Bioequivalence (BE) usually is considered from the viewpoint of pharmacokineticscomparison of the absorption of the API into the body between a test product and a reference product. But before BE is achieved and demonstrated, it should be started way aheadfrom the CMC point of view.

Regarding generic drugs and other pharmaceuticals, the CMC issues are crucial for the consistency of manufacturing and characterization of the test product with its ability to deliver the same therapeutic effect as the reference product.

What is the CMC Perspective of Bioequivalence?

The CMC perspective of bioequivalence centers on the pharmaceutical aspects and manufacturing considerations that can affect performance of drugs. Where the bioequivalence study confirms the similarity in performance of two drugs clinically or pharmacokinetically, CMC information will confirm the reason behind the similar performance of the two products.

Important factors considered in the CMC perspective include active pharmaceutical ingredient (API), formulation, manufacturing process, critical material attributes (CMA), critical process parameters (CPP), specifications, analytical methods, and stability of the product.

This is not just about replication of the reference product, but about having a strong manufacturing process capable of producing a product with desired qualities and performance characteristics.



Development of Formulation and Critical Quality Attributes

The development of formulations is one of the main connections between CMC and bioequivalence. The variations in the nature, amount, size, grade, and functionality of the excipient may cause changes in the dissolution, release, absorption, and finally pharmacokinetics of the product.

It becomes necessary to identify and control Critical Quality Attributes like assay, content uniformity, dissolution, impurities, moisture content, and physical attributes.

In case of orally administered immediate release products, dissolution plays a very critical role. Dissolution comparison studies offer strong evidence about whether the test formulation behaves similarly to the reference product in terms of releasing the API.

The Manufacturing Process is Important

If a formulation is effective in the development phase, it should also work consistently in the manufacturing process. The variation in equipment, batch size, mixing, granulation, compression, coating, and many other factors may affect the effectiveness of the drug product.

This is one reason why process understanding and control are critical parts of CMC development.

A control strategy will include all variables that could affect the critical quality attributes (CQAs). This will become especially critical while scaling up from small batches for BE studies to commercial batches.

Analytical Methods and Comparative Analysis

Robust analytical methods are essential in CMC and BE study. Analytical methods employed in assessing assay, impurities, dissolution, content uniformity, and other quality attributes must be properly developed and validated.

Comparison of analytical results may also be important in contributing to the overall strength of the BE package. In some cases depending on the product and regulatory strategy, it is important to show similarities in dissolution profile, physicochemical properties, and other quality attributes.

This is especially true if there are differences in formulations or if a biowaiver approach is utilized.



Scale Up, Manufacturing Changes and BE Risk

One of the important issues would be ensuring that the batch for the BE test is representative of the batch to be eventually launched commercially.

In case of significant formulation and manufacturing changes after the pivotal BE study, there could be questions raised regarding the relevance of the BE results in relation to the final product, depending upon the change made.

Thus, BE and CMC teams need to coordinate right at the start of the project.



Integrated CMC/BE Approach

A well-executed development program will have a link between pharmaceutical development, analysis, manufacturing and BE studies.

Identification of the critical quality attributes early can help in selection and development of the right formulation. Just like CMC activities, understanding of what influences the release and absorption of the drugs can help CMC identify important activities.

Such an approach will lead to reduced risk in development, unnecessary reformulations and improved scientific rationale.



Conclusion

Bioequivalence is not simply a pharmacokinetic evaluation of two drugs. The CMC basis is what will decide whether the pharmaceutical drug can be produced at an acceptable quality level for such an evaluation to take place.

CMC aspects are intertwined in the whole BE program process from formulation design, dissolution testing, process control, analysis, scale-up to BE post-manufacturing changes.

For pharmaceutical companies producing generics and other multisource products, collaboration of the CMC and BE groups may result in a better scientific approach to product development and regulatory justification.

Join our upcoming The CMC Side of Bioequivalence Masterclass, where the crucial discussion will take place!

By Shara Najimudeen, Digital Marketing Executive, GLC Europe, Colombo Office, Sri Lanka.