プリオンに焦点を当てた生物製剤業界の問題

Abstract

Transmissible spongiform encephalopathy (TSE) agents, or prions as they are commonly referred to, are a significant concern to the biologicals and biotechnology industries. With the BSE epidemic in the UK in the nineteen eighties and the subsequent demonstration that the BSE prion has crossed the species barrier and manifested itself in humans as variant Creutzfeldt-Jakob Disease (vCJD), risk assessment when ruminant and specifically, bovine-sourced materials are used in the manufacture of biopharmaceuticals is imperative. The altered tissue tropism of vCJD (localized in the lymphoid tissues rather than the central nervous system), combined with the resilience of prions to most inactivating agents, the extended incubation period (measured in years and decades rather than days and months) and lack of validated prion detection assays for detection during the subclinical phase of the disease have escalated the stakes for biotherapeutics from a TSE-safety standpoint.

There is no evidence to date that BSE has been transmitted by the use of ruminant-derived raw materials during the manufacture of biopharmaceuticals. Whether blood and blood products transmit prions is not unequivocal; nevertheless, researchers have demonstrated that blood could potentially transmit prion infections in experimental animals. While every effort is being made to move away from ruminant-sourced products such as enzymes, media additives and serum during biopharmaceuticals manufacturing, these products cannot be totally excluded from many manufacturing processes. As BSE continues to be a pandemic problem, in the interests of protecting public health and safety, the potential risks of exposure to these agents must be minimized.

Scope

This Report offers valuable insight into the challenges encountered during manufacture of plasma-derived products or ruminant-sourced raw materials employed in biopharmaceutical manufacturing. The Report highlights the importance of risk management in order to ensure biopharmaceutical safety from a prion-safety standpoint. In addition, this Report provides information on the nature of prions based upon currently available knowledge, and covers specifically the issues that need to be addressed in biopharmaceuticals manufacturing in order to produce a safe and efficacious product and comply with the regulations.

Key Reasons to Buy

• Get an up-to-date perspective on TSE agents (prions) through a state-of-the-art overview of issues related to prions and their relevance for biopharmaceutical safety.
• Discover the implications for medicinal products that either directly use bovine-sourced products or are supplemented with bovine products during the various stages of manufacturing and downstream processing.
• Understand the crucial contribution of controlled sourcing through a comprehensive look at the various production process control approaches and their relevance in strategic and long-range planning.
• Gain insight into available detection methodologies via a complete review of the various prion detection methods used in biopharmaceutical manufacturing process validation and research studies.
• Obtain information on manufacturing methods with potential for prion clearance through a discussion of various industry-validated and innovative technologies.
• Recognize the pivotal role of risk minimization and management from a prion safety standpoint.
• Learn about process validation (clearance evaluation) study design for prion clearance and pitfalls to avoid with coverage of the issues that need to be addressed.

Table of Contents

1. Executive Summary

2. General Overview

• What are TSEs?
• Spectrum of TSE (Prion) Diseases
• Etiology of Prion Diseases
• Characteristics of the Prion Protein
• Transmissibility:
• Summary Comments

3. Control of Production Processes

• General Considerations
• Evaluation of Raw Materials Used in the Manufacturing Processes
• General Requirements for All Raw Materials (from a TSE-Compliance Standpoint)
• Requirements for Specific Products
• GMP Considerations and TSE Compliance
• Summary Comments

4. Prion Detection: General Comments

• Biological Assays
• Methods Based on PrP Detection
• Surrogates of Infection
• Summary Comments

5. Regulatory Considerations

• Risk Assessment: General Considerations
• Risk Evaluation: Factors for Consideration
• Risk-Benefit Analysis
• Minimization of Risk of Transmitting Animal Spongiform Encephalopathies for Regulated Products
• Manufacturing Process Considerations
• Risk Minimization in Manufacture of Specific Products (plasma-derived medicinal products, urine-derived medicinal products, iatrogenic exposure)
• Risk Minimization: Specific Products (collagen, gelatin, tallow derivatives, bovine blood derivatives)
• Risk Management
• Summary Comments

6. Prions: Decontamination and Clearance Considerations

• Prion Clearance - General Considerations
• Prion Inactivation Methods
• Decontamination Considerations
• Prion Clearance Studies
• Summary Comments

7. Process Clearance Evaluation (Validation) for Prion Clearance

• General Considerations
• Considerations in Study Design
• Technical Aspects of Study Design
• Prion Clearance Evaluation (Validation) Studies:
• Considerations in Data Interpretation and Estimating Prion Clearance
• Summary Comments

8. Glossary