Non-biological complex drugs (NBCDs) represent a class of diverse synthetic drugs midway between conventional low molecular weight chemical drugs and high molecular weight biologics in terms of complexity. Apart from their chemical origin, NBCDs have little in common with pharmaceuticals. However, they resemble biologics in terms of structural complexity, molecular weight range, physico-chemical stability, and to some extent, immunogenicity potential.
An NBCD is defined as a medicine that consists of a complex multitude of structurally closely related substances that cannot be fully characterised, and which collectively, represent the active pharmaceutical ingredient (API). As with biologics, quality and batch-to-batch consistency is highly dependent on the manufacturing process, which means that different manufacturing processes using the same starting materials may produce products that could have different safety and efficacy profiles. Examples of NBCDs include iron-carbohydrate (iron-sugar) drugs or colloids, glatiramoids (copolymer mixtures of the amino acids L-glutamic acid, L-alanine, L-lysine and L-tyrosine), liposomes, and nanoparticulate systems.
Whilst generics and biosimilars have well-defined regulatory procedures to guide their marketing authorisations in almost all jurisdictions, this is not the case for follow-on versions of NBCDs. Although the EMA has issued reflection papers for follow-on or copy versions of iron-based nano-colloidal products and liposomal NBCDs, a relatively recent survey of NBCD follow-on products (up to November 2018) authorised in several European countries found that of 85 marketed NBCDs, 45 were approved via the decentralised procedure, 30 via the national procedure, 11 by the mutual recognition procedure and two via the centralised procedure. For example, of 10 follow-on NBCDs approved in Germany, seven were for generic applications, one was a hybrid application and two were biosimilar applications. In the Netherlands, six were generic applications and seven hybrid applications. In Portugal, Italy and Finland, the follow-on NBCDs were all approved as generic applications. Thus, there was a lot of variation in the regulatory approaches to NBCDs, which predominantly relied on non-centralised procedures.
In South Africa, follow-on NBCDs were mostly handled on a case-by-case basis by the Pharmaceutical & Analytical Committee of the MCC. It is very likely, for example, that for iron-sugar complexes criteria were not always applied consistently; hence, some could have been approved as generics and for others additional, mostly clinical data were requested, i.e., they were treated as hybrid applications. To prevent further inconsistencies and to prepare for the new generation of nanotechnology drugs, it has become imperative for SAHPRA to develop a specific guideline to evaluate follow-on NBCDs. Regulatory guidance documents for such complex drugs are being prepared by other regulatory agencies, such as by Health Canada, National Medical Products Administration (China) and the Therapeutics Goods Administration (Australia). In the US and EU (as mentioned earlier) published guidelines for these complex products are already in place.
Bibliography
Crommelin DJ, et al. The similarity question for biologicals and non-biological complex drugs. Eur J Pharm Sci. 2015;76:10-7.
Hussaarts L, Mühlebach S, Shah VP, McNeil S, Borchard G, Flühmann B, Weinstein V, Neervannan S, Griffiths E, Jiang W, Wolff-Holz E, Crommelin DJA, de Vlieger JSB. Equivalence of complex drug products: advances in and challenges for current regulatory frameworks. Ann N Y Acad Sci. 2017 Nov; 1407(1):39-49. doi: 10.1111/nyas.13347. Epub 2017 Apr 26. PMID: 28445611.
Schellekens H, Stegemann S, Weinstein V, et al. How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J. 2014;16 (1):15-21. doi:10.1208/s12248-013-9533-z
Crommelin DJ, de Vlieger JS, Weinstein V, Mühlebach S, Shah VP, Schellekens H. Different pharmaceutical products need similar terminology. AAPS J. 2014 Jan;16(1):11-4. doi: 10.1208/s12248-013-9532-0. Epub 2013 Sep 25. PMID: 24065599; PMCID: PMC3889525.
Klein K, StolkP, De Bruin ML, Leufkens HGM, Crommelin DJA, De Vlieger JSB. The EU regulatory landscape of non-biological complex drugs (NBCDs) follow-on products: Observations and recommendations, European Journal of Pharmaceutical Sciences, Volume 133, 2019, Pages 228-235, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2019.03.029.
