Submitted: 14 May 2021; Revised: 14 May 2021; Accepted: 3 June 2021; Published online first: 10 June 2021
Medicines regulatory authorities aim to address rising healthcare costs and promote access to medicines worldwide through review and approval of quality generic drug products that are interchangeable with the corresponding reference medicinal product.
The Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP) aims to promote greater collaboration, regulatory convergence and potential mutual reliance on respective bioequivalence assessments in the longer term. At the time of this survey, this group was composed of the regulators of the following jurisdictions: Argentina, Australia, Brazil, Canada, Colombia, the European Union (EU), Japan, Mexico, New Zealand, the Republic of Korea, Singapore, South Africa, Switzerland, Taiwan, the US, as well as the World Health Organization (WHO) which participates as an observer.
In addition to the waivers of in vivo bioequivalence studies (biowaivers) for immediate release (IR) solid oral dosage forms based on the Biopharmaceutics Classification System, i.e. BCS biowaivers, and the biowaivers of additional strengths with respect to the strength for which in vivo bioequivalence has been shown, biowaivers may also apply to certain dosage forms irrespective of the BCS biowaiver criteria.
The BEWGG of IPRP published the current regulatory requirements to waive the in vivo> demonstration of bioequivalence for oral and injectable dosage forms among the regulators of the IPRP BEWGG. The sharing of this information is a first step towards regulatory convergence in this area.
In vivo bioequivalence studies for oral solutions can be waived in all jurisdictions except Japan, where biowaivers for aqueous solutions are not accepted.
In the case of oily oral solutions, Taiwan and the US would accept a biowaiver, whereas Brazil and the Republic of Korea would not. For other jurisdictions, this would depend on the physicochemical properties of the dosage form. For example, some members of the IPRP BEWGG would require that the type of oil used in the vehicle be the same as that in the reference product.
For other types of oral solutions, a biowaiver would be considered acceptable based on the qualitative and quantitative differences in the non-medicinal ingredients/excipients. Qualitative differences in excipients are acceptable in principle if the excipients are not considered to be critical, i.e. known not to affect the bioavailability of the active ingredient(s), e.g. preservatives, viscosity agents, pH buffers, colorants, flavours, some sweeteners. However, qualitative similarity and remarkably close quantitative similarity would be expected for excipients that enhance absorption, e.g. polysorbate 80. Some members assess the similarity of excipients in oral solutions according to the requirements for BCS-based biowaivers, where non-critical excipients can be modified for oral solutions containing BCS class I drugs, but not for oral solutions containing BCS class II, III and IV drugs where the excipients must be qualitatively the same and quantitatively similar. In Canada, any difference beyond the described criteria should be scientifically justified. Similarly, in the US, the different amount of any excipient should be within US Food and Drug Administration (FDA) inactive ingredients database limits and the new amounts should not be associated with safety or efficacy concerns.
For excipients that are considered critical because they are known to potentially affect the bioavailability of active ingredients by altering the gastrointestinal transit, permeability or stability of the active ingredients, most members do not allow qualitatively changes, but permit minor quantitative changes. In the US and Argentina, critical excipients can be changed qualitatively and quantitatively within certain justified limits. The list of critical excipients is not exhaustive but includes surfactants, e.g. SLS, castor oil ethoxylate, polysorbate 80; sweeteners, e.g. sorbitol and mannitol, excipients that affect transporters, e.g. PEG-400; co-solvents and complexing agents, e.g. cyclodextrins. Each jurisdiction may have different criteria on the types of excipients that are considered critical, and the quantitative differences allowed.
In the case of powders for reconstitution of oral solutions, the same requirements apply because the product is an oral solution at the time of administration.
South Africa, Australia and Singapore will consider biowaivers for oral suspensions for systemic action if they have similar (South Africa) or identical (Australia and Singapore) quantitative formulations and the physicochemical equivalence of justified parameters, e.g. polymorphic form, particle size distribution, viscosity, pH and dissolution profiles across the pH range 1.2 to 6.8. In all other jurisdictions, in vivo bioequivalence studies are required.
In the case of locally acting suspensions, biowaivers can be accepted in Brazil and Singapore, and considered on a case-by-case basis in most of the other members if the drug substance is not systemically absorbed. In the US, specific examples where a biowaiver is accepted are sevelamer, colesevelam and cholestyramine. Japan and Mexico do not accept biowaivers for locally acting suspensions.
In the case of powders for reconstitution of oral suspensions, the same requirements apply because the product is an oral suspension at the time of administration.
Soft gelatin capsules
With the exception of Brazil, Canada, Japan and the Republic of Korea, a biowaiver from conducting in vivo bioequivalence studies could be acceptable in the remaining jurisdictions, if the drug substance is in solution inside the capsule and the fill liquid is qualitatively the same and quantitatively similar or identical (depending on the jurisdiction) to that of the comparator product. In the US, for example, a biowaiver could be accepted for products containing omega-3-acid ethyl esters; however, in most cases in vivo studies are required, e.g. products containing progesterone.
In vivo bioequivalence studies for simple intravenous solutions for injection or infusion may be waived in all jurisdictions. For Canada, the formulations of the generic and the reference medicinal product should be qualitatively the same and quantitatively essentially the same (excipient variation between products is within ±10% unless data are available to support a wider variation). Any differences beyond the criteria should be scientifically justified. Only preservatives, buffers, antioxidants can be different in the Republic of Korea and the US, while isotonic agents can also be changed in the other jurisdictions. Excipients that may affect disposition and/or safety, e.g. surfactants like Cremophor, should not differ in most of these countries. For Brazil, any excipient can be changed as long as the new excipients are well established for intravenous administration and used in suitable concentrations, but any differences in preservatives, buffers and thickening agents need to be justified.
In Brazil and Canada, a physicochemical comparison is always required. In some jurisdictions, a physicochemical comparison is required in cases of differences in excipient composition, whereas in other jurisdictions, compliance with pharmacopoeial requirements for intravenous solutions is considered sufficient without any comparison with the comparator product.
In the case of powders for reconstitution of intravenous solutions, the same requirements apply because the product is an intravenous solution at the time of administration.
Intramuscular and subcutaneous solutions for injections
All members except Japan accept biowaivers for subcutaneous and intramuscular solutions. In Japan, these waivers are not described in current guidelines, and they are assessed on a case-by-case basis. The US would require in vivo pharmacodynamic studies for certain products to demonstrate similar activities, e.g. dalteparin, enoxaparin, however, other jurisdictions would classify low molecular-weight heparins as biosimilars in this context.
In most members, a biowaiver is possible for oily solutions only if the same oily vehicle is used.
Qualitative and quantitative differences in buffer agents, antioxidants and preservatives are acceptable in principle for all jurisdictions if the differences are scientifically justified. Most members also accept differences in isotonic agents. Excipients such as those affecting viscosity, surfactants and complexing agents should not be changed in most countries. In contrast, Brazil and Argentina assess changes on a case-by-case basis. The requirements for physicochemical comparisons are the same as for intravenous injections described above.
In the case of powders for reconstitution of subcutaneous or intramuscular solutions, the same requirements apply because the product is a solution at the time of administration. In the US and Japan, this is not described in the guidelines. Nevertheless, the US would apply the same principles, while Japan assesses this on a case-by-case basis.
Intramuscular and subcutaneous suspensions for injections
For intramuscular and subcutaneous suspensions for injection, a biowaiver is not acceptable in principle in any of the jurisdictions. However, in rare instances, a biowaiver may be acceptable, e.g. azacytidine, as specified in the product-specific guidances from FDA and Brazil. Azacitidine powder for suspension for injection products have been waived in Australia, Canada, the EU and Switzerland as exceptional cases, since azacitidine is not completely soluble at room temperature (25°C), but rather is soluble at 37°C, when all in vitro tests have shown to be similar.
Emulsions for intravenous injection
In most participating countries, a biowaiver is possible for emulsions for intravenous injection, e.g. aprepitant, clevidipine and propofol, whereas a biowaiver is not possible in Brazil, Japan and Taiwan. In Australia, Canada, New Zealand, Singapore and South Africa the excipient composition should be qualitatively the same and quantitatively very similar to that of the comparator product, while minor differences, e.g. antioxidants, have been accepted in the EU, the Republic of Korea and Switzerland. The biowaiver is based on physicochemical comparability of droplet size distribution in the dispersed lipid phase, viscosity/rheological properties, pH, osmolarity, specific gravity, surface properties such as zeta potential.
Biowaiver requirements for such products are not currently described in guidance documents from Argentina, Canada, Colombia and WHO.
Micellar solutions for intravenous injection
The US does not consider injectable micelles as a distinct dosage form; instead, they are designated as injections or injectable solutions. In most countries, a biowaiver is possible for micellar solutions for injection, e.g. docetaxel micellar solutions, whereas in Argentina and Brazil, the biowaiver requirements are not addressed in current guidelines and applications are assessed case-by-case. In those jurisdictions where a biowaiver is acceptable, the excipient composition should be qualitatively the same and quantitatively very similar, although minor qualitative differences in buffer agents, antioxidant and preservatives are accepted. In addition, some jurisdictions could accept qualitative changes in the co-solvents if they are not considered critical, e.g. alcohol and PEG. The biowaiver is based on physicochemical comparability of critical micellar concentration (CMC), micelle size distribution, solubilisation capacity (free and bound amounts) and pH, osmolarity and viscosity. In Japan and Taiwan, biowaivers are not acceptable for such products.
A waiver from in vivo demonstration of bioequivalence may be applied to several orally administered and systemically acting dosage forms like oral solutions, oral suspensions and soft gelatin capsules, and some systemically acting parenteral dosage forms like intravenous injections, subcutaneous and intramuscular injections, emulsions for injection and micellar solutions for injection. The survey showed that the biowaiver criteria for these dosage forms are diverse among the participating BEWGG member organizations and that the complexity of the dosage forms correlates with the risks associated with accepting biowaivers. This may explain why the biowaiver requirements for the more complex dosage forms, e.g. suspensions, micellar injection, tend to be more variable among the participating members, while there is more similarity in requirements for the less complex dosage forms, e.g. oral solutions, IV injections, as there are less risk factors to consider that may influence the safety and efficacy of the product. The sharing of this information is a first step towards regulatory convergence in this area since, for some dosage forms, large differences between members of the BEWGG of the IPRP have been identified. The next steps should involve identifying areas that could be harmonized based on sound scientific justifications. Convergence in this area would be useful for pharmaceutical companies developing generic medicinal products for more than one of these jurisdictions.
Article  abstracted by Alfredo García-Arieta, World Health Organisation (WHO) Prequalification of Medicines Programme and Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), División de Farmacología y Evaluación Clínica, Subdirección General de Medicamentos de Uso Humano, C/ Campezo 1, Edificio 8, ES-28022 Madrid, Spain; and Clare Rodrigues, Health Sciences Authority (HSA), Health Products Regulation Group, Medicinal Products Pre-Marketing Cluster, Therapeutic Products Branch, Singapore.
Competing interests: None
Provenance and peer review: Commissioned; internally peer reviewed.
1. Garcia Arieta A, Simon C, Tam A, Mendes Lima Santos G, Freitas Fernandes EA, Rodríguez Martínez Z, et al. A survey of the regulatory requirements for the waiver of in vivo bioequivalence studies of generic products in certain dosage forms by participating regulators and organisations of the International Pharmaceutical Regulators Programme. J Pharm Pharm Sci. 2021;24:113-26.
Disclosure of Conflict of Interest Statement is available upon request.
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