Exciting progress is being made in the development of consensus in best practice recommendations and standardization guides for single-use disposable technologies, facilitating implementation, quality, and safety. These industry efforts include the Parenteral Drug Association’s (PDA) forthcoming new technical report; the BioProcess Systems Alliance’s (BPSA) new single-use guides; and in collaboration with the BioPhorum Operators Group (BPOG) and the American Society for Mechanical Engineering-BioProcess Equipment Committee (ASME-BPE), BPSA’s constructive discussions towards standardizing supplier extractables test data for single-use components.
New PDA Single-use Technical Report
PDA’s Technical Report on Single-Use System Manufacturing Strategy is currently pending for final approval by PDA’s Scientific Advisory Board (1). This extensive guide, to be published by PDA in 2014, provides extensive recommendations on how to consider and adopt single-use technologies. These recommendations are written by a broad panel of industry experts from end-user and single-use equipment supplier companies, as well as regulators and consultants. The goal of this document is not to be prescriptive, but rather to provide an understanding of key principles and concepts for selection, qualification, validation, and use of single-use technologies. It should serve to better enable people at various levels in an organization to ask the right questions and make better decisions for their individual situations. Organizations will be able to draw an effective road map to single-use implementation that suits them best, regardless of whether they are small or large, dedicated or multi-product, or contract manufacturers.
The manufacturing strategies section covers variables including process compatibility, facility requirements, and operational considerations. The business drivers section covers capital design, fixed and variable operating costs, and other factors. The qualification section includes recommendations on supplier qualification; verification of materials, components and completed assemblies, including extractables and leachables issues; risk evaluation (i.e., balancing pro and cons for multi-use and single-use systems); microbial control and sterilization; system process validation; filter integrity and leak testing; installation qualification and acceptance tests; and supplier audits. The implementation section introduces themes of stakeholder management, technical feasibility and risk management, scoping and technology survey, making the business case, and a project execution plan including user requirements. Once these are established, recommendations are provided for approaches to testing and validation, process control strategies, integration considerations (e.g., facility, equipment, and operational deployment), operator training and safety, supplier agreements, technical diligence, materials management, logistics practices, and waste management.
BPSA Single-Use Particulates Guide
BPSA has also been active in preparing new best-practice guides. A key topic of discussion at the 2013 BPSA International Single-Use Summit (ISUS) was the concern for particles in SUS flow paths, especially those without inline filtration, as employed for non-filter sterilizable vaccines manufactured under aseptic sterile conditions, or simply downstream of sterilizing filters in single-use systems designed for filling of bulk or final dosage protein biopharmaceuticals and vaccines.
To address these concerns and provide users and system suppliers with best practices to minimize risks of particles from the systems potentially reaching final dosages, BPSA has developed Recommendations for Control, Testing and Evaluation of Particulates in Single-Use Process Equipment (2). This document, developed jointly by technical and engineering representatives of user and supplier member companies, contains major sections on risks of particles, characterization and sources of particles in single-use technologies, chain of responsibility, measurement methods, and visual inspection (surveillance) programs. Also included are major sections on recommended methods for suppliers to control introduction of particles, best practices for handling single-use components to minimize risk of particulate generation, evaluation of single-use containers and filling systems for particulates during end-user manufacturing, and recommendations for developing a particulate deviation response and mitigation plan.
The BPSA document will be of interest to vaccine manufacturers and final filling operators employing single-use disposable filling technologies. It will be published in July 2014 in coordination with the BPSA International Single-Use Summit annual meeting. It will also be made available via the BPSA website, www.bpsalliance.org.
BPSA Single-Use Component Quality Test Reference Matrices
BPSA’s first best practices guide for single-use equipment, the BioProcess Systems Alliance Component Quality Test Matrices, published in 2007, provided a supplier consensus of standards, regulatory guidance documents, and industry guides applied in the manufacture of single-use components for qualification, validation, and quality control to ensure product quality and performance claims, consistent with requirements of the biopharmaceutical industry (3). The document was divided into four sections for biocontainers, tubing, connectors, and filters.
In the ensuing years, the industry has been well served with this easy-to-use reference guide to supplier component quality testing. In the ensuing years, however, many newcomers to the field have been unaware of it, some new references have come to be implemented, and new components have come into broader use, that were not considered in the original document, namely single-use (or campaign) chromatography modules and single-use sensors for bioreactors and other systems.
The newly updated and expanded BPSA Single-Use Manufacturing Component Quality Test Matrices will be published in July 2014 in coordination with the BPSA International Single-Use Summit annual meeting (4). It will be made available via the BPSA website, www.bpsalliance.org.
BPSA Single-use Equipment Quality Agreement Template
BPSA has recognized a need among end-users and suppliers for a common template for quality agreements. End-users have been challenged to herd a variety of single-use component and system suppliers to agree to common requirements, or to managing different agreements among multiple suppliers. Likewise, suppliers engage in quality agreement discussions with end-users, many of whom have disparate sets of requests and requirements. This challenges suppliers to manage differing requirements and agreements among multiple customers, and often, instead, acts as a barrier to the establishment of effective quality agreements.
The forthcoming BPSA Consensus Quality Agreement Template for Single-Use Bio/pharmaceutical Manufacturing Products is intended to provide a common structure for quality agreements between suppliers and end-users of single-use products (5). The template is not intended to substitute for close dialog and negotiation between the two parties, but rather, it will hopefully serve to facilitate that discussion by providing a common structure to follow. The template’s content will better enable end-users to communicate specific expectations and for suppliers to communicate the attributes of their quality system and operating procedures, more readily providing the content for the final quality agreement between the two parties.
As a template, the document does not proscribe all activities and specify provisions. These still have to be negotiated between the parties to establish an effective agreement. There are areas where the template is left intentionally blank for the supplier and end-user co-authors to propose, negotiate, and either discard, change, or complete to establish a final agreement. The template should support the process, however, and facilitate the establishment of quality agreements to build the partnership and transparency needed for successful implementation of single-use technologies. As with the BPSA Particulates Recommendations and Component Quality Test Reference Matrices, the BPSA Quality Agreement Template will also be published in July 2014 in coordination with the BPSA ISUS annual meeting and it also will be made available from the BPSA website, www.bpsalliance.org.
Progress towards Extractables Standardization
Early in 2013, the extractables committee of the BioPhorum Operators Group (BPOG), a consortium of end-user companies, released a proposal for standardized extractables testing and analysis it would like to see provided by single-use component suppliers (6). While suppliers recognized the benefit to end-users of standardized component extractables data packages, especially in terms of extraction sample size, solvents, and conditions, extraction temperatures and times, analytical methods and data presentation, there was also objection by suppliers to some of the test requirements and rationales, and the overall extent of testing proposed, which would demand extensive resources and time commitments. Supplier responses were consolidated by BPSA, and after meeting with BPOG representatives at the July 2013 BPSA ISUS meeting, negotiation between the two groups began in Autumn 2013 to harmonize a consensus proposal that could be submitted to a standards body such as ASTM. Negotiations have proceeded over the winter, and much has been agreed to, especially in regard to many of the extraction conditions and analytic methods. At time of this writing, it is hoped that a document that recognizes both the interests of end users (and regulators) and the resources of suppliers can be brought to consensus by the July 2014 BPSA ISUS meeting.
Other organizations are also looking at developing extractables testing standards. The United States Pharmacopeia (USP) has proposed a new section to its standards Chapter <661> on Plastic Containers currently under revision. A sub-chapter <661.3>, Plastic Systems Used for Manufacturing Pharmaceutical Products (differentiated from Sub-chapter 661.2 on Plastic Packaging Systems for Pharmaceutical Use), is currently on hold pending draft revisions of subchapters 661.1 and 661.2, along with evaluation of an ultimate BPOG/BPSA consensus proposal (7). Independently, ASME-BPE has approved an expansion of their Bioprocess Equipment Standard Part PM, Polymeric and Other Nonmetallic Materials, section PM 3.2 on Extractables and Leachables, which will be published at the end of this year (8). The ASME-BPE Standard Extractables and Leachables section 3.2 covers key concepts and includes a non-mandatory appendix suggesting possible extraction solvents. These general recommendations are useful in principle, but do not achieve the degree of supplier extractables data standardization proposed by the BPOG Extractables Committee. There will be more to come in this area, but real progress toward the standardization of supplier extractables data packages desired by end-users is being made. These efforts will ultimately serve to reduce a perceived barrier to further implementation of single-use technology.
1. PDA, Technical Report on Single-use System Manufacturing Strategy (DRAFT), publication pending Spring/Summer 2014, accessed Apr. 4, 2014.
2. BPSA, Recommendations for Control, Testing and Evaluation of Particulates in Single-Use Process Equipment (DRAFT), publication pending Summer 2014, accessed Apr. 4, 2014.
3. BPSA, Bioprocess System Alliance Component Quality Test Matrices, BioProcess International, April-May 2007, accessed Apr. 4, 2014.
4. BPSA, Single-use Manufacturing Component Quality Test Matrices (DRAFT), publication pending Summer 2014, accessed Apr. 4, 2014.
5. BPSA, Consensus Quality Agreement Template for Single-Use Bio/pharmaceutical Manufacturing Products (DRAFT), publication pending Summer 2014, accessed Apr. 4, 2014.
6. Wong, K., “Extractable Protocol Standardisation Efforts for Disposable Systems from BPOG Working Group,” Biopharma Asia, Jan. 27th, 2014.
7. USP, Chapter <661> “Plastic Packaging Systems And Their Materials of Construction” (DRAFT), Pharmacopeial Forum, 39(5), Sept.-Oct. 2013
8. ASME, Bioprocess Equipment Standard Part PM, Polymeric and Other Nonmetallic Materials, section PM 3.2 on Extractables and Leachables (DRAFT), publication pending Fall 2014.
About the Author
Jerold Martin is Sr. VP Global Scientific Affairs at Pall Life Sciences, Port Washington, NY and Chairman of the Board, Technology Committee Bio-Process Systems Alliance, 1.516.801.9086, [email protected]