Somasundaram Gopalakrishnan, is senior consultant, Global Biopharm Center of Excellence, Merck Pte. Ltd.

Somasundaram Gopalakrishnan

The COVID-19 pandemic has given the bio/pharma industry lessons on being prepared to manufacture parenteral formulations for human use in emergency situations. Vaccines, remdesivir injection and amphotericin injection, are such recent examples. The challenge then becomes having enough flexibility in the manufacturing lines to facilitate manufacture of large volumes of unit doses of injectables as may be required with shorter changeover times, while assuring compliance and patient safety from the product contact parts used in the manufacturing line. Single-use manufacturing solutions provide the flexibility in terms of batch sizes, fill volumes, and ease of manufacturing, especially in terms of manufacturing different products in the same line with minimum line changeover requirements. This article reviews and elaborates the initial risk assessment process for extractable and leachables arising from single-use product contact manufacturing parts as per 

) chapters <665> and <1665>, which go into effect May 1, 2026 (1,2). The determined risk can then be used to build the level of extractable profiling and process equipment-related leachables (PERLs) followed by assessing the patient safety for regulatory submissions. 

Application of the Risk Evaluation Matrix as per 

<665> and <1665> for Evaluation of Leachables Risk from Single-Use Components Used in Biomanufacturing

Pharmaceutical Technology’s Trends in Manufacturing

Manufacturing systems used for biopharmaceutical drug substances or drug products can be partially or completely constructed from plastic materials. During the manufacturing process, the drug product and its components could directly come in contact with the plastics and potentially interact with one or more of the manufacturing system’s product contact components. The substances that leach from a product contact manufacturing component could become incorporated into the process stream. If these leached substances persist in the process stream and continue through the process operations, they could accumulate in the drug substance or drug product as PERLs (1,2). When present in the drug product, these PERLs can potentially alter the critical quality attributes of the drug product, such as its stability, efficacy, and safety. 

Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products

, addresses these interactions by providing a risk-based means for chemically characterizing and qualifying plastic components used to manufacture biopharmaceutical drug substances and pharmaceutical and biopharmaceutical drug products. 

Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products

, communicates the key concepts behind and provides additional information and guidance regarding the applicability and the application of 

 <665>. The authors discuss a practical approach by which 

 <1665> can be applied in a step-by-step manner for the risk assessment, using a case study involving the manufacturing process for remdesivir injection and single-use technologies (Merck).

The testing of a product contact component is driven by the risk that the component may be unsuited for its intended use based on chemical or biological effects attributed to PERLs (1). As such risks increase, the degree of required testing also increases. The risk assessment process is accomplished by a risk evaluation matrix that establishes the appropriate contributors to the dimension of risk, provides a quantifying means for the risk in each dimension, quantifies the total risk for each dimension, and links the quantified risk to an appropriate characterization strategy.

Pharmaceutical Technology’s Trends in Manufacturing May 2024 eBook

 <665>, Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products. 

 <1665>, Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products. 

Ramesh Raju Mavuleti*, rrajum@gmail.com, is head of operations, Validation Services India. Subhasis Banerjee, PhD, is principal technical application expert, Bioprocessing APAC. Tathagata Ray is consultant, Global Strategy Deployment; all at Merck Life Sciences Pvt, Ltd. K. Vasantakumar Pai, PhD, is professor and chairman, PG Department of studies & research in Industrial Chemistry, Kuvempu University. K. Sreedhara Ranganath Pai, PhD, is professor, Department of Pharmacology, Manipal Academy of Higher Education. Somasundaram Gopalakrishnan is senior consultant, Global Biopharm Center of Excellence, Merck Pte. Ltd.

*To whom all correspondence should be addressed.

When referring to this article, please cite it as Mavuleti, R. R.; Pai, K. V.; Pai, K. S. R.; et al. Application of the Risk Evaluation Matrix as per 

<665> and <1665> for Evaluation of Leachables Risk from Single-Use Components Used in Biomanufacturing. 

Articles

Determining E&L risk from single-use components can be used to build the level of extractable profiling and PERLs.

Application of the Risk Evaluation Matrix as per USP <665> and <1665> for Evaluation of Leachables Risk from Single-Use Components Used in Biomanufacturing

The adoption of single-use technologies (SUTs) in biopharmaceutical manufacturing reduces manufacturing costs, increases the manufacturing line flexibility, and improves the speed and efficacy of the line changeovers or the batch turnaround times. The closed manufacturing systems also facilitate production of a safe and regulatory-compliant product. SUTs are used throughout the biopharma manufacturing process flow, the single-use filter capsules, tubing, and connectors being the most widely used in the final fill/finish applications of the injectable preparations. The single-use bioreactor bags and buffer storage bags are used for upstream applications. This paper reviews the drivers for adoption of SUTs and how the risks from the use of these technologies can be overcome in a planned, proactive, and compliant manner. 

Review of SUT Adoption in Biopharma Manufacturing

 Pharmaceutical Technology’s Quality and Regulatory Sourcebook 2024

The adoption of single-use components emerged from the mid-1980s. Initially, blood bags replaced glass bottles and soon became available with a plastic tube or two as well as connectors, valves, and vials for taking biological samples. The polyvinyl chloride blood bags used for blood donations were more than just bags. Evolving from these examples are the current single-uses systems (SUS) that are gaining wider use in the biopharmaceuticals industry, especially for the production of specialized and/or small-batch biopharmaceutical drugs. These SUS are the alternatives to the systems made of relatively inflexible stainless-steel vessels and reactors, hard piping, valves, and so on. Such fixed systems must be cleaned and sterilized between batches, a relatively labor and energy-intensive operation. The adoption of aseptic connectors, tubing, mixers, storage bags, and sampling bags and usage of capsule filters in a wide range of applications in the late 1990s lead to the “plastic factory” concept in the 2000s. The technology was further expanded to the upstream and downstream unit operations in the biopharma industry, such as the bioreactors, chromatography, virus removal filtration, concentration, and purification steps. This expansion has evolved over time to the current-day concept of closed continuous processing technology, which is almost completely based on SUTs and assemblies (1,2).

Single-use or disposable bioprocessing equipment is now used for ≥85% of pre-commercial scale (i.e., preclinical and clinical) biopharma manufacturing and is increasingly being adopted for commercial product manufacturing, according to an industry survey (3). The leading reasons cited in the survey as being “very important” for the adoption of SUS include a decrease in the risk of cross-product contamination, cited by 46.2% survey respondents; eliminating cleaning requirements, cited by 41.2% of respondents; reducing time to get facility up and running, cited by 44.1% of respondents; and reduction in capital investment in facility and equipment, cited by 40.4% of respondents.

A study found that SUTs, when adopted, required 87% less water (primarily by reducing steaming in place [SIP], cleaning, and changeover between batches), 21% less labor (primarily by reducing cleaning in place [CIP] activities), 38% less space, and 29% less energy (4). According to industry sources (5), SUS lower operating costs by offering 46% water and energy reductions, a 35% more favorable carbon dioxide footprint due to lower facility emissions, and a 40% lower initial investment cost. The technology allows biopharma manufacturers to push products to market faster by increasing throughput and making scalability easier (5). The availability of this technology has made new biopharma companies adopt SUS, as it requires less upfront capital investment and enables quick advancement of development efforts towards new products (6).

1. Rathore, A. S.; Agarwal, H.; Sharma, A. K.; Pathak, M.; Muthukumar, S. Continuous Processing for Production of Biopharmaceuticals. 

 (8), 836–849. DOI: 10.1080/10826068.2014.985834.
2. Klutz, S.; Magnus, J.; Lobedann, M.; et al. Developing the Biofacility of the Future Based on Continuous Processing and SUT. 

, 120–130. DOI: 10.1016/j.jbiotec.2015.06.388
3. Langer, E. S.; Rader, R. A. Biopharmaceutical Manufacturing is Shifting to SUS. Are the Dinosaurs, the Large Stainless-Steel Facilities, Becoming Extinct? 

 online, Oct. 23, 2018.
4. Lim, J.; Cox, S.; Leveen, L.; Monge, M.; Sinclairm A. The Environmental Impact of Disposable Technologies. 

.
5. Single Use Support. Pioneering Biopharma. 

 (accessed Jan. 21, 2024).
6. Das, S. The Appeal of Single-use Tech. 

Ramesh Raju Mavuleti*, rrajum@gmail.com, is head of operations, Validation Services India; Subhasis Banerjee, PhD, is principal technical application expert, Bioprocessing APAC; and Tathagata Ray, is consultant, Global Strategy Deployment; all at Merck Life Sciences Pvt, Ltd.; K. Vasantakumar Pai, PhD , is professor and chairman, PG Department of studies & research in Industrial Chemistry, Kuvempu University; K. Sreedhara Ranganath Pai, PhD, is professor, epartment of Pharmacology, Manipal Academy of Higher Education; and Somasundaram Gopalakrishnan, is senior consultant, Global Biopharm Center of Excellence, Merck Pte. Ltd.

When referring to this article, please cite it as Mavuleti, R. R.; Pai, K. V.; Pai, K. S. R.; et al. Review of SUT Adoption in Biopharma Manufacturing. 

Pharmaceutical Technology Quality and Regulatory Sourcebook

The evolution of therapeutic modalities drives the adoption of single-use technologies.