Approving generics of polymer-based parenteral long-acting drugs

To assure the safety and the efficacy of drugs, quality and batch-to-batch reproducibility need to be guaranteed. In the case of parenteral long-acting products, the regulatory authorities in the European Union (EU) and the US deviate in their guidance, differences include how to define such products and in vitro release assays.

Despite their relevance, there are few in vitro experimental set-ups that allow for discrimination among products with different in vivo behaviour. Consequently, most copies of such products are authorized through hybrid applications, instead of generic ones. Therefore, authors Francesca Selmin and colleagues from the University of Milan, Italy, reviewed the regulatory frameworks evaluating in vitro release tests for polymer-based long-acting parenteral drugs [1].

Definitions
They found that the definition of long-acting injectables (LAIs) in the three main pharmacopoeias was not harmonized. According to the Japanese Pharmacopeia (JP) LAI are listed among ‘Preparations for injection’ and their classification is primarily based on the administration process. The US Pharmacopeia (USP), on the other hand, includes LAI in two different monographs, namely ‘Suspension’ and ‘Implant’. Whereas, in the European Pharmacopoeia (Ph. Eur.) ‘parenteral preparations’ are divided in two categories depending on the physical state of the dosage form, namely ‘Implants’ and ‘Gels for injections’.

Drug release evaluations
As with most dosage forms, an in vitro drug release test provides the fundamental information required to assess the product quality and, therefore, to support the batch release. Due to the expense, time, labour and need for human subjects and/or animals to test in vitro performance, in vitro release is gaining attention as a surrogate for product performance. In both cases, the definition of a suitable protocol is critical for a LAI.

In the EU, the lack of specific and harmonized protocols leaves room for interpretation and EMA evaluates the appropriateness of the chosen method during the assessment of the marketing authorization application. However, according to the authors, ‘the availability of harmonized dissolution protocols could accelerate the development of new and generic drug products, other than post-marketing variations’ by facilitating comparison between products. In the US, on the other hand, FDA has prepared a database listing recommended in vitro methods to aid the development of generics for LAIs that do not have a dissolution test method in the USP.

Approval pathways
For LAIs containing an authorized active pharmaceutical ingredient (API) for the same or similar therapeutic indications and where both the pharmaceutical form and strength are the same, the marketing authorization relies upon the demonstration of therapeutic equivalence with respect to the originator. If it is demonstrated by bioequivalence studies, a simplified dossier can be submitted to FDA, European Medicines Agency (EMA) or a national regulatory agency.

In the US, the abbreviated new drug application (ANDA) procedure should be followed, while in the EU a generic drug application should be submitted through a centralized, decentralized or mutual recognition procedure. In both cases, the application generally does not require preclinical and clinical data to establish safety and efficacy. Instead, the applicant must scientifically demonstrate that the therapeutic performance of the generic and originator drug are equivalent.

However, therapeutically equivalent copies of LAIs cannot be authorized following the procedure used for generics when:
a) the test product does not fulfil the Q1/Q2 sameness requirement or the generic drug definition in the US and EU, respectively, e.g. changes in active substance, strength, pharmaceutical form
b) bioequivalence cannot be considered as a surrogate of the therapeutic equivalence, e.g. locally applied and locally acting drug products
c) the route of administration is changed with respect to the reference product, but a therapeutic improvement is not expected

In these conditions, a hybrid application including preclinical and clinical data to demonstrate the therapeutic equivalence of the test and reference products. The body of data included in the comparability studies will vary on a case-by-case basis according to the complexity of the drug product or the therapeutic indications.

The authors concluded that ‘the variety and complexity of the technologies used to produce LAIs, which are designed to meet specific medical needs, dictate an assessment of in vitro testing on a case-by-case basis. To speed up their development, more product-dedicated guidelines or in vitro compendial tests should be elaborated to support formulation, testing and approval’.

Conflict of interest
The authors of the research paper [1] did not provide any conflict of interest statement.

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Reference
1. Selmin F, Musazzi UM, Magri G, et al. Regulatory aspects and quality controls of polymer-based parenteral long-acting drug products: the challenge of approving copies. Drug Discov Today. 2020;25(2):321-9.

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