Why Small Molecules Impurities are Becoming More Complex than APIs

The impurity profile is one of the essential and critical parts of small molecule drug development. Every pharmaceutical organisation must understand the impurity profile of the API it manufactures or develops, and must know the control strategy throughout the life cycle of the API. This well-organised, controlled impurity profile strategy ensures product quality, improves process quality batch by batch, and establishes safety. All these parameters also help with seamless regulatory submissions. The process of developing an API with a controlled strategy to monitor its impurities is very complex — often more complex than the API itself.

Today, small molecule impurities are more complex to manage than the API because of the highly sophisticated, multistep synthetic routes followed to produce APIs, the need to develop APIs for more potent therapies, and regulatory agencies’ demands to ensure robust process control measures. Although small in molecular size, these APIs are structurally complex and difficult to synthesise. The associated impurities, byproducts, and intermediates are similarly complex with respect to molecular weight and structural complexity when compared to the API. These drugs are synthesised by long, multistep synthetic processes, which creates opportunities for the introduction of several impurities, including isomers, intermediates, and side products.

Several additional reasons are discussed below.

1. Complex Synthetic Route:

1a. Byproduct Formation in Multistep Synthesis

Modern API synthesis, often targeted at complex diseases, employs sophisticated methods. Having 10 to 15 or more synthetic steps often increases the chances of byproduct formation; these byproducts can be complex with respect to molecular weight and structure. In many processes, intermediates and key starting materials are not fully removed and become complex impurities in the finished API.

1b. Chirality, Metal Catalysts, and Solvent Interactions

In some cases, a drug with axial chirality can produce isomers that are chemically very similar to the parent compound and difficult to identify and separate. Many processes use transition metals as catalysts; these reactions can lead to the formation of metallic residues. In some reactions, complex solvent systems are used for purification, and the use of such systems can lead to the formation of various solvent API interaction products. The need for highly potent APIs in specific therapeutic areas, such as oncology, introduces significant toxicological considerations; impurities formed during the process can therefore be more complex and more hazardous than the drug substance itself.

2. Degradation and Stability Issues:

2a. Environmental and Formulation-Related Degradation

Many APIs synthesised by new processes are highly unstable and degrade quickly to form complex mixtures of compounds. Environmental factors such as heat, humidity, and light can cause degradation. These degradation products often have chemical properties similar to the API, making them difficult to isolate in pure form and thus more complex than the API itself. Impurities may also form when the drug substance interacts with packaging materials or excipients used in the formulation, leading to many unexpected and novel complex impurities.

2b. Cross-Contamination in Multi-Product Facilities

In multi-product manufacturing facilities, carryover from a previous manufacturing campaign can interact with the current API batch, leading to unexpected and difficult-to-predict impurities. These are typically non-reproducible and non-repetitive, making isolation and identification of the source particularly challenging. Today, the pharmaceutical industry is increasingly adopting novel, sophisticatedly designed, multistep synthetic processes, moving away from simpler approaches. These highly sophisticated processes also produce complex byproducts, making those byproducts or impurities more complex than the API itself.

3. Raw Material Variability:

To keep products cost-effective, manufacturers often source low-cost raw materials. These lower-cost raw materials can present a variable impurity profile. A variable impurity level, sometimes below 0.10% and sometimes above 0.10% can lead to unpredictable complex impurities in the finished API. In most cases, rapid development timelines make it difficult to ensure an optimised and fully verified synthetic route, leading to elevated levels of complex impurities when the synthetic process has not been fully validated.

4. Regulatory Requirements:

4a. Identification and Characterisation Burden

As most manufacturing organisations use new, complex, multistep synthetic processes, the resulting impurities are often unknown and require intensive work to identify, isolate, and characterise. This work can take longer than the manufacture of the API itself. All regulatory bodies demand the identification and quantification of these unknown impurities at very low levels.

4b. ICH M7 and Trace-Level Impurity Control

Regulatory expectations around mutagenic impurities have intensified in recent years. The ICH M7 guideline requires manufacturers to identify and quantify potentially mutagenic impurities at trace levels, as these impurities can be toxic even at very low concentrations.

5. Analytical Challenges:

5a. Co-elution and Structural Similarity

Impurity identification and characterisation are always challenging processes requiring specific analytical techniques. Co-elution is a common issue encountered during analysis, as many impurities have chemical structures very similar to the API.

5b. Instrumentation Costs and Accessibility

Sophisticated, high-precision analytical instruments are required for impurity analysis. These instruments are very costly, making impurity analysis expensive and sometimes unaffordable for smaller manufacturers. Impurity characterisation represents a significantly more advanced analytical undertaking than API analysis itself, which contributes to the overall complexity and cost of impurity management.

Conclusion:

Most APIs developed today target specific therapeutic indications and are manufactured through complex, multistep chemistry — all while meeting increasingly demanding regulatory expectations. As a result, API manufacturing is no longer a straightforward endeavour and grows more challenging with each passing year. The characterisation of impurities generated during this manufacturing process is even more critical and complex than the manufacture of the drug substance itself. Impurities are analytically more challenging to manage than APIs. They frequently appear at trace levels, exhibit structural diversity, and demand resources that exceed those required for the API itself.

FAQ:

Reference:

• ICH. INTERNATIONAL CONFERENCE on HARMONISATION of TECHNICAL REQUIREMENTS for REGISTRATION of PHARMACEUTICALS for HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE IMPURITIES in NEW DRUG PRODUCTS Q3B(R2). 2006, database.ich.org/sites/default/files/Q3B%28R2%29%20Guideline.pdf.