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Key issues

compartment where it exerts is action. Therefore, what is measured in plasma can bear little relationship to the timing or magnitude of response. Moreover, variations in release rate of the active ingredient could affect the overall safety and efficacy of the drug. An example of this is an iron sucrose follow-on product that released iron more rapidly than the originator resulting in oxidative stress and inflammation.4

Differences that appear to

be small can have big effect. In some cases there is the added difficulty of uncertainty about the precise identity of the active pharmaceutical ingredient and how it exerts its effects.


Although NBCDs are not of biological origin, some are polypeptides or synthetic proteins and some can form immunogenic aggregates, so the risk of immunogenicity is a real concern. Indeed, the risk of unforeseen immune reactions is the clinician’s worst nightmare. Immune responses can take a number of forms including the formation of neutralising antibodies that progressively attenuate the drug’s effects and hypersensitivity reactions that can be life-threatening. Because NBCDs and their follow-on products are a mixed bag of compounds immunogenicity needs to be assessed on a case-by-case basis. NBCDs and their follow-on products cannot be presumed to have the same immunogenic profiles as innovator complex drugs.4


immune response is influenced by patient factors such as immune status and genetic background and product-related factors such as manufacturing processes. There are three major classes of authorised NBCDs at present, each of which present different immunogenicity issues: liposomes, iron-carbohydrate products and glatiramoids.

Liposomal drugs Liposomes act as vehicles to deliver drugs to specific target sites thereby avoiding or reducing systemic toxicity. Nanoparticles of active drug are encapsulated in phospholipid spheres. Liposomal delivery systems are used to deliver cytotoxic agents, for example, doxorubicin and synthetic antigenic peptides.5

In the case 8

of liposomal vaccines, augmenting an immune response is the main purpose of treatment. However, the interactions between liposomes and the immune systems are complex and adverse immune effects can include both stimulatory (for

example, hypersensitivity reactions) and inhibitory effects (for example, Doxil- induced immunosuppression).6

of the problem appears to be that larger nanoparticles can have size, shape or surface characteristics that attract the attention of the immune system.6


liposome technology advances, the understanding of adverse immune responses is likely to assume ever greater importance. Variations in manufacturing processes could have profound effects on pharmacokinetic and clinical responses to liposomal drugs. Both clinical and non-clinical studies may be needed to detect clinically meaningful differences in therapeutic activity, toxicity and immunogenicity of follow-on liposomal drug products.

Iron-carbohydrate drugs

Fatal and life-threatening hypersensitivity reactions have been reported with intravenous iron-carbohydrate products. The mechanisms for these reactions are unknown.7

A number of iron-sucrose and other iron carbohydrate follow-on products have now been authorised.

Glatiramoids The first and most thoroughly studied glatiramoid is glatiramer acetate (Copaxone, Teva Pharmaceutical Industry), which is a complex heterogenous mixture of synthetic proteins and polypeptide nanoparticles. It is a polymer of glutamic acid, lysine, alanine, and tyrosine. It has immunomodulatory activity and is approved for treatment of relapsing- remitting multiple sclerosis. Copaxone works as a therapeutic vaccine and therefore anti-drug antibodies are detectable in all treated patients.4 These antibodies do not neutralise biological activity or clinical efficacy and are not associated with local or systemic adverse effects in MS patients receiving chronic treatment. However, development of follow-on products has been halted due to adverse immune effects.4

Interchangeability and substitution Interchangeability and substitution remain critical issues for both purchasers of medicines and clinicians.

Interchangeability at the population level means that both products can be used for treatment of the same condition in the same population. Interchangeability at the patient level means that for an

individual patient, the products can be alternated or switched.8

The crux

‘Substitution’ is a

policy that allows replacement at the patient level of a medicinal product for a similar/bioequivalent product.8


substitution can only be justified if two products are interchangeable. A clear understanding of these concepts is of key importance to the pharmacist when dispensing a prescribed medicinal product.

When the EMA recommends market approval for a biosimilar, this does not mean that the product is automatically interchangeable and can be substituted throughout the EU. In order to obtain approval for interchangeability for biological drugs, the risk in terms of safety or diminished efficacy of alternating or switching between the biosimilar product and the originator product must be no greater than continuing to use the originator product.4

A key aspect of pending legislation for biosimilars and follow-on NBCDs will be the development of science-based criteria and policies for interchangeability and drug substitution. l

References 1. Rottembourg J et al. Do two intravenous iron sucrose preparations have the same efficacy? Nephrol Dial Transplant 2011;26(10):3262–7.

2. Crommelin D et al. Different pharmaceutical products need similar terminology. AAPS J 2014;16:11–14.

3. Muhlebach S et al. The authorisation of non-biological complex drugs (NBCDs) follow-on versions: specific regulatory and interchangeability rules ahead? GaBI journal 2013; 2:204-207

4. Nicholas JM. Clinical development, immunogenicity and interchangeabillity of follow-on complex drugs. GaBI journal 2014;3:71–8.

5. Schwendener RA. Liposomes as vaccine delivery systems: a review of the recent advances. Ther Adv Vaccines 2014;2:159–82.

6. Szebeni J, Barenholz Y. Adverse immune effects of liposomes: Complement activation, immunogenicity and immune suppression. http:// uploads/2014/10/2009_Liposomes.pdf.

7. European Medicines Agency. New recommendations to manage risk of allergic reactions with intravenous iron-containing medicines. EMA/377372/2013. 28 June 2013 [homepage on the Internet]. 2013 Jun [cited 2014 Feb 24]. document_library/Press_release/2013/06/ WC500144874.pdf (accessed March 2016).

8. Crommelin DJA et al. The similarity question for biologicals and non-biological complex drugs. Eur J Pharm Sci 2015;76:10–17.

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