Advance Therapy Medicinal Products (ATMPs) are novel drugs that meet patients’ specific needs. But they drastically increase the cost of treatment. Generic alternatives provide relief in terms of treatment cost with a quality drug of similar effectiveness.

A complex generic product is generally similar to brand-name generics. However, there are differences between the two (02) in manufacturing and quality control procedures. An innovator molecule may have critical procedures that govern the nature of the molecule. Critical parameters of a molecule may make it difficult to replicate while developing a generic version of the medication. In such cases, Standard Operating Procedures (SOPs) will help meet the optimal requirements for the molecule while developing complex generic products for in-vitro studies, in-vivo studies, and drug product quality testing. To facilitate the entry of generic alternatives in such therapeutic areas, the United States Food and Drug Administration (US FDA) publishes product-specific guidance on novel molecules that has recommended strategies to mitigate the challenges associated while drafting the procedures. 

Introduction to Complex Generics

The FDA ascertains the population that all the drugs approved by the Health Authority (HA) are of good quality grade, safe, and effective for the stated indication. The HA defines that complex generics have special requirements because they use multiple active ingredients or Active Pharmaceutical Ingredients (APIs). The manufacturing process must be designed with utmost care to ensure consistent quality since complex generics are typically more expensive than standard generics.

The FDA has published several guidance documents on how to conduct the development of generic drugs, including the ‘Guidance for Industry: Generic Drug Quality System,’ which outlines good practices for developing new generic drugs. To caution complex generic manufacturers of any critical parameters adopted while manufacturing an innovator drug, the HA publishes product-specific guidelines that avoid any formulation-related mishaps.

Complex Generics - Development Considerations

Creating a complex generic product is challenging since the novel drug molecule can have critical parameters that are way beyond the control of the manufacturing facility. There is a wide range of elements to consider during development.

A complex generic has the following:

  1. Multiple active ingredients
  2. Varying dosage strengths
  3. Multiple dosage forms (tablets and capsules)
  4. Miscellaneous routes of administration (oral, topical, or injectable
  5. Different indications for different therapeutic uses - for example, one may treat high blood pressure while another might help ease muscle spasms associated with Parkinson's disease.

Simplifying Complex Generics – Bioequivalence and Pharmacokinetic (PK)/Pharmacodynamic (PD) Studies

One of the most important factors to consider in the development phase of a generic product is its bioequivalence with the existing innovator molecule. Bioequivalence studies establish the effectiveness of active pharmaceutical ingredients in a dosage form. Such studies mimic how molecules are absorbed, distributed, and metabolized in physiology. 

Complex generics vary in bioavailability due to the stereochemistry and chemical nature of the molecule. Understanding the molecular properties allows innovators to maintain a checklist of the parameters to be aware of while developing a generic of the given formulation.

As mentioned before, complex generics offer alternatives to ATMPs that increase the overall cost of the treatment. HAs provide support and guidance to develop and manufacture complex generics. Seasoned efforts well-versed with industry-published, product-specific guidance can drastically shorten the lag time to your next Abbreviated New Drug Application (ANDA). Consult a proven Regulatory expert like Freyr to help you assist on the next submission. Explore more about ANDA at Abbreviated New Drug Application (ANDA) Submissions.


Akancha Singh
Senior Associate


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