Elemental Impurities Compliance - Good Example of Quality by Design (QbD)

The implementation of requirements concerning elemental impurities in a drug product is a good example to understand how quality is built into the product to ensure the safety of the product. 

At the outset, I would like to share some basic aspects of elemental impurities. These are most often added during synthesis and manufacturing of an API or excipients as a catalyst, but it may also be present at the source in the raw material. Sometimes an element may leach out, during processing/manufacturing from the equipment used during manufacturing. It may also leach out during stability testing from the packaging component. These impurities have no therapeutic benefit but have a potential toxic effect and, hence is required to be removed to the extent possible. If it cannot be completely removed, then it must be controlled within a permissible or acceptable limit. There are different classes of elemental impurities defined in ICH, USP, EP and other Pharmacopeias. The classes and limits are defined according to the inherent risk associated with it based on their chemical structure while also additionally considering the dosage form and route of administration. Guidelines and general chapters in USP and EP, on elemental impurity came into existence as the previous method of heavy metals testing was a qualitative method that was not very specific and that was not designed to eliminate the risk associated with many elemental impurities. Another objective was achieving harmonization between ICH and official book of standards like USP and EP.

As per the new requirement, the drug product manufacturer must ensure that the elements are monitored in their product after an appropriate risk assessment and the limits are based on an approach of establishing permitted daily exposures (PDEs) for these impurities in a drug product. This led to gathering information from the API and excipient manufacturers and even requesting them to identify and quantify these using validated methods if they cannot be completely removed. API and excipient manufacturers were expected to report the levels to the drug product/finished formulation manufacturer for appropriate risk assessment. 

When these requirements were introduced by ICH, USP, EP, and other pharmacopoeias, there were a lot of challenges faced by Industry. These tests were not routinely done and were not part of the specification for many API and almost all the excipients. The certification from the suppliers only claimed that these were not present in their product as it was not added in the manufacturing process. Other sources of contamination were never considered or evaluated. Most excipients were not tested and hence finding the actual metal concentration was not possible. The risk assessment for the product was not easy due to the lack of data. The finished product manufacturers would need to conduct extensive testing on the finished formulations/ drug product to ensure compliance. There were technical challenges too. The method to test the elemental impurities (like ICP-MS) was not commonly employed and the instruments were also expensive. Not many contract laboratories were equipped to conduct this test. Training was required to use and for qualification of the new equipment and methodology and all these were time-consuming.

IPEC America developed a template for exchange of information between the vendors or suppliers of API and excipients and the manufacturers of the finished product. This template acted as a guiding tool to all stakeholders involved as it resulted into a better understanding of the metal impurity level that led to a meaningful risk assessment. 

It was clear that for implementation the industry had to develop an action plan. It became extremely critical for the pharmaceutical industry to communicate extensively with the API and excipients manufacturers. A collective approach of implementation was highly desired. Suppliers had to gear up and ensure that this did not lead to any disruption of the supply of materials. Drug product manufacturers had to get equipped for conducting a risk assessment of each metal which could potentially be present, setting a specification based on permitted daily exposure limit and testing by a validated method (Pharmacopeia or alternate developed new method). 

The good news is that the industry was able to manage all these challenges and ensure compliance to requirements of elemental impurities by the time it was mandated for registration of new drugs or new generics by various countries and health authorities. Compliance for products which were already registered and in the market was also achieved in a phase-wise manner and updated information was provided from time to time, product by product, to health authorities by most firms.

The elements which make it a good case study for QbD is listed below:

1)      Implementation of this required the industry to work with a holistic approach, to identify the sources of contamination through which an element would be introduced into the product - such as from APIs, excipients, packaging components, water source, equipment’s or interactions between the dosage form and packaging component.

2)      It emphasized heavily on risk-based evaluations and establishing control strategies only after thorough risk assessment.

3)      It required working with a data-driven approach in terms of evaluating both the generated information and any published data available on the elements and its toxic potential.

Regulatory professionals may have experienced the challenges and would agree with me on the point that ensuring compliance for elemental impurities was a long process that necessitated working on the principles of QbD to achieve desired outcome. For complete information about the elemental impurities test and methodology please refer to ICH Q3D, USP general chapter <232> and <233>.

My next blogs will be on data integrity and continuous manufacturing. See you soon!!