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Awareness of recently implemented—or ongoing—advances by the pharmacopoeias can help biotherapeutic manufacturers remain compliant with current requirements.
The increased number and complexity of biotherapeutic products available to patients has spurred a commensurate increase in publicly available quality standards from the pharmacopoeias. These standards, including general chapters, monographs, and physical reference standards, can help guide manufacturers to ensure the identity, strength, quality, and purity of their products. Additionally, the global COVID-19 pandemic has necessitated a swift response from the pharmacopoeias to update existing standards and create new standards and toolkits for their stakeholders. This article highlights recently implemented or ongoing advances from the pharmacopoeias.
The pharmacopoeias—the European Pharmacopoeia (Ph.Eur.) in particular—have published monographs for some biological products since the 1990s, including human insulin, somatropin, interferon, erythropoietin, and vaccines (1). With the bio/pharmaceutical industry’s increased focus on developing complex biotherapeutic products (BTPs), pharmacopoeias have been exploring a variety of approaches for developing public quality standards for these products (2). The status of pharmacopoeia standards for BTPs, including product-specific monographs, performance-based and product class standards, and general chapters, was summarized in an article published in March 2020 (3). The authors now provide an update on the development of these standards over the past two years, serving as a reminder that companies need to stay up to date with evolving pharmacopoeia requirements. The pharmacopoeias’ response to the COVID-19 pandemic is also described.
The COVID-19 global pandemic significantly affected patients, healthcare providers, and the pharmaceutical industry. The pharmacopoeia bodies responded by preparing new or updating currently available information. The US Pharmacopeia (USP) provided two toolkits to stakeholders. The first can be used for assessing vaccine handling and gives cold chain requirements for the messenger RNA (mRNA)-based COVID-19 vaccines (4). The toolkit provides frontline practitioners with the most updated and relevant COVID-19 vaccine information. The toolkit also included a visual inspection guide to help identify falsified COVID-19 vaccines. USP’s second toolkit was focused on the available documentary standards that support vaccine laboratory assessments (5). The second toolkit navigates the documentary standards that are provided by the manufacturing platform rather than product-specific guidance.
Similarly, the European Directorate for the Quality of Medicines and HealthCare (EDQM) made texts from the Ph.Eur. for vaccine developers available free on their website (6). EDQM also released a guidance on recombinant viral vectored vaccines, which was not available before the pandemic (7). Both USP and EDQM collaborated with other pharmacopoeias (India, Japan, Mexico, World Health Organization, etc.) to work on monographs of potential interest for COVID-19 treatments (8).
USP revised their monographs for alcohol (ethanol and dehydrated ethanol) and isopropyl alcohol due to concerns with possible methanol contamination. Methanol was found in several hand sanitizers used by the public to stop the spread of the virus (9). The revision to add identification testing of methanol was done in response to an FDA request (10) due to the toxicity risk the public faced should methanol be present in the hand sanitizers. This affected most, if not all, bio/pharmaceutical manufacturers that supply the US market with excipients, drug substances, and drug products.
Product-specific monographs for complex biologics, such as monoclonal antibodies (mAbs), are still quite rare in pharmacopoeia publications. EDQM published monographs in the Ph.Eur. for etanercept (11) and infliximab concentrated solution (12) in 2018. Based on the most current work plan (13) for the Ph.Eur., there are five more product-specific monographs for complex biologics currently being elaborated. The monographs for golimumab concentrated solution and golimumab injection (the first product-specific monograph for a mAb drug product) were published for comment in Pharmeuropa (14). Additionally, a monograph for the TNF-alpha inhibitor adalimumab is being elaborated via the P1 procedure with multiple manufacturers invited to participate in the process (13). Lastly, ustekinumab concentrated solution and ustekinumab injection are the first IL-12/IL-23 inhibitors to be studied by EDQM for monograph development via the P4 process (13).
There are no product-specific mAb monographs currently published in the US Pharmacopeia (USP). However, USP has indicated that it is open to begin elaboration of a product-specific mAb monograph, should a company wish to donate the necessary information (15). USP would notify stakeholders through a compendial notice that it is undertaking the elaboration of the donated monograph. This would allow all manufacturers and stakeholders to respond to USP with concerns or to state any objections.
The Chinese Pharmacopoeia (ChP) had begun elaboration of several mAb monographs (16), but to date, no drafts of the monographs have been published for comments. It is expected the monographs will become official in either ChP 2020 Supplement 1 (expected 2023) or in ChP 2025.
During the elaboration of the infliximab concentrated solution and etanercept monographs, EDQM recognized that flexibility with methods would be integral to the useability of the monographs. The production section of the product-specific monographs contains a key test for glycans or N-Glycans for either infliximab or etanercept, respectively. EDQM introduced the method published in the monograph with the following language: “The following procedure is given as an example” (12). This approach was used because a manufacturer could employ a variety of method techniques to meet a requirement as allowed in Ph. Eur. general monograph— “Monoclonal Antibodies for Human Use (2031).”
The phrase “for example” was originally defined in a technical guide from EDQM but could be easily misinterpreted as a requirement rather than a suggestion. EDQM has now added a definition of “for example methods” to the General Notices in the Ph. Eur., explaining the intent and compliance expectations for a method of this type (17). The addition of the definition to the General Notices is a significant and welcome change for stakeholders. The revised General Notices clearly explain that monographs containing the statement, “The following procedure is given as an example,” indicates the method has been validated for its intended purpose. A manufacturer may choose to implement the “for example” method as written with appropriate verification on its product, or it may use a suitably validated procedure that is approved by the competent authority. If using a different method than the “for example” method, the manufacturer does not have to show the equivalence of its suitably validated method to the “for example” method.
Today, there are several TNF-alpha inhibitor products available, and manufacturers have used a wide variety of methods to assess the potency of these mAbs. EDQM has completed a multi-lab evaluation wherein four approved bioassay methods for specific products were studied to determine their respective suitability for the entire class of TNF-alpha antagonist products (18). The result of these studies has produced a new general chapter: “Cell-based Assays for Potency Determination of TNF-alpha Antagonists (2.7.26)”. The general chapter will become official in Ph. Eur. volume 11, supplement 1 (official date: April 2023).
This general chapter is referred to as a horizontal standard, meaning the content of the chapter is widely applicable to multiple product-specific monographs. The general chapter provides manufacturers with the flexibility to choose from the four assay types presented in the chapter or use a different cell-based assay (with the approval of a competent authority). Two product-specific monographs (etanercept and infliximab concentrated solution) have been updated to indicate the example procedure would be the specific cell-based assay originally used and that the other three cell-based assay test procedures in 2.7.26 that were verified by the study are also suitable for specific products (18).
This is the first of three horizontal standards that EDQM intends to elaborate and make official. Two other horizontal standards are currently being elaborated by EDQM: “Capillary Isoelectric Focusing for Recombinant Therapeutic Monoclonal antibodies (2.5.44)” and “Size Exclusion Chromatography for Recombinant Therapeutic Monoclonal Antibodies (2.5.43)” (19).
EDQM has either updated or is currently revising several Ph. Eur. general chapters that will be applicable for emerging cell and gene therapy (CGT) products that are being approved and developed (20). The general chapter, “Gene Transfer Medicinal Products (GTMPs) for Human Use (5.14),” is being divided into a general monograph, “Gene Therapy Medicinal Products for Human Use (3186)” and a new general chapter “Additional Information on Gene Therapy Medicinal Products for Human Use (5.34).” The general monograph provides new information for genetically modified autologous human cells and oncolytic herpes simplex virus for human cells. Additionally, information related to the definition, general requirements on the production of GTMPs, recombinant vectors, and genetically modified cells previously found in the general chapter (5.14) has been revised for inclusion in the general monograph. The new general chapter provides new information for genetically modified bacterial cells for human use and updated requirements for retroviridae-derived vectors for human use.
The final change to CGT standards is to general chapter “Raw Materials of Biological Origin for the Production of Cell-based Therapy Medicinal Products (5.2.12).” The chapter is under revision to indicate it is no longer a stand-alone, and vector requirements will now reference the new general monograph 3186.
The British Pharmacopoeia published a best practice guidance for Advanced Therapy Medicinal Products (ATMP) Flow Cytometry and Vector Copy Number (21). The guidance addresses the complexity and risk associated with each stage of assay development of advanced therapy medicinal products. The guidance offers a practical and phase appropriate validation tool to help ensure the success of a manufacturer’s CGT program.
USP has manufactured four mAb performance standards and has made them available for purchase (22). These mAb standards have molecular weights between 146K and 150K daltons with different isoelectric points and can be used as system suitability controls in a variety of commonly used methods for mAb analysis, such as charged variants, molecular weight determination, and glycosylation. The development of the standards was driven by stakeholder engagement sessions led by USP. USP indicates that these standards can be reliably and reproducibly manufactured to ensure a long-term supply and can serve as a control for a newly developed assay.
Additionally, USP is focusing on the development of oligonucleotide-related standards (performance standards) for raw materials (23). Phosphoramidites are the target for initial standard development due to their criticality to the supply of this emerging therapeutic class. Five performance standards are characterized by mass spectrometry and 31P and 1H NMR. These performance standards can be used for controlling and monitoring reactive impurities in phosphoramidites.
As more biotherapeutics products come to market, it is important for manufacturers to ensure their products comply with current pharmacopoeial standards, which are constantly evolving. The new and revised quality standards published by the world’s pharmacopoeia serve to ensure patients receive drug products of the appropriate identity, strength, quality, and purity. Manufacturers can expect that these new standards will continue to be elaborated for the foreseeable future, and it is critical that they maintain a surveillance process to identify and assess the changes as they happen.
Joseph A. Albanese is the managing director and consultant with Albanese Consulting, LLC. J. Mark Wiggins is the owner and compendial consultant with Global Pharmacopoeia Solutions, LLC.
Volume 35, Number 10
When referring to this article, please cite it as J. A. Albanese and J. M. Wiggins, “Biologic Standards in the Pharmacopoeias: An Update,” BioPharm International 35 (10) (2022).