Introduction: The Ins and Outs of Market Demand

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From transport and holding of bulk drug substance to shipping, warehousing, tracking, and distribution of final packaged drug products, biopharmaceutical supply chain logistics can be described as an industry in itself. And that’s just one side of the story. Even though much of the work of establishing and maintaining supply chains might happen outside the manufacturing environment, all organizations that develop processes and final products depend on having the raw materials and available components and resources to do their work.

A biopharmaceutical company’s “upstream” supply chain can be diverse, including everything from plastic components and the bioreactors they are used in, to cells, buffers, filters, columns, media, and more. All supplies must be subject to qualified procurement practices as determined and overseen by myriad departments and project managers. Sponsors of marketed products must ensure that they have adequate supplies of a consistent quality of all equipment and materials needed for each product — a true challenge for companies with diverse product portfolios and for contract development and manufacturing organizations (CDMOs) working with products from multiple clients. Raw materials must be available in quantities that will be sufficient for their use where and when they will be needed — but not so much that they waste valuable storage space.

When biopharmaceutical materials — both “upstream” (that is, on the raw materials side) and “downstream” (final products) — must be stored for a time or transported elsewhere, such as to a testing laboratory or manufacturing/distribution facility, environmental conditions must be monitored during transport. These and other logistical elements are critical throughout biopharmaceutical development and manufacturing, and they continue to support a product and the patients who depend on its uninterrupted supply throughout its lifetime and theirs.

Key issues in securing a supply chain include managing costs and consistent quality at development and eventual manufacturing scales, monitoring safety and quality issues for materials used in drug formulations (to prevent adverse patient reactions), knowing what level of quality is needed at what stage for different types of products (a means of controlling costs), ensuring that suppliers provide needed documentation (including having a change-notification process in place), understanding good manufacturing practices (GMPs) and other applicable standards based on a product’s intended use, ensuring traceability of materials, and identifying reliable suppliers (often across borders and regulatory agencies) (1). When it comes to final products, their protection from harm becomes paramount — driven by the needs of patients as well as the value of the products themselves. Important aspects include serialization, tracking and tracing, temperature/humidity control, timing and shipping methods, and even anticounterfeiting efforts.

Industry forces shaping today’s supply-chain management are much the same as those currently transforming other departments (and the biopharmaceutical industry as a whole). Supply-chain managers face

Additionally, most biopharmaceutical formulations must be stored in colder conditions than room temperature, and such key environmental parameters must be maintained throughout shipment and storage at distribution warehouses, pharmacies, and clinics. And the complexity of the supply chain increases for emerging therapies (especially cell/tissue therapies), personalized formulations, and multiproduct manufacturing. Maintaining the necessary storage conditions for drugs with differing environmental needs can place a strain on inventory management.

Two Sides to the Story
BPI’s May 2017 special issue and extended eBook outlined these key points and followed the evolution of supply-chain logistics through a chronological review of BPI articles from 2003 to 2017 (2). We looked at the “ins” of procurement on the upstream side, specific to intake of raw materials and equipment; and the “outs” on the downstream side, specific to final product distribution. For this featured report, we’ve chosen two articles that illustrate how manufacturers of biotherapeutics are addressing specific challenges on each side of the supply chain.

In “Standardizing Human MSCs As Critical Raw Materials in Cell therapy Products: Streamlining Clinical Translation,” Majumder, Olson, and Rowley address what industry analysts have feared would be a major impediment to the success of cell therapies at manufacturing scales: the difficulty of producing the predicted trillions of cells needed for such therapies while (critically) reducing the final costs borne by patients and insurers. Their company, RoosterBio, seeks to disrupt this industry segment by making cells readily available to developers for expansion into multiple product types and classes, thereby eliminating a large portion of the costs of sourcing and internal development. In BPI’s main issue this month, a complementary article details how RoosterBio developed its platform technology.

In “Spray Freeze-Drying Technology: Enabling Flexibility of Supply Chain and Drug-Product Presentation for Biologics,” Lowe, Mehta, and Gupta describe Biogen’s strategy to alleviate risks associated with the need for a complex cold-chain infrastructure by manufacturing biopharmaceutical drug substances as bulk powders. Through a new alternative to the old standby procedure of lyophilization (spray freeze-drying), the potential for long-term, room-temperature stability in dry-powder form could facilitate commercial manufacturing, especially into developing markets.

A Functional Framework
Just a look through titles of supply-chain articles in BPI’s archive (see “For Further Reading,” below) reveals the complexity of supply chain development, maintenance, and security. Whether through cold-chain development and storage, data management, risk assessments, business impacts, quality issues, distribution, particulate control in raw materials, change-control management, and other key components, in parallel with the maturation of the biopharmaceutical industry, those who oversee supply chains also are hoping to work faster, increase safety, and (if possible) decrease the costs of biopharmaceutical medicines. From procurement and quality control of raw materials to distribution and safety of final products, the supply chain provides a framework within which process development, manufacturing, testing, and sales of biopharmaceuticals can function.

References
1 Hager R. The Global Cold Chain. BioProcess Int. 10(10) 2012: 24–28, 65; https://bioprocessintl.com/business/pre-clinical-and-clinical-trials/the-global-cold-chain-337115/

2 Montgomery SA. The Supply-Chain Management Perspective: Managing Risks and Guarding Against Disruption. BioProcess Int. 15(6) 2017;

For Further Reading: From The BPI Archives
Ask the Expert. Secondary Packaging: Creating Value with Product Lifecycle Management. Vetter (white paper); https://bioprocessintl.com/sponsored-content/secondary-packaging-creating-value-with-product-lifecycle-management/

Beck G, et al, Raw Material Control Strategies for Bioprocesses. BioProcess Int. 7(8) 2009: 18–29.

Cappia J-M, et al. Outsourcing to Enhance Assurance of Supply: Application of Counterintuitive Supply Chain Strategies — A Case Study. BioProcess Int. 14(5)s 2016: 20–23.

Cappia, J-M, et al. Enhanced Assurance of Supply for Single-Use Bags: Based on Material Science, Quality By Design, and Partnership with Suppliers. BioProcess Int. 12(8) s 2014: 43–26.

Davidson S. Risk Assessment and Business Impact Analysis of the Supply Chain: A Cautionary Tale in Contingency Planning. BioProcess Int. 11(1) 2013: 12–17.

de Boer E. Optimizing Vaccine Supply Chains Through Quality Management in Manufacturing. BioProcess Int. 6(10) 2008: 38–40.

Forgione P. Data Management in the Supply Chain. BioProcess Int. 10(9) 2008: 20–26.

Isom E. Requirements for Outsourced Cold Chain Logistics and Storage in Biopharmaceutical Development. BioProcess Int. 9(8) 2006: 48–50.

Jagschies G, Westman D, Raw D. Supply Chain Challenges in the Biopharmaceutical Industry: A Case Study Following the 2011 Tsunami in Japan. BioProcess Int.12(8) 2014: 18 –22, 73.

Johnston R. Reconsidering the Supply Chain. BioProcess Int. 6(5) 2008: 72.

Kapp T. Regulatory Compliance in Single-Use BioManufacturing Facilities Requires a Collaborative Approach with your Supply Chain; https://bioprocessintl.com/bpi-theater/regulatory-compliance-single-use-biomanufacturing-facilities-requires-collaborative-approach-supply-chain/

Masser D, Chandarana N. Controlling Particulates Through a Supply Chain; https://bioprocessintl.com/bpi-theater/controlling-particulate-through-a-supply-chain/

Mattuschka J, Santa-Maria V. A Critical Mission: Clinical Trial Material Storage and Distribution. BioProcess Int. 12(8) 2014: 12–17.

Mattuschka J. Clinical Supply Chain: A FourDimensional Mission. BioProcess Int. 14(3) 2016: 16–17. https://bioprocessintl.com/bpi-theater/controlling-particulate-through-a-supply-chain/

Noferi JF, Dillon RL. Defending the Supply Chain: Lessons from Sun Tzu. BioProcess Int. 7(1) 2009 10–17.

Priebe P. Innovative Raw Material Management and Product Design Strategy for Enhanced Quality, Assurance of Supply, Validation, and Change Control of Single-Use Systems (Video); https://bioprocessintl.com/sponsored-content/innovative-raw-material-management-and-product-design-strategy-for-enhanced-quality-assurance-of-supply-validation-and-change-control-of-single-use-systems/

Shimoni Y, et al. Viral Risk Evaluation of Raw Materials Used in Biopharmaceutical Production. BioProcess Int. 14(9) 2016: 22–30.

Shimoni Y, Srinivasan V, von Gruchalla-Wesierski M. A Risk-Based Approach to Supplier and Raw Materials Management. BioProcess Int. 13(10) 2015: 10–15.

Toro A, et al. Setting Raw-Material Specifications Using Prediction Models: Determination of a Specification Limit for a Raw-Material Impurity in mPEG-Aldehyde. BioProcess Int. 15(1) 2017: 40–43.

Ward M. Addressing Variability in Product Labeling: Explore Dynamic Labeling for Your Global Enterprise. BioProcess Int.14(4) 2016: 76.

Wisher M. Virus Risk Mitigation for Raw Materials: A European Perspective. BioProcess Int. 11(9) 2013: 12–15, 39.

Relevant Guidance Documents
ICH Q11. Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities);  https://www.ich.org/products/guidelines/quality/quality-single/article/development-and-manufacture-of-drug-substances-chemical-entities-and-biotechnologicalbiological-en.html

Guidelines of 5 November: Good Distribution Practice of Medicinal Products for Human Use. Off. J. European Un. 3 November 2013: www.girp.eu/sites/default/files/documents/european_good_distribution_practice_guidelines_5_november_2013.pdf

Guideline on the Use of Bovine Serum in the Manufacture of Human Biological Medicinal Products. EMA/CHMP/BWP/457920/2012 rev. 1;   https://www.ema.europa.eu/documents/scientific-guideline/guideline-use-bovine-serum-manufacture-human-biological-medicinal-products_en.pdf

Guideline on the Use of Porcine Trypsin Used in the Manufacture of Human Biological Medicinal Products. EMA/CHMP/ BWP/814397/2011;  https://www.ema.europa.eu/documents/scientific-guideline/guideline-use-porcine-trypsin-used-manufacture-human-biological-medicinal-products_en.pdf

Note for Guidance on Virus Validation Studies: The Design, Contribution, and Interpretation of Studies Validating the Inactivation and Removal of Viruses. EMA/CPMP/BWP/208/95; https://www.ema.europa.eu/documents/scientific-guideline/note-guidance-virus-validation-studies-design-contribution-interpretation-studies-validating_en.pdf

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use (2004);  https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2016_161/reg_2016_161_en.pdf

Falisified Medicines. EU Medicinal Products for Human Use. European Commission;  https://ec.europa.eu/health/human-use/falsified_medicines_en

S. Anne Montgomery is cofounder and editor in chief of BioProcess International; [email protected].