source of elemental impurities arises from the use of metal catalysts in the synthesis of drug substances, especially if used in the latter stages of synthesis. It also states that:
“Knowledge of potential elemental impurities in synthetic steps prior to the final drug substance may provide information that can assist in the preparation of the risk assessment.”
This is an interesting point and one that cuts to the heart of the uncertainties around practical implementation. While a valid point, it raises key questions such as how many steps prior to the API should be assessed? Clearly this will be process/product specific, but it is a very real question any risk assessment will have to tackle.
Another interesting point made in the module is the potential for “platform” risk assessments. This is the concept of a risk assessment applicable across a series of products. One such platform may be for example, oligonucleotides.(3) In such instances, where the manufacturing process in terms of reagent type, equipment, and process conditions are similar irrespective of the precise end product, it should be possible to conduct an assessment based on one process and for this to relevant/transposable to comparable processes.
Module 6—Control of Elemental Impurities—also provides useful advice emphasizing the importance of control across the product lifecycle. In the context of the manufacture of the API, this requires oversight and governance over changes to the process that may affect the risk assessment, e.g., change in catalyst load, and so forth. Such changes require a re-evaluation and possibly confirmatory testing. Another point emphasized in the module is that routine testing of Class 1 metals, i.e., arsenic (As), mercury (Hg), cadmium (Cd), and lead (Pb), is NOT required unless there is an identified risk. This is a very important and helpful point clearly reiterating the core principle of ICH Q3D that any control strategy should be based on the risk assessment. This is especially important as several regulatory queries have been reported asking for data for Class 1 and also Class 2A metals for APIs.
One area described in Module 6 is the concept of periodic testing. This is an area of potential concern and ambiguity. It states that:
“Where the risk assessment indicates that routine testing is considered unnecessary but some additional assurance is needed post approval, periodic testing of the drug product or one or more individual components may be proposed by the applicant and implemented upon acceptance by the regional regulatory authority.”
An example is provided relating to use of a Pt catalyst in the manufacture of the API, this being the final step used in the API synthesis. In the example detectable levels of Pt at ∼ 20% of the PDE are observed (below the 30% limit stated in ICH Q3D), based on this periodic testing being proposed. In the case study described this may seem sensible but how close to reality is such an example? In such a case would an applicant simply not specify Pt on the API specification? The worry is that the option for periodic testing may be blunt instrument and be something that is regularly requested.
USP Chapter ⟨232⟩
USP very recently announced(4) a series of revisions to USP Chapter ⟨232⟩, Elemental Impurities, the revisions made being intended to align the general chapter more closely to ICH Q3D. One of the most significant is the removal of the need to routinely screen for Class 1 metals as part of any analysis, the final sentence in the text outlined below being deleted.
If, by process monitoring and supply chain control, manufacturers can demonstrate compliance, then further testing may not be needed. When testing is done to demonstrate compliance, proceed as directed in Elemental Impurities—Procedures ⟨233⟩.
This is a welcome and important amendment; the previous requirement making little scientific sense, there being no actual evidence that Class 1 metals would be more prevalent, for example, where a platinum catalyst was used than in the absence of a catalyst. Such catalysts are not a source of class 1 metals.
Overall there are likely to be challenges/uncertainties associated with ICH Q3D leading up to and for some period after the effective date as the guideline beds in, but the crucial fact is that all of the evidence to date indicates it is unlikely that there will be a widespread impact caused by issues of excessive levels of any elemental impurity whereby effective control cannot be realized.
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