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Stephen Wicks, PhD, is the scientific regulatory policy and intelligence officer of the European Directorate for the Quality of Medicines & HealthCare (EDQM) of the Council of Europe, Stephen.WICKS@edqm.eu. EDQM is a leading organization that protects public health and amongst other things is responsible for the European Pharmacopoeia.
The European Pharmacopoeia addresses the need for monographs for biologicals to keep pace with recent analytical technology advances.
The European Pharmacopoeia (Ph. Eur.), which celebrated its 50th anniversary in 2014, provides common standards throughout Europe for the quality of medicines and substances used to manufacture those medicines. The Ph. Eur. is recognized worldwide for its essential role in ensuring the quality of chemical APIs and excipients, yet it also plays a vital role in providing quality standards for medicinal products and substances of biological origin. Biologicals are those products derived from biological sources such as tissues and cell extracts, fermentation using micro-organisms, plasma, plants, or those produced by recombinant DNA technology. The use of materials of biological origin in medicine has a long history, and the quality control of biologicals has been in place for many years.
The Ph. Eur. began elaborating monographs on biologicals as an early priority with the first biological monographs on vaccines for human use, immunosera, and immunoglobulins appearing in Volume 2 of the first edition of the Ph. Eur. in 1971. The second edition of the Ph. Eur. (first published in 1980) saw the elaboration of monographs that concerned substances extracted from animal tissues (such as heparins) and human blood and plasma-derived medicinal products. In 1992, a general monograph for products of recombinant technology was included in the Ph. Eur. This was followed by monographs for an increasing number of biotechnology products in the 1990s and 2000s. As the Ph. Eur. moved into the 21st Century, it increased its activity in the biological field to address increasing numbers of biologicals and challenges driven by development of biosimilar products.
Pharmacopeial standards for biologicals
Biologicals are large and often highly complex molecules. The Ph. Eur. has established general monographs that cover common quality attributes and that are applicable to a specific class of biologicals such as monoclonal antibodies (mAbs), rDNA products, or vaccines for human use and veterinary use. The Ph. Eur. also contains individual monographs that cover diverse biological substances and products (e.g., insulin and insulin analogues, peptide hormones, human growth factor, human granulocyte colony stimulating factor, interferons, erythropoietin, recombinant vaccines, and blood coagulation factors). These individual monographs provide analytical procedures and acceptance criteria to allow demonstration that a substance or product meets the required quality standards. The monographs are based on licensed specifications (for the drug substance or finished product) backed up by batch data.
Additionally, the Ph. Eur. monographs are supported by a large number of general chapters that describe standard methods. These general chapters give requirements for equipment and equipment verification and instructions on how to perform a method, such as peptide mapping. Ph. Eur. monographs and general chapters for biologicals make reference to the use of chemical reference standards and biological reference preparations (BRPs) for identification, purity testing, and assay (content/potency) of biologicals. BRPs are established in view of achieving standardization of test methods for the quality control of biologicals. Collaborative studies are undertaken to establish these reference preparations leading to the refinement of Ph. Eur. monographs. As regards to reference standards, a one-standard-fits-all approach is not possible for all biologicals due to their heterogeneity (e.g., for glycoproteins). Therefore, for glycoproteins, this issue has been overcome by using the Ph. Eur. reference standard to demonstrate system suitability, and users are requested to establish their own in-house reference preparation for glycan analysis.
A similar biological or biosimilar is a biological medicinal product that contains a version of the active substance of an already authorized original biological medicinal product (reference medicinal product) in the European Economic Area (EEA). The first biosimilar was approved in Europe in 2006, and there are now 20 biosimilars authorized in Europe. Importantly, the Ph. Eur. provides a framework for the quality requirements for biosimilars of increasing complexity. As stated in the European Medicines Agency (EMA) Guideline on Similar Biological Medicinal Products (1), “Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy, of the similar biological medicinal product and the chosen reference medicinal product authorized in the EEA.” With regard to quality, Ph. Eur. standards have a role during the development of biosimilars as they are used for method qualification and validation. Where biosimilars have been approved for use in the European Union, there are corresponding Ph. Eur. monographs that cover the product classes of human growth hormone, granulocyte colony-stimulating factor, erythropoietin, and insulin. Although the Ph. Eur. recognizes that monographs provide public standards for the quality of medicinal products and their constituents, the monographs are not sufficient to assess identity and similarity of medicinal products that are required to establish the comparability of a biosimilar to an original biological product in the context of a marketing authorization application.
Even though users of the Ph. Eur. are supportive of the existing general chapters and monographs, the Ph. Eur. acknowledges that there are number of challenges to address in the future development of individual monographs for biologicals. First, there is a need for flexibility within biological monographs because of the requirement to cover heterogeneous products manufactured by different production methods. Nevertheless, there is a need for monographs to provide enough detail for a user to be able to perform the analytical methods. Second, there is a need to balance the inclusion of new technologies in monographs with the robustness of existing analytical methods.
The Ph. Eur. is often challenged on why individual monographs are elaborated for biologicals due to their unique complexity and inherent heterogeneity. The elaboration of biological monographs is a tiered process starting with the originator product, but the monograph may be subsequently adapted to account for biosimilar products. For complex biologicals, the Ph. Eur.’s current focus is to introduce classes of quality attributes and have specific acceptance criteria; this is exemplified by the recent monograph for recombinant human coagulation factor IX where the glycan analysis test is described in the production section of the monograph and calls for the use of an in house reference preparation shown to be representative of clinically tested batches and batches used to demonstrate consistency of production. Also, no acceptance criteria are given for the test; this decision on the criteria is left to the discretion of the competent authority. The rationale is that there is a direct relationship between glycosylation and the manufacturing process. This new approach is aligned with the development approach for biosimilars and involves communication channels between the main regulatory players in Europe: EMA, national authorities, and the European Directorate for the Quality of Medicines & HealthCare.
The Ph. Eur. intends to undertake further refinement of the format and content of monographs for biologicals to keep pace with recent approaches and meet the needs of its users (e.g., the new approach to include “Glycan analysis” in the Production section of the monograph).
Advanced therapy medicinal products
The Ph. Eur. has also worked to address the emergent field of advanced therapy medicinal products (ATMPs), or cell based and gene therapy medicinal products, and has developed a chapter that addresses quality requirements of the biological raw materials that are used for the production of these types of products. This informational chapter, which is intended to be published by the end of 2015, has undergone public enquiry and gives examples of the critical quality attributes specific to each class of raw material with the aim of harmonizing the variable practices that are currently adopted for biological raw materials. The development of this chapter has been performed in close collaboration with members of the EMA Committee for Advanced Therapies and the Biologics Working Party.
Thus, the existing Ph. Eur. monographs and chapters and the continued development of monographs and chapters for biologicals supports the Ph. Eur.’s mission to facilitate patient access to high quality medicines.
1. EMA, Guideline on Similar Biological Medicinal Products (Committee for Medicinal Products for Human Use, April 2013), CHMP/437/04 Rev 1.
Article DetailsPharmaceutical Technology
Vol. 39, No. 5
Citation: When referring to this article, please cite it as S. Wicks, “Ensuring the Quality of Biologicals,” Pharmaceutical Technology39 (5) 2015.