Role of Public Standards in the Safety and Efficacy of Biologic Medicines

Abstract

In this report, we emphasize the importance of public monographs with reference materials, coupled with careful process and change control and attention to GMPs, as a means of advancing access to good quality, safe, and effective medicines, with emphasis on available and incoming biologic medicines. With adequate control of articles covered by a monograph, these public standards can form the basis for a global public quality platform that covers reference products, non-interchangeable reference products, biosimilars, and interchangeable biosimilars. Working collaboratively with all stakeholders, new approaches allow these public standards to emerge nationally and globally in a timely way. Yet, there are increasing limitations in the availability of public standards for biologic medicines, which may reverse many decades of progress. Solutions are considered in this report.

APPENDIX

Case Studies

Case Study 1: USP’s Erythropoietin Bioassay Reference Standard

Epoetin alpha is the USAN of a drug substance that is marketed in the USA as epoetin alpha for injection by Amgen for general anemia beginning in 1989 and by Johnson and Johnson for anemias of cancer also beginning in 1989. USAN has given two additional names for erythropoietin (EPO): beta and delta, even though only the alpha form is marketed in the USA. The beta form is marketed in Europe as NeoRecormon by Roche. The WHO has created three EPO international standards (IS) in 1990, 2003, and 2012, respectively. The second IS was composed of a mixture of the alpha and beta forms. There is no indication that the alpha and beta forms produce different clinical effects, and the two different forms can only be distinguished with high resolution charge separations or glycan analysis that can address glycosylation microheterogeneity. In the absence of a monograph for erythropoietin, USP’s Biologics & Biotechnology Monographs 1 Expert Committee prepared general chapter Erythropoietin Bioassay <124> (25) that provides procedures for two in vivo animal assays, one in normocythemic and one in polycythemic mice. It also provides further guidance on how an in vitro bioassay might be calibrated relative to the in vivo assays. The candidate reference material for this general chapter is the same material as the recently established third international reference standard (RS) for erythropoietin (WHO’s BRM). USP’s laboratories did not participate in this collaborative study, but the results from the WHO collaborative study were used to establish USP’s EPO potency standard in general chapter <124> with the same unit assignment as the WHO third IS. Additional studies will be needed to develop a reference material for the physicochemical tests of the planned epoetin alpha drug substance monograph in USP. The third IS for erythropoietin is no longer a mixture of alpha and beta erythropoietin but contains only epoetin alpha, and the third IS is the same material referenced in general chapter <124>, even though the USP material is considered a secondary national reference material.

Use of the USP Reference Standard in the Context of In Vitro Bioassays

The USP erythropoietin (EPO) for bioassay reference standard (RS) is directly traceable to the third WHO international standard for EPO which is calibrated by in vivo bioassay in IU. Transfer of the unitage (IU) from the USP potency standard to any process-specific EPO material, where that material has the potential to differ in its ratio of biological activities from the USP potency standard, must be made with a full understanding of the biological properties of the material.

The USP EPO for bioassay RS is assigned a unitage of 1,500 units/IU by in vivo assay. The USP potency standard may be used directly in the normocythemic mouse bioassay, as described in chapter <124>, and for the calibration of any process-specific EPO preparation. However, if the intention is to use an in vitro assay and to transfer the unitage from the USP EPO for bioassay RS to a preparation of EPO, then it is necessary to demonstrate that the USP potency standard and the material in question exhibit equivalent ratios of in vitro to in vivo potency (25). When these ratios are not equivalent, then the standard may not be used with its assigned in vivo potency in the in vitro assay, and the ratio determined for the material being tested should then be used to assign a process-specific, in vitro assay unitage to the USP EPO for bioassay RS. The USP EPO for bioassay RS, with its adjusted in vitro assay unitage, may then be used in the in vitro assay to transfer the unitage from the USP EPO for bioassay RS to the material being tested.

Case Study 2: Pegfilgrastim (PEG-G-CSF) Potency Test and Reference Materials

Filgrastim (G-CSF) binds to high-affinity G-CSF receptors and regulates the maturation and proliferation of neutrophils within the bone marrow. Therapeutically, the drug is used to reduce the neutropenic phase arising from certain disorders or as a result of cancer chemotherapy. Pegfilgrastim (Peg-G-CSF) is a mono-pegylated form of the recombinant human granulocyte colony-stimulating factor analog, filgrastim. It is a single chain, 175 amino acid, pegylated polypeptide. It is prepared by coupling a linear polyethylene glycol (PEG) molecule, of an average molecular weight of 20 kDa, to the N-terminus of the filgrastim protein. The change decreases renal clearance and allows reduction in the frequency of dosing. The drug has been marketed in the USA and in Europe under the brand name Neulasta by Amgen since 2002 and has recently been one of the most notable targets for the development of both non-interchangeable and biosimilar products. Products have already been launched in Europe (Teva) or are in late clinical development (Sandoz), demonstrating that the time is right for the development of a public standard that can reconcile key quality expectations for the global market.

The PEG-G-CSF drug substance monograph for USP’s Medicines Compendium (MC) was developed in USP India Private Limited Laboratories in Hyderabad, in consultation with the Council of Experts MC Biologics Expert Committee. Critical quality attributes for the tests, procedures, and acceptance criteria of the monograph were determined. Candidate procedures were validated using donated materials from six manufacturers and a reference product, Neulasta, procured from the Indian market. The potency test for the MC monograph is based on a cell proliferation assay with read-out expressed in fluorescence. In parallel with USP’s effort, the NIBSC conducted a global collaborative study to develop the WHO first IS for in vitro bioactivity of PEG-G-CSF in medicinal products or their ingredients. Three manufacturers donated material to NIBSC for this study. Two materials were lyophilized as per WHO specifications, and the study was conducted in the following laboratories: four from China (including the National Institute for Food and Drug Control in Beijing), four from Europe (including NIBSC), eight from India (including the National Institute for Biologics near Delhi and USP facilities in Hyderabad and Rockville), two from South Korea, three from Latin America, and USP’s laboratories in Rockville. For the first time, two USP laboratories have participated in an international study for the establishment of an IS for a recombinant therapy. Based on the results of the collaborative study, NIBSC has prepared 4,700 ampules at 1 μg/mL with a value assignment of 10,000 IU/ampule. NIBSC submitted a report to the World Health Organization’s Expert Committee on Biological Standardization at their October 2013 meeting and thereafter made the first IS for a PEG-G-CSF BRM available to the global community. Since the standard has only been evaluated for use in an in vitro bioassay, it cannot be assumed to be suitable for evaluation in vivo or for pharmacokinetic studies or for other purposes without suitable validation.

Typically, WHO’s BRM materials are provided only in small amounts for calibration of national primary and manufacturer secondary standards. The material is not intended for batch release testing. Because the candidate reference material for the USP MC potency test was also assessed in the NIBSC collaborative study, this material may be used throughout the world for batch release testing, using the potency test procedures described in the USP MC monograph or in any other procedure where unitage is linked to the WHO first IS PEG-G-CSF BRM. With availability of the first IS from WHO for PEG-G-CSF for potency testing, national primary and industry second standards should be recalibrated to this material to assure consistency in unitage across all PEG-G-GSF medicinal products where possible.

USP is also developing a physicochemical RS for pegfilgrastim to support the MC monograph. This will be a qualitative RS designed to (1) identify peaks/bands, (2) match peaks/bands for purpose of identification and detection, (3) match peptide map profiles, (4) evaluate and resolve chromatography peaks, and (5) demonstrate method performance. The RS will not be used to assign a value (potency or purity), although it will have an assigned concentration for purposes of sample dilution. Collaborative testing will include USP India, USP Rockville, NIBSC, and manufacturers from India and abroad.