As public standards for the quality of medicines in Europe, the monographs and reference standards of the European Pharmacopoeia (Ph. Eur.) play a major role in ensuring the quality of biotherapeutics, including biosimilars, thereby contributing to overall patient safety. The Ph. Eur. standards are designed to meet the needs of stakeholders, including industry, OMCLs and regulatory authorities.
Following the publication of the general monograph Products of recombinant DNA technology (0784) in 1992, the Ph. Eur. actively developed monographs for many first-generation biotherapeutics using the multisource approach, which involved working closely with the various manufacturers of biotherapeutics (Procedure 1; Guide for the work of the Ph. Eur.). During the last decade, however, the majority of Ph. Eur. monographs for biotherapeutics have been developed via an alternative mechanism, which is applied to substances still under patent protection and is based on a close collaboration with the Innovator company, offering the advantage of having a public standard in place by the time further products reach the market (Procedure 4; Guide for the work of the Ph. Eur.). The latter procedure was launched in 2008 in a pilot phase for biotherapeutics (P4-BIO pilot phase) which successfully concluded at the 156th plenary session of the Ph. Eur. Commission in November 2016. The work under P4-BIO procedure is currently focused on the elaboration of two new individual monographs for monoclonal antibodies, i.e. Golimumab concentrated solution (3103) and Ustekinumab (3165).
Following the publication of the general monograph Monoclonal antibodies for human use (2031) in 2004, the Ph. Eur. Commission embarked upon the setting of public standards for therapeutic monoclonal antibodies by launching the so-called MAB pilot phase in 2014. As part of this pilot phase, the Ph. Eur. Commission achieved a significant milestone in setting standards for complex biotherapeutics by adopting the first individual monograph for a full monoclonal antibody, Infliximab concentrated solution (2928), at its 159th plenary session in November 2017. The work in this field continues with a focus on the development of horizontal standards applicable to monoclonal antibodies, while progressing in parallel with the elaboration of a new multi-source product monograph. The approaches applied to the elaboration of monographs for biotherapeutics have evolved in recent years, with the focus now on greater flexibility as a means for better addressing the structural complexity and heterogeneity of new biotherapeutics.
Dialogue with Stakeholders
As part of the continuous dialogue with stakeholders, the EDQM organises numerous consultations dedicated to the role of the Ph. Eur. in the biotherapeutics standard-setting field. Monographs for biotherapeutics were the subject of discussion at the 2011 EDQM workshop ‘The future of monographs in the field of biologicals’, as well as at the workshop session on biologicals that took place during the International EDQM Conference entitled ’50 years of leadership in the quality of medicines – paving the way for the future’ in 2014, celebrating the 50th anniversary of the European Pharmacopoeia Convention. The latest monographs elaborated as part of the P4-BIO and MAB pilot phases were discussed at the workshop ‘Setting pharmacopoeia standards for biotherapeutic products’, held during the International EDQM Conference entitled ‘European Pharmacopoeia: Tackling future challenges of the quality of medicines together’ on the occasion of the publication of the 9th Edition of the Ph. Eur. in 2016. Driven by the growing interest in the field of biosimilars, a Joint EDQM/EMA Workshop on biosimilars was organised in 2017 to clarify the role that monographs play (and do not play) in the assessment and marketing authorisation of biosimilars. These events attracted participants from industry, regulatory agencies, OMCLs and academia from all over the world. In addition, the last workshop was broadcast live, further increasing its outreach. Further dialogue with stakeholders on the development of public standards for biotherapeutics took place during the dedicated workshop of the International Conference entitled ‘EDQM & European Pharmacopoeia: State-of-the-art science for tomorrow’s medicines’ on the occasion of the publication of the 10th Edition of the Ph. Eur. in 2019.
The EDQM also regularly organises webinars, such as the biologicals-dedicated webinar ‘Biologicals of the twenty-PhEur-st century’ (2015), and Ph. Eur. training sessions. The recording of the most recent training session on biologicals (2020), addressing also in details the concept of monograph flexibility, can be found here. All European Pharmacopoeia training resources available in the public domain can be accessed here.
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The Ph. Eur. sets public standards providing harmonised quality requirements for medicinal products throughout Europe, regardless of the regulatory process according to which a given product was approved. The regulatory pathway for biosimilars, biological medicinal products that are highly similar to an already approved biological medicinal product (the “reference medicinal product”), is defined in EMA and WHO guidelines, according to which their evaluation by licensing authorities takes place whether or not a compendial standard exists. If a monograph is available, compliance with such a written standard is required; however, demonstration of biosimilarity to the reference medicinal product cannot be inferred. The EMA Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues clearly states that comparison of the biosimilar to a publicly available standard, e.g. a pharmacopoeial monograph, is not sufficient for the purpose of comparability. Similarly, the reference standards described in Ph. Eur. monographs are not intended to be used as reference medicinal products (comparators) for the demonstration of biosimilarity. As indicated in the Ph. Eur. general chapter on Reference standards (5.12), the Ph. Eur. reference standards are shown to be suitable for their intended purpose and are to be used within the scope of Ph. Eur. monographs and chapters only.
For more than twenty years, the European Pharmacopoeia (Ph. Eur.) monographs for biotherapeutic proteins have been elaborated using the multisource approach – the so-called Procedure 1 ‒ which has led to robust quality standards for many of the first-generation biotherapeutics. In order to ensure that suitable public standards are in place for biotherapeutics as they come off-patent, as well as to strengthen the quality of upcoming products, the Ph. Eur. Commission launched a pilot phase in 2008 for the elaboration of monographs using Procedure 4 (P4-BIO). Procedure 4 has been used successfully for chemical entities since 2002, and allows the elaboration of biotherapeutic product monographs for which a single interested manufacturer has been identified. It is usually applied to substances still under patent protection and is thus based on a close collaboration with the Innovator manufacturer of the substance/product. Importantly, whichever procedure is used, Ph. Eur. monographs take account of approved products on the European market, while the basis for monograph elaboration is the approved licensing specification(s) backed up by batch data.
Given the regulatory and industry interest in insulins and coagulation factors, the P4-BIO pilot phase began with the elaboration of monographs for an insulin analogue (insulin glargine) and two recombinant human coagulation factors (factors VIIa and IX), respectively. It was subsequently expanded with the aim of addressing more diverse and complex classes of biotherapeutics licensed in Europe ‒ this led to the addition to the work programme of a hormone (teriparatide), a fusion protein (etanercept) and a pegylated protein (pegfilgrastim) in 2011, as well as a hyperglycosylated protein (darbepoetin alfa) in 2015.
The following monographs were elaborated within the scope of the P4-BIO pilot phase and have been published in the Ph. Eur.:
|Monograph||since Ph. Eur||Initial Implementation date|
|Insulin glargine (2571)||8.0||1 January 2014|
|Human coagulation factor VIIa (rDNA) concentrated solution (2534)||8.0||1 January 2014|
|Human coagulation factor IX (rDNA) concentrated solution (2522)||8.2||1 July 2014|
|Teriparatide (2829)||9.0||1 January 2017|
|Human coagulation factor IX (rDNA) powder for solution for injection (2994)||9.3||1 January 2018|
|Etanercept (2895)||9.5||1 July 2018|
The work performed during the P4-BIO pilot phase successfully proved that it is possible and extremely useful to elaborate monographs for complex biotherapeutics. In light of this success, the P4-BIO pilot phase was concluded at the 156th session of the Ph. Eur. Commission in November 2016 and thus became an established mechanism within the Ph. Eur. framework for setting public standards for biotherapeutic proteins.
More recently, the Ph. Eur. Commission decided on elaboration of two monographs for monoclonal antibodies under the P4-BIO procedure. Golimumab concentrated solution (3103) and Ustekinumab (3165) were added to the work programme at 160th (March 2018) and 167th (June 2020) Ph. Eur. Commission sessions, respectively, and the work on the elaboration of these monographs is ongoing.
Extensive consultations with stakeholders have taken place regarding the role of the Ph. Eur. in the field of setting public standards for biotherapeutics (See above 'Dialogue with Stakeholders'). Notably, the EDQM workshop entitled ‘The future of monographs in the field of biologicals’ (2011) reflected the rising demand for further Ph. Eur. standards for biotherapeutics while highlighting the usefulness of individual monographs, in addition to general monographs and standardised methodologies, for monoclonal antibodies (mAbs). This prompted the Ph. Eur. Commission to approve pursuit of a pilot phase for the development of quality standards for mAbs (MAB pilot phase) through a bottom-up approach, going progressively from specific (i.e. individual monographs) to general (i.e. general methodologies, product-class/sub-class monographs) quality attribute requirements.
As part of the MAB pilot phase, infliximab, a recombinant chimeric human-murine IgG1 monoclonal antibody against tumour necrosis factor alpha (TNF-α), was chosen as a case study to demonstrate the feasibility of establishing an individual monograph for a complex monoclonal antibody.
The adoption of the first individual monograph for a monoclonal antibody, Infliximab concentrated solution (2928), by the Ph. Eur. Commission in November 2017 marks a significant milestone in setting quality standards for complex biotherapeutics. The experience gained during the elaboration of the Infliximab monograph now serves as a basis for the development of horizontal standards applicable to mAbs. Work is currently ongoing on the elaboration of general requirements and methodologies for potency determination for anti-TNF-α products (i.e. Cell-based assays for potency determination of TNF-alpha antagonists (2.7.26)), as well as for physico-chemical testing applied to various mAbs (e.g. Capillary isoelectric focusing for recombinant therapeutic monoclonal antibodies (2.5.44), Size-exclusion chromatography for recombinant therapeutic monoclonal antibodies (2.5.43)). More recently, at its 167th session in June 2020, the Ph. Eur. Commission tasked the MAB WP with elaboration of a monograph on Adalimumab concentrated solution (3147) in the frame of the ongoing pilot phase.
The concept of flexibility is integrated in the Ph. Eur. General Notices and envisages the use of alternatives to the official methods described in the Ph. Eur., as long as they lead to the same pass/fail results and subject to the agreement of the competent authority. It also envisages the possibility of omitting certain test(s) if assurance that a product is of Pharmacopoeia quality is obtained on the basis of its design, together with its control strategy and relevant data (e.g. derived from validation studies of the manufacturing process). In addition, the use of process analytical technology and/or real-time release testing (including parametric release) is also acknowledged in the General Notices.
The Ph. Eur. has always recognised the complexity of biologicals in the development of its texts, and the need for flexibility in monographs had already been the subject of discussions in the 1980s. These debates led, in 1991, to the creation of a Production section in monographs for biological preparations that draws attention to particular aspects of the manufacturing process but is not necessarily comprehensive. The Ph. Eur. General Notices further explain that the statements included in the Production section may relate, for example, to source materials, to the manufacturing process itself and its validation and control, to in-process testing, or to testing that is to be carried out by the manufacturer on the final article, either on selected batches or on each batch prior to release. They constitute mandatory requirements for manufacturers, unless otherwise stated, but cannot necessarily be verified on a sample of the final article by an independent analyst.
While establishing monographs for biotherapeutics, it became evident that additional flexibility was needed to address the structural complexity and naturally occurring heterogeneity, as well as the potential diversity of the compound resulting from different manufacturing processes. As a result, tests related to process-dependent heterogeneity (e.g. glycosylation, charge variants) were introduced in the Production section of a number of monographs (e.g. Human coagulation factor VIIa rDNA concentrated solution (2534), Human coagulation factor IX (rDNA) concentrated solution (2522), Etanercept (2895), Infliximab concentrated solution (2928) and in the revised version of Erythropoietin concentrated solution (1316)). In addition, the respective monograph acceptance criteria are not expressed in numerical limits, as no “one-size-fits-all” specification is possible for such process-dependent quality attributes.
Furthermore, for complex test procedures and assays, an outline of a suitable test method (e.g. essential steps in the procedure) is typically given as a requirement. Detailed analytical procedures with specific instructions – including sample preparation, quantities/concentrations/composition of reagents and buffers, chromatographic conditions, plate design for cell assays, readout, etc., use of dedicated Ph. Eur. reference standards for calibration and method performance verification, notably system suitability criteria – may be described as examples. This indicates that the test method described may be used as is or may be replaced by another suitable, validated procedure without having to demonstrate its equivalence to the “example” method, subject to approval by the competent authority. These considerations were reflected in the revised version of the Technical guide for the elaboration of monographs on synthetic peptides and recombinant DNA proteins.