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Why A Closed-Loop Supply Chain System?
Category: Supply Chain Management | 12/01/2012 - 06:15:43
Improving compliance and efficiency in the pharmaceutical supply chain with reduced cost and risk
Handling and Storage of Investigational Products
The International Conference on Harmonization's (ICH) Topic E6 entitled "Good Clinical Practice: Consolidated Guidance" is a commonly referenced industry document that has gained regulatory acceptance in the EU, Japan and the United States. Section 5.14.3 states that "the sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The procedure should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s)".
Although this regulation is aimed at enhancing GCP at the investigator level, the reality is that most of these functions are executed by, or in conjunction with, third parties - transport, storage and delivery personnel who are, in most cases, untrained in pharmaceutical standards. When taking into consideration that as many as 40% of all clinical trials are now conducted in emerging nations in Asia, Latin America and Africa, most IMP travels thousands of miles over extended periods of time under the guardianship of non-pharmaceutical personnel before arriving at individual research sites. How does the sponsor ensure that product transfer conforms to the same established written procedures demanded at the investigator level throughout the full length of the supply chain, or more specifically while in the hands of non-pharmaceutical, non-investigator personnel?
While these third parties are perforce governed by general GMP directives and specific GSP/GDP guidelines such as from WHO (WHO technical report series no. 957/2010 and no. 961/2011), IMB (Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances/2011), Health Canada (Guidelines for Temperature Control of Drug Products during Storage and Transportation/2011) as well as from PDA (Technical Report 052/2011), the cornerstone of clinical research rests on the assumption that the IMP arriving at the investigator site meets all legitimate product specifications. Is that, however, a fair assumption? How can this assumption be tested, corroborated, and more importantly, be transformed from conjecture into fact? Adding to the urgency is today's increased focus on ICH Q9 which calls for more formalized Quality Risk Management (QRM) assessments and decision-making to ensure that long-term product quality remains consistent with key product attributes in evidence during the clinical study. Clearly the need to proactively protect the integrity of clinical products that will ultimately function as quality benchmarks has never been more critical, particularly in the face of the growing complexity and scope of risks precipitated by distant study locales.
Closed-Loop Supply Chains
Achieving More Stringent External Compliance
Choosing a logistics supplier that operates a high-quality closed-loop clinical supply chain system ensures that all critical functions outlined in the ICH guidelines - transport and reception of clinical product in-country, its handling and storage, the preparation of patient kits for individual sites, their subsequent distribution, and the documentation and management of returned drugs - are performed by the same service provider from origin right through to destination in keeping with verifiable, global SOPs.
This type of all-inclusive service offering can significantly reduce the cost, and inconvenience of dealing with multiple suppliers and effectively eliminate many of the miscommunications, technical errors and conflicting SOPs that are inherent in the hand-off of product between numerous third parties. By offering a full series of complementary services, the closed-loop supply chain provider is better able to deliver customized options that address the sponsor's unique situation without needing to "sell" a specific type of service or make the difficult choice between a sale and the best interests of the customer. The following example illustrates.
One Supplier vs Multiple Suppliers
An international pharmaceutical company is planning a Phase III cancer study in China. The duration of the study is 12 months. Eight in-country sites will participate. The investigational drugs must be maintained within a temperature range of +2oC to +8oC. Each site will receive one shipment per month. The sponsor is considering three different suppliers to provide services. The first (Company A) is an international transportation company. The second (Company B) is a pharmaceutical warehousing company in China capable of storing investigational drugs in-country and arranging for local distribution. The third (Company C) is a closed-loop logistics company able to offer a suite of fully-integrated supply chain services.
True to its organizational capabilities, Company A quotes on a "direct-to-site" solution, proposing that one consignment be shipped to each investigator site each month - 96 shipments in all (8 sites x 12 months). Operationally, each shipment must be consigned directly to the ultimate recipient (the lab or hospital administering that part of the trial), necessitating an individual import permit and separate customs clearance for each shipment - a costly and laborious procedure for the clinical team that can result in indeterminate delays if paperwork is imprecise or incomplete. Should delays prove significant, temperature- controlled mediums can conceivably fail, compromising product quality. In other instances, delays may result in shipments arriving too late to be of use, resulting in missed dosing schedules. With no benefits to be derived from consolidation, this is arguably the most expensive and least effective transport solution. It is based on an old, just-in-time distribution model that pre-dates the advent of local temperature-controlled storage facilities and requires service roll-out that runs like clockwork to avoid unnecessary delays or storage at the investigational site.
In keeping with its business model, Company B proposes an in-country warehousing option that will significantly reduce the number of shipments in transit and with it, the risk for clearance delays. It is proposed that a three-month supply of investigational drug for each site be forwarded to the Chinese warehouse on a quarterly basis, or the equivalent of 24 direct-to-site shipments (8 sites x 3 months). In all, then, just four larger batch shipments will be dispatched during the course of the year-long study. Since the investigational drugs will be centrally stockpiled for in-country distribution, the sponsor will enjoy more flexibility in managing the shipping timeline. Shipments can be sent with enough lead-time to manage any potential customs delays, resulting in less opportunity for missed dosings at the local level. At the same time, the clinical team will significantly reduce the amount of time spent preparing paperwork and import permit applications, and monitoring individual shipments. Transportation costs would also drop significantly, given the greatly reduced number of shipments (four versus 96).
Because Company B cannot execute the physical in-country distribution, however, a new local supplier must now enter the mix. Will a single supplier handle all eight shipments/sites, or will eight suppliers each handle one? Does/do the local supplier(s) conform with internationally accepted SOPs governing the transport of pharmaceutical products used in clinical trials? Are the local transport providers' SOPs in sync with those of the warehousing company? Who will design, prepare and provide the temperature-controlled packaging - warehouser or transporter? Who is responsible for packing and labeling the shipments? Who will the sponsor or CRO contact if an investigator site does not receive a shipment as planned or if temperatures fall out of specification? Who will assume ultimate responsibility if miscommunications occur, if temperature control fails, or it the product is unusable? A request for the return/destruction of unused medications and supplies creates an equally clumsy, cumbersome and time-consuming process that remains largely devoid of a clear chain of custody. While the simple warehousing solution clearly reconciles many of the inherent transport difficulties that can occur with direct-to-site routings, it also raises many new questions and with them, the potential for conflicting SOPs, human or technical error, and miscommunication.
The final provider, Company C, offers a fully-integrated closed-loop supply chain system that is able to deliver all required services from origin to destination: international transport (including packaging and clearance), local storage in certified facilities, in-country distribution according to a pre-determined schedule, the expediting of emergency shipments and return / destruction capabilities if required - all performed by the same service provider and linked by a single online data system.
By selecting Company C's local warehousing solution, the sponsor enjoys the same economies of scale as outlined above, achieved by shipping four large batch shipments instead of multiple (96) direct-to-site shipments. Transport costs are significantly reduced, but more importantly, so is the manpower expended by the clinical team not only in the preparation of import/export paperwork, but in qualifying third-party vendors, coordinating the hand-off between suppliers, monitoring shipments, and resolving queries and problems that inevitably arise when multiple providers are involved. At the same time, the sponsor also benefits from superior quality assurance and product control including in-country inventory management and a vastly improved chain of custody that can be managed through a single contact or access point. Remedial actions can be anticipated and expedited (i.e. rectifying an inventory shortage by dispatching an emergency replacement shipment) with the ultimate objective of streamlining the clinical trial process, and ensuring that in-spec products and materials are where they should be when needed.