Significance and Use 4.1 This guide focuses on upstream and downstream processes for biopharmaceutical products with a particular focus on antibody production processes. For further information, see Appendix X1 and Refs (1-3). 4.2 Bioprocesses traditionally consist of discrete unit operations labeled as upstream, downstream, and fill/finish operations. The objectives at each stage are significantly different, as are the operating parameters and control processes, that can make complete integration impractical initially (Appendix X1). This guide does not imply that complete integration is a prerequisite. A higher degree of integration may be possible over time as a better understanding of the dynamics of processes become established. 4.2.1 Upstream Processes—The purpose of upstream processes is to generate sufficient product to meet patient requirements preferably in the fewest number of batches. This starts with increasing biomass (cell-line expansion from working cell bank to production inoculation) to a production bioreactor in which the focus shifts to producing product. The material within a bioreactor during extended growth is heterogenous, for example, cells will differ in age, there may be genetic drift, secreted product can differ in the residence time spent in the bioreactor, and cell debris accumulates throughout the process. 4.2.2 Downstream Processes—The purpose of downstream processes is to harvest product and purify it from process- and product-related impurities (for example, cell debris, nucleic acids, and misfolds) to the desired level. Solids are first separated from solutes; solutes are then separated from each other in the process of purification. Certain processes may at best be semi-continuous, and some steps may be prone to fouling, which may require manual intervention. 4.2.3 Fill/Finish Operations—The purpose of fill/finish operations is to formulate the purified product in a form that ensures stability and sterility and provides a dosage form consistent with the desired product profile. Operations may also include inclusion in a delivery system as a combination product. In this guide, operations up to and including final bulk fill for final drugs substance are addressed. Fill/finish operations for drug product and combination products are out of scope for this guide. 4.3 This guide does not advocate the following: 4.3.1 CM is suitable for the manufacture of all biopharmaceutical products and processes; 4.3.2 Guidance on issues related to the safe operation of a CM process or continuous biomanufacturing equipment. It is the responsibility of the user of this guide to establish appropriate health and safety practices and determine the applicability of regulatory limitations before use; and 4.3.3 Specific designs or operating regimes for CM.Scope 1.1 This guide is intended as a complement to Guide E2968. It provides key concepts and principles to assist in the appropriate selection, development, and operation of continuous processing technologies for the manufacture of biologically derived products. 1.2 Several of the principles covered in Guide E2968 are applicable to biomanufacturing. However, processes for biologically derived products differ from those for synthetic drugs in a number of fundamental ways in addition to their source (for example, format: aqueous liquids versus powders; scope: genesis to final formulation). This guide is intended to provide greater clarity for biomanufacturing. It does not imply that topics in Guide E2968 that are not covered here do not apply to continuous manufacturing (CM) for biologics. 1.3 Biologically derived products also differ widely from each other in terms of modalities, source materials, and the manufacturing technologies used, not all of which are equally amenable to operating in a continuous mode. 1.4 Opportunities do exist for the introduction of continuous technologies, for example, efforts are ongoing to adapt processes for large-scale manufacture of broadly applicable modalities such as monoclonal antibodies to a continuous format. This guide is intended to provide guidance to the design and implementation of antibody processes. 1.5 The principles can be applicable to unit operations or processes or both for other modalities but may not be applicable to all bioprocesses. 1.6 Particular consideration should be given to the development and application of the appropriate scientific understanding and engineering principles that differentiate CM from traditional batch manufacturing. 1.7 Since much of the processing is done under conditions amenable to microbial growth, maintaining process streams free from external biological impurities and microbial contamination (for example, bioburden, viruses, and mycoplasma) is critical. 1.8 This guide is intended to apply in both the development of a new process or the redesign of an existing one. 1.9 A manufacturer may choose to implement continuous manufacturing for discrete unit operations in stages as they develop process understanding before implementing a fully connected or continuous manufacturing process. 1.10 Units—The values stated in SI units are to be regarded as the standard. No other units of measurement are included in this standard. 1.11 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use. 1.12 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
