By Rob Taylor, Pharmaceutical Segment Manager, Malvern Panalytical

Sometimes you must take things apart to rebuild them. For a child with a LEGO masterpiece, this can be heartbreaking. But in the world of pharmaceuticals, reverse-engineering drugs is crucial for the development of less expensive, more accessible generic products. Chemical and structural reverse engineering, also known as product deformulation, involves highly detailed analysis of the constituent components of Reference Listed Drugs (RLDs). Like with the LEGO house, this means scrutinizing the structure, type, and amount of each chemical ‘block’ in the RLD to find out how to recreate the drug in the future.

Deformulation is a challenging process that aims to decode the physicochemical formulation of a drug and provide information about how it was manufactured. It’s also time-critical and competitive, with multiple companies often racing to develop generic alternatives to drug products with recently expired (or soon-to-expire) patents. Deformulation relies on analytical technologies to obtain precise information about both the active pharmaceutical ingredients (APIs) and the excipients, and the quality of analysis can make or break a generic product development project.

Here, we discuss the importance of analytical technologies such as Morphologically Directed Raman Spectroscopy (MDRS) in deformulation and show an example of how such techniques can help developers decode RLD formulations to inform the manufacturing processes for generics.

The wider uses of analytical technologies in drug innovation

While analytical technologies like Morphologically Directed Raman Spectroscopy (MDRS) have important applications for the development of generic drugs, as described in this article, they also have similar uses in developing and formulating innovator drugs. MDRS has several applications, from confirming the particle size of the active pharmaceutical ingredient (API) or other ingredients in a pharmaceutical formulation, to understanding the impact on the API or excipient when manufacturing processes change, and even identifying the sources of counterfeit drugs by analyzing their chemical composition.

Quality design of generic drugs requires analytical precision

Before a pharmaceutical equivalent can be developed, the RLD must be thoroughly characterized. Generic drug development is steered by regulatory guidance, which sets out the key steps to overcome scientific challenges unique to the development of generic drugs,¹ founded on the Quality by Design (QbD) approach. QbD recognizes the dependency on analytical technologies from the outset of any generic development project, in order to develop a full scientific picture of the RLD. These techniques are used to create a comprehensive ‘blueprint’ of a drug product which fully describes the complexity of its chemical ingredients and microstructure. Armed with this critical foundational detail, drug developers can then begin to remake the generic version of the drug, or in some cases even reformulate it to improve a product’s efficacy or safety profile.

Profiling APIs and excipients

During a drug product’s deformulation, analytical technologies are used to characterize its API(s), and excipients. Techniques including analytical imaging and X-ray diffraction are essential to determine characteristics like particle shape, chemical identity and crystal structure. These features of the API can provide clues about the efficacy and stability of the final drug product. For example, the size and shape of API particles can affect the drug’s absorption rate, influencing the timeline for a drug to enter the bloodstream, reach its target organ and exert its desired therapeutic effect. Detecting and characterizing the polymorphic form of the active substance are particularly important capabilities of analytical technologies, as different API crystal structures can affect the bioavailability and therapeutic effect of a drug, as well as impact the related intellectual property and patents.

Analytical technologies also enable developers to analyze excipients in the drug formulation. Some excipients are added simply to increase the bulk of the formulation, but it is also common for manufacturers to add excipients designed to modify the properties of the drug in the system. Controlled release agents, stabilizers, and surface-active agents can all be added to change the behavior and fate of the product (for example, API coating technologies can be used to slow the release rate of the active substance in the stomach). Analytical technologies like laser diffraction and analytical imaging can provide data to differentiate and independently characterize excipient and API particles. For example, MDRS is used in the preparation of dry powder inhalers (DPIs) to analyze the structure of excipients. Excipient structure can affect the aerodynamic performance of the DPI, so characterization can provide valuable information about the product’s overall performance.

Analytical technique spotlight: Morphologically Directed Raman Spectroscopy (MDRS)

The aim of applying the QbD approach in drug deformulation is to follow rigorous design principles, which are consistent throughout the development process, to ensure the quality of the final product. Analytical technologies provide the means to extract the required information that enables developers to start from an informed position and work from strong foundations when creating a bioequivalent generic drug that meets the same therapeutic needs as the RLD.

MDRS extracts both morphological and chemical information to classify particles within a sample based on their physicochemical attributes. The technique utilizes automated analytical imaging to gather a wide range of statistically relevant data about the size and shape of chemical components. Automated Raman spectroscopy is then applied to interrogate a population of particles, comparing the resulting spectra to reference libraries to determine component-specific morphological information.

Case study: generic versus branded cold and flu remedies

MDRS was used to analyze two cold and flu remedies: a branded and a generic version. MDRS provided data about the particle size distributions, returning specific data about each product. The technique identified different particle size distribution profiles for each product, with the generic remedy having relatively higher amounts of larger particles than the branded remedy (Figure 1).

From this graph, we can see the size profile of the particles in each product, but this information does not tell us what the components are, and how they might impact the efficacy of the remedies. However, MDRS can provide this information by identifying each chemical component during the same analysis by matching spectra against a library and returning the relative proportions of different components in the generic and branded remedies. In this case, Raman spectroscopic analysis returned data that showed two primary ingredients in the remedies: sucrose and the API.

The analysis showed that the generic drug contained relatively higher amounts of the API. However, quantity isn’t everything, and further analysis was needed to offer an indication of the rate at which the API would be absorbed. MDRS provided information about the particle size distribution for each component and showed that the branded product contained higher quantities of finer API particles (Figure 2).

 

As discussed earlier, the particle size profile of active substances in drug products can have a significant impact on their behavior, and therefore their rate of absorption and therapeutic effect. While this information cannot categorically link API properties with therapeutic effect, the smaller size distribution in the branded product may improve the absorption of this remedy, enabling it to reduce cold and ‘flu symptoms more quickly and effectively.

Decoding manufacturing processes for drug deformulation

Using MDRS to provide morphological data about APIs can provide valuable clues to the manufacturing methods used to make the drug in the first place. For example, analyzing API shape features like elongation (Figure 3) reveals a lot about manufacturing methods used to reduce particle size (for example, tap milling and micronization).

Tap milling creates API particles with higher elongation values than those produced by micronization. This kind of analysis aids in ensuring bioequivalence when developing new drugs, specifically identifying the techniques and methods used in the manufacturing process to help match the resulting product. From a business perspective, these data help inform the design of an equivalent manufacturing process and identify processing partners and collaborators if these techniques lie outside the scope of current production capabilities.

Final thoughts

In drug deformulation, obtaining a detailed chemical ‘blueprint’ of complex drug products is a key analytical challenge. New techniques such as MDRS are providing drug developers with highly detailed analysis of the components of drug products and delivering preliminary insight into how their composition might affect drug efficacy and safety in vivo. Moreover, such techniques provide developers with the tools to assess how pharmaceutical products are manufactured, opening doors for replication of the production process.

 

References

1. fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-development