SC IX Similar Biological Medicinal Products

This Supplementary Chapter provides a statement on the Pharmacopoeial position in relation to similar biological medicinal products and aspects for consideration concerning preparation of relevant monographs.

Pharmacopoeial position

Introduction

The term ‘similar biological medicinal product’ is used for a biological product that has been developed to be similar to an authorised biological medicinal product (‘reference’ product). The term ‘biosimilar’ has been used interchangeably with ‘similar biological medicinal product’. Reference for more information should be made to the applicable Committee for Medicinal Products for Human Use (CHMP) Guidelines on similar biological medicinal products and other related position papers published by the European Medicines Agency (EMA).

Consistent with the established principles set out in Directive 2001/83/EC (as amended) biological medicinal products, in view of their complexity, differ from conventional medicinal products based on chemically synthesised substances. Similar biological products cannot be regarded as equivalent to generic medicinal products. They are likely to be derived from starting materials or manufacturing processes different from those used for the authorised reference biological product. Consequently, even though a ‘similar biological medicinal product’ is developed to be as close as possible in structure and activity to the reference product, there may be differences in the detailed structure of the active ingredient from that of the ‘reference’ product. Any difference may result in altered properties that impact on the immunogenicity and clinical performance. Such differences have led to recommendations that similar biological medicinal products, even though having demonstrated similarity to the ‘reference’ product, are not interchangeable and should be prescribed by brand only. Additional requirements for proof of safety and efficacy have usually been required when compared to those expected for generic products of chemical origin and before marketing authorisation is granted.

British Pharmacopoeia: Monographs for formulated preparations The general policy of the British Pharmacopoeia Commission is that a monograph for a single dosage form should be prepared to cover each available medicinal product of a particular pharmaceutical form containing the same active substance. Preparation of a product-specific monograph is avoided where possible. However, similar biological medicinal products present a different situation because, unlike other active pharmaceutical ingredients, for small molecules produced by chemical synthesis, the structures, although very similar, may not be identical. This has an impact on the approach used for the preparation of pharmacopoeial specifications which depend on the degree of similarity or otherwise: whether the differences are translational or post-translational and whether or not test methodology is available to distinguish between similar biological medicinal products and the reference product. In certain cases a single monograph may be possible for the ‘reference’ product and any biological medicinal products authorised subsequently whereas in other cases separate monographs may be needed. Consequently the BP Commission has acknowledged that similar biological medicinal products should be considered on a case-by-case basis as to whether a single monograph is sufficient or a group monograph, that covers more than one subsequently authorised product, or several individual monographs are needed.

BP monographs for dosage forms assist in providing an assurance on the quality expected for a medicinal product during its shelf life and provide a framework for use by the manufacturer. However, the analytical tests used are limited in their ability to detect all characteristics in a similar biological medicinal product that may affect clinical efficacy and safety. Aspects such as excipients, pH, buffers, exposure to surfaces, freezing/thawing and mechanical stresses may result in aggregation effects and/or chemical changes during formulation and storage. These may impact on the immunogenicity and clinical performance.

As with other pharmacopoeial monographs, it is recognised that revision of a published monograph for a dosage form may become necessary in order to take account of additional similar biological medicinal products as they become available. Manufacturers are encouraged to inform the BP Secretariat of revisions considered necessary and to provide constructive comments. A list of contact points in the Secretariat is to be found in Supplementary Chapter III A.

Monograph development for similar biological medicinal bulk materials and products

The following aspects are considered when elaborating monographs.

Group or single monograph

If possible, a single monograph is prepared for one or more similar biological medicinal bulk materials and products that have been granted marketing authorisations by comparison with an appropriate reference material. The following points are taken into consideration as to whether one or more monographs are prepared.

1. Active substance with a protein backbone Where the substance is a protein of known structure and amino acid sequence without modification, a single monograph, or modification of an existing monograph, for example to take account of a new method of production, may suffice.

2. Active substance with translational differences Where there is a difference in an amino acid sequence of the protein backbone it is likely that separate monographs will be needed for the resulting substances whether or not similar products exist. Examples of this are Human Insulin, the separate monographs for Insulin Aspart and Insulin Lispro and their relevant injection monographs. For the development of separate monographs, identification methods are needed to distinguish between the structurally related active substances.

3. Active substance with post-translational modifications Substances with identical amino acid sequences in the protein backbone, but with post-translation differences, may be encompassed by one group monograph. The differences may be in the glycosylation, acetylation and/or sulfation. The erythropoietins, a family of closely-related glycoproteins, having the same amino acid sequence in the protein backbone and differences in their isoform compositions, are covered by the bulk material monograph for Erythropoietin Concentrated Solution and a single monograph for the injection.

4. Glycosaminoglycans Separate monographs may need to be prepared for this class of compounds. For example, in the case of low molecular weight heparins, a group (family) monograph for Low-Molecular-Weight Heparins, that cross-refers to the bulk material monographs for Heparin Sodium and Heparin Calcium, applies to all the low molecular weight bulk material monographs (such as Dalteparin Sodium, Enoxaprin Sodium and Tinzaparin Sodium). Injection monographs for these three low molecular weight heparins are included in the British Pharmacopoeia.

Specific considerations for BP monographs for formulated preparations

The main considerations needed for similar biological medicinal products are equivalent to those used for other biotechnologically-produced biological formulations.

Monographs for formulated preparations are elaborated taking into account points 1 to 4 above. The monographs are prepared in line with the current Commission policy relating to generic products where possible, as explained in Supplementary Chapter III D, and in accord with the following statement given in the Chapter: Formulated preparations: ‘The tests applied to the bulk drug substance, including those for impurities arising in manufacture of the bulk drug substance, should be applied, wherever possible - with any necessary modification - in order to demonstrate that material of pharmacopoeial quality has been used in making the formulation.’. For elaboration of a monograph, information is sought on impurities arising from the manufacture and/or storage of the dosage form.

The specifications in the monograph for the medicinal substance are used as a basis for the preparation of the first draft monograph for the dosage form. However, not all tests may be applicable, such as in the presence of excipients or when there is a very small amount of the active pharmaceutical ingredient in the formulation. In such situations alternative procedures and/or methods of detection with increased sensitivity are necessary and validated alternative methods are sought from stakeholders. Any validation studies must take into account the appropriate ICH Guidelines on the validation of analytical procedures.

Test methodology in monographs

When elaborating monographs for similar biological medicinal products consideration is given to inclusion of the test methods that are specified in the Ph. Eur. monograph for the medicinal substance which are primarily as follows.

Identification Identity tests based on the unique characteristics of the product, such as molecular size, charge and structure are included together with a cross-reference to the biological or physico-chemical assay. Two tests are usually included in the draft monograph. The test methodologies used in the current specific monographs for formulated preparations are predominantly reverse-phase liquid chromatography, size-exclusion chromatography, polyacrylamide gel electrophoresis and capillary electrophoresis; their inclusion depends on the characteristics of the molecule under investigation.

Tests Tests for heterogeneity, aggregation, impurities and degradation products are considered for inclusion depending on the characteristics of the active substance and formulation properties. As for identification, the methodology used is predominantly reverse-phase liquid chromatography, size-exclusion chromatography, polyacrylamide gel electrophoresis and capillary electrophoresis.

More than one method may be included for the same test in circumstances where interference from an excipient may occur in the drug product. An example of this is in the monograph for Erythropoietin Injection where two methods, A and B, are given in the test for Dimers and related substances of higher molecular weight.

Bacterial endotoxins A test for bacterial endotoxins, or a validated monocyte-activation test, is included for parenteral preparations.

Assay The assay in the monograph for the medicinal substance is included where possible.