Good Distribution Practice Is Evolving — Here's How

By Shalaka Purohit, founder and principal, Suveda Solutions LLC

Every pharmaceutical development program depends on the efficient, timely, and cost-effective transport of intermediates and finished products across the supply chain. This movement must preserve product integrity, ensure chain of custody, and comply with quality and regulatory guidelines from agencies such as the FDA and EMA — as well as with relevant interstate and international trade regulations. Logistics management lies at the heart of a robust supply chain strategy and is crucial to executing the interdependent and geographically disperse development activities across the entities involved.

Logistics management has three main focus areas:

• long-term storage,
• inventory management, and
• transportation.

Across the spectrum of pharmaceutical products, logistics management for biologics presents greater complexity due to the characteristics of the products and processes. Emerging new modalities within biologics, such as cell and gene therapy, pose even more unique challenges.

Regardless of organizational size, all sponsors face similar logistics management challenges and must comply with the same sets of standards and regulations while developing similar products. While larger organizations may have access to dedicated in-house departments handling all aspects of supply chain, including logistics, in smaller organizations, this responsibility often falls on scientists, technologists, and associates who are not trained on or familiar with the global trade, accounting, and commercial aspects involved. This lack of understanding can often lead to logistics management failures.

This article aims to provide an overview of the best practices for navigating the complexities of logistics management for globally dispersed supply chains, with a focus on biologics.

Complex Modalities Inherently Have Complicated Supply Chains

Advances in drug development continue to add diverse entities, such as peptides, nucleotides, antibodies, antibody-drug conjugates, stem cells, cell and gene therapy, etc., to the list of pharmaceuticals. The increasing number of biologics has complicated and globalized production supply chains. Rare and orphan disorders with sparse and dispersed patient populations have had a similar effect on clinical trial geographies. Good distribution practices (GDPs) guidance for biologics has rapidly evolved, eliciting a significant paradigm shift in the logistics management of pharmaceuticals.

Refrigerated, frozen, and ultra-low temperature storage and transportation, with the shortest possible transit times, across distant geographies are critical to maintaining product integrity for biologics.

This is a significant shift from the relatively thermostable synthetic small-molecule drugs, where controlled room temperatures and controlled humidity are adequate. The overall regulatory landscape is ever-evolving to keep pace with the diversity of biopharmaceutical products. A variety of regulatory bodies maintain oversight of pharmaceuticals and intermediates crossing international borders. Logistics management becomes increasingly complex due to the need for special permits, driven by the variety of host production systems and processes, and the challenges of navigating international import-export regulations.

Key Drivers Of A Logistics Management Plan

During development, numerous intermediates and finished goods are shipped to different destinations for further processing or end use. The characteristics of the materials, cross-border regulations, stakeholders, activities, and timelines in the context of the overall supply chain form the basis of the logistics management strategy.

The product

Maintaining the integrity, safety, and GMP or non-GMP status of the material being stored or transported is crucial. Storage temperature, relative humidity, and avoiding light exposure for photosensitive products are key considerations. The chemical or biohazard levels (BSL categories) dictate the requisite safety measures to be followed while shipping and handling. For example, live cells, tissues, blood, and blood products have heightened containment requirements to de-risk exposure hazards. While their stability and safety aspects are identical, GMP materials always carry higher documentation and compliance burden compared to their non-GMP counterparts for storage and shipment.

Third-party logistics providers

3PLs are valuable resources, especially for smaller companies. They provide the real estate and infrastructure to support storage, inventory management, and shipment support services while managing the compliance burden. Materials ranging from cell banks or histopathology samples to clinical supply intermediates can be stored. Multinational locations serve as hubs or depots to achieve efficiencies like shorter transit times to production nodes or reduced regulatory burden. Moreover, the exposure risk of critical inventory to catastrophic natural disasters or fire hazards, etc., can be significantly mitigated by splitting storage across multiple locations of a 3PL provider, thereby strengthening business continuity. Access to their inventory management systems enables sponsors to view real-time information, generate reports, support demand-supply and production planning, etc., without needing to invest in and maintain their own.

By providing access to multiple couriers, inventory management systems, and knowledgeable staff, these vendors can be a good substitute for an in-house logistics department.

Shipments

Planning any shipment involves consideration of the packaging requirements and transit times, as well as lead times for customs and other approvals for international shipments.

• Couriers: Pharmaceutical transportation is a vertical for commercial couriers such as DHL, FedEx, and UPS. However, there are a number of specialty couriers catering solely to the pharmaceutical industry, including World Courier, Biocair, Marken, Cardinal Health, etc., to name a few. Clinical distribution CMOs or CROs often harness these couriers’ global depots to close gaps within their own networks.
• Temperature-sensitive shipments: Maintenance of the cold chain is paramount to the product integrity of biologics, which dictates the use of qualified insulated shippers, coolants, and temperature monitors for these shipments. Qualified shippers are validated to maintain temperatures over a certain time, and one in the right size, qualified for the duration exceeding the transit time, should be selected. Blue ice (gel packs), dry ice (carbon dioxide based), and liquid nitrogen are coolants for refrigerated, frozen, and cryogenic shipments, respectively. With frozen shipments, a secondary containment for the primary containers (e.g., mylar bags) is advisable to prevent the ingress of carbon dioxide from the dry ice and a potential drop in pH of the product, which can lead to instability. Liquid nitrogen dewars are recommended for cell banks since they can hold the ultra-low temperatures for as long as 10 days, an expected transit and clearance time for international shipments. A temperature monitor is a key accessory for all temperature-controlled shipments to confirm that the cold chain remains intact from pickup to delivery. While measures should be taken to avoid false temperature excursions, having adequate stability data to adjudicate any excursions will minimize the quarantine-related delays or inability to utilize the material.
• Packaging: Couriers can provide qualified shippers in multiple dimensions to fit shipments of various sizes. Additionally, they can provide temperature monitors, blue and dry ice, LN2 dewars, and other accessories, eliminating the need for the sponsor to stock these items.
• Chain of custody: Tamper-evident seals ensure that the shipment contents are only accessed by authorized users. All couriers support tracking shipment progress from pickup to delivery via their portals. Digital monitoring technologies like RFID and telematics enable real-time tracking and oversight of the chain of custody. Digital proofs of delivery/receipt acknowledgements provide sustainable and easy record-keeping.
• Trade regulations, customs, and duties: For international shipments, obtaining customs preclearance from the destination country’s authorities, prior to consignment pickup, guarantees its clearance at the port of entry and smooth delivery to the recipient. Submission and review of a customs invoice before shipment facilitates this process. A typical invoice includes the shipper and consignee contact information, the list of contents, their cost for customs purposes, the Harmonized Tariff Schedule (HTS) code, responsibility for payment of duty, statements regarding the biological/chemical safety, freedom from pathogens, end use, etc.
• Permits, qualified persons, etc.: Depending on the product, its production host, end use, and the shipment’s origin and destination, various permits are often required for shipping biologics. Besides the pharmaceutical regulatory bodies, the U.S. Fish and Wildlife Service, CITES, and Australia’s BICON are examples of such permitting agencies. The permit application and review processes are complex, document-heavy, and lengthy. Permits may even be needed to transport materials across state lines within the country, and some place restrictions on quantities in individual shipments. Researching the permit requirements and the application process should be a key task, and lead times to obtain approval must be factored into the program timeline. Executing a “practice” shipment before the critical shipment reduces the risk of failure and delays. For clinical trials in geographies requiring qualified person (QP) release, the long lead times and careful coordination across multiple stakeholders must be taken into account when forecasting first patient in (FPI).

Biopharma Supply Chain’s Complexity Can Create Weak Links

Biologics, biosimilars, and personalized medicine products are comprising a larger percentage of pharmaceutical products. Supply chains are getting increasingly complex and global. A typical development life cycle is several years long. Changes in the political, economic, and trade regulation landscapes over such a period are inevitable and significantly influence the supply chain. These changes are hard, if not impossible, to predict. Logistics management plans need to pivot, adapt, and keep pace with these changes while remaining cost-efficient and fail-safe.

Even the most seasoned logistics professional must conduct their research across multiple sources of information for the interpretation and application/enforcement of regulatory or trade guidelines. There are many nuances and exceptions to the applicability of certain regulations, to the specific product type or production host, etc., and one often needs to rely on their own assessment regarding the same. This makes the outcomes of the review of applications and the granting of pre-clearances and permits vulnerable to uncertainties and delays.

The chance of acute natural disasters is another factor that increases the exposure risk for stored or in-transit inventory. Maintaining additional inventory/cargo insurance is highly recommended to mitigate this risk, at least from a financial perspective.

Conclusion

Logistics management and its complexities should be a key consideration in the selection of contract service providers and their locations. Production of cell banks (biopharma), drug substances, drug products, and clinical and commercial supply are all interdependent and require shipping and delivery from one node to the next. Delivery failures of input materials to the next production node due to poor logistics management can lead to missed production slots, hefty cancelation costs, significant delays, and missed milestones, proving detrimental to the success of the overall program. This domino effect underscores the importance of achieving “near zero-failure” rates while managing logistics throughout the product life cycle, from development to commercialization.

Transportation lead times, storage and shipping costs, and applicable compliance burden are all aspects of logistics management that heavily influence the overall program timeline and budgets. Logistics management comprises over 10% of the overall drug development costs. These costs are even higher for biopharmaceuticals and any products requiring a cold chain and global distribution. As an example, a study by Applied Clinical Trials found that courier and depot costs alone accounted for 49% of clinical supply logistics spending.

For small or virtual companies with limited technical staff, engaging 3PL providers, specialty couriers with a proven track record for cold chain management, supply chain consultants who can support advance planning for customs, permits, and other regulatory clearances can level the playing field (at least for logistics management) with larger corporations.

About The Author:

Shalaka Purohit is the founder and principal at Suveda Solutions LLC. Her areas of expertise include CMC strategy, technology transfer, process scale-up, program road map development, resourcing, supply chain, compliance and alliance, program, and risk management. She has more than 28 years of diverse industry experience in the bioprocess and product development space spanning biopharmaceuticals, industrial biotech, and biofuels, bringing a holistic perspective to the projects she consults on. Her clients include virtual to midsize biotech companies developing pharmaceuticals in various phases of development, from incubation to late-stage clinical. She has worked on a variety of therapeutics ranging from antibodies to vaccines, including an approved COVID vaccine. Connect with her on LinkedIn.