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This innovative method increases flexibility, saves money, and supports the Critical Path Initiative.
With the increasing number of patient-specific and genetically based medications being developed and the globalization of clinical trials, pharmaceutical and biotechnology companies are facing greater pressures to increase efficiencies in clinical trial material (CTM) management. In particular, there is growing demand on clinical supplies teams to minimize CTM repackaging or overage, shorten packaging and labeling timelines, have the flexibility to customize supplies, and reduce the overall costs associated with CTM management. Oftentimes, these demands are implicit even in situations where significant last-minute protocol changes that affect CTM have been made—including changes in number of patients, sites, locations, duration of treatment, and dose regimen.
Photography: Comstock Illustration: Paul A. Belci
Traditional packaging and labeling methods involve the mass preparation of clinical supplies for a clinical trial. They require long lead times (six–ten weeks) and offer little flexibility: If a study change that affects supplies is made, or if forecasted amounts differ greatly from actual needed amounts, traditional methods result in CTM overage and waste, or costly overlabeling or relabeling efforts.1 Yet, the traditional methods have been accepted as the standard for many years due to the lack of better alternatives and the general acceptance of current systems as "good enough."
In this article, a new solution called "on-demand packaging and labeling" is introduced. This strategy offers a high degree of flexibility, permits the shortest possible timelines for packaging and labeling CTM, and helps reduce costs in the clinical supply chain.
On-demand packaging and labeling is the packaging and labeling of CTM for a specific subject or block of subjects, upon request. This is a significant departure from traditional packaging and labeling in that clinical supplies are made immediately prior to each specific shipment, instead of being prepared en masse prior to the first shipment.
A preproduction batch record listing step-by-step instructions is prepared and approved prior to executing the packaging and labeling operation. As supplies are requested, they are pulled from the stock inventory and packaged and labeled. The execution of each packaging and labeling step is documented in a postproduction batch record in which each packaged unit is treated as a batch. A qualified reviewer reconciles the labels and components of each packaged unit, and releases the product for clinical use. Assuming that label text has been approved and bulk drug product has been released, the typical lead time for on-demand packaging and labeling is two–three weeks.
The controls for on-demand packaging and labeling of clinical trial material are specified in the current Good Manufacturing Practices (cGMP, 21 CFR 211). As with traditional packaging and labeling, there must be written procedures in place for the receipt, storage, handling, and sampling of all materials and labels before, during, and after the packaging and labeling process, as well as for label issuance and inspection. Steps taken to ensure room clearance, product identification, and prevention of mix-ups are likewise described in procedures to preclude mislabeling errors (cGMP, 21 CFR 211.130). Additionally, specific instructions for the issuance, control, and reconciliation of labels used in the packaging process must be written and followed (cGMP, 21 CFR 211.125). Finally, as mentioned above, approved preproduction batch records are used to guide the process, and postproduction batch records are approved prior to the release of materials.
On-demand and traditional packaging and labeling share many fundamental traits—both require adherence to GMPs and approved pre- and postproduction batch records. However, some key differences set these two strategies apart.
Because supplies are prepared only as needed with on-demand packaging and labeling, study changes affecting clinical supplies (such as changes in dosage regimen, label text, packaging design, number of sites, patient enrollment, expiration/re-assay date) may be implemented almost immediately, thus allowing great flexibility. The preproduction batch record has to be revised and approved, any label changes must be made and approved, and then the CTM is ready to be packaged and labeled in the new configuration as it is requested. By postponing the labeling of supplies until material is requested, one can increase the flexibility of the CTM inventory to meet the changing needs of clinical development.
With traditional packaging and labeling, study changes just before or during a study often cause significant delays and costs. In addition to the need to create and approve a new preproduction batch record and revise and approve any label changes, all of the unused CTM has to be repackaged and/or relabeled, and released by a quality unit before it can be distributed.
With traditional packaging and labeling, bulk drug is allocated to particular studies and then packaged and labeled for the studies. With on-demand packaging and labeling, bulk inventory is stored at the packaging and labeling site and can be packaged and labeled on demand for multiple studies, thus resulting in highly customizable CTM. The need to forecast the quantity of bulk drug to be packaged and the errors associated with this forecasting are eliminated. Forecasted overages for CTM are typically 50%–200%; eliminating this overage results in a significant benefit for study drugs in short supply, and for drugs and comparators that are expensive.
The lead time for on-demand packaging and labeling includes time to set up the packaging and labeling area, perform the packaging and labeling operation, review the batch records, and release the material for distribution. For traditional packaging and labeling, the lead time includes the same items, but the average run involves many more kits, which must fit into a production schedule. Thus, the production timeline is longer, and if other packaging runs have been scheduled production can be delayed significantly.
The typical lead time for having clinical supplies ready for distribution is two–eight weeks shorter for on-demand packaging and labeling than for traditional packaging and labeling. The shorter initial lead time helps the clinical team meet the milestone of first patient enrolled sooner and allows faster responses to changes that affect clinical supplies. When clinical supplies are requested by a site, on-demand packaging and labeling may require one–two days to prepare and ship depending on the quantities needed. Traditional methods, on the other hand, theoretically allow immediate processing of a shipment request. However, in traditional methods, the shipping department usually requires a lead time of one–two days to actually ship the CTM. Thus, the timeline for shipping CTM via on demand is comparable to that for shipping in traditional packaging and labeling.
On-demand packaging and labeling strategies can result in significantly reduced costs compared to traditional packaging and labeling. Overall clinical supply needs are reduced with on-demand strategies because CTM may be allocated to studies as needed, rather than being committed to studies in large quantities at the onset of a clinical trial. In situations where bulk drug is scarce or expensive to manufacture, or a required comparator drug is expensive, great cost savings can be achieved by this more efficient and conservative allocation. In addition, significantly less waste is generated with on-demand packaging and labeling because packaged supply overages are not required. Only CTM requested for shipment by the clinical group is packaged and labeled.
Cost savings are also realized in storage. Less bulk material needs to be stored, and clinical supplies that have not been packaged take up significantly less space than their packaged counterparts. Hence, on-demand packaging and labeling results in significantly lower storage costs, especially for companies conducting a large clinical trial or multiple clinical trials.
Finally, for on-demand studies that are changed significantly or stopped mid-stream, only the CTM that was distributed is lost —the rest remains unpackaged and unlabeled in inventory and can be packaged and labeled in another configuration for the same or a different study. With traditionally packaged and labeled CTM, the entire supply remaining at the distribution warehouse would have to be repackaged and relabeled, or discarded—an expensive outcome.
Several variations in the on-demand packaging and labeling strategy may be used to optimize the process. Labels may be printed on demand rather than being preprinted en masse. This strategy increases the flexibility of the packaging and labeling process because any changes needed to the label text can be implemented quickly. It also facilitates the use of labels containing variable text, for example, site information and patient-specific information. This capability will become increasingly important as the number of patient-specific medications under development increases.
Another strategy is to use on-demand packaging and labeling in combination with traditional packaging and labeling to exploit the benefits of both strategies. For example, if initial supplies are needed in a short timeframe, CTM may be packaged and labeled on demand at the start of the study to seed sites with supplies quickly, while the majority of CTM is packaged and labeled in the traditional way and distributed as needed. A further benefit may be achieved by packaging and labeling less than the expected needed amount of CTM in the traditional way and packaging and labeling the final supplies needed on demand. This strategy will result in a reduced amount of unused overage because it reduces the likelihood of over-forecasted supplies. This combination strategy exploits the advantages of the individual strategies—it allows sites to receive initial supplies quickly (on demand), allows sites to be resupplied quickly (traditional), and prevents loss associated with unused overage (on demand).
The preparation of clinical supplies is often an expensive and rate-limiting step in the critical path of the drug development process. On-demand packaging and labeling is an innovative yet simple way for pharmaceutical and biotechnology companies to greatly increase the flexibility of their clinical supply chain, shorten their study start timeline, and reduce costs associated with overage, waste, and repackaging or relabeling efforts. Additionally, on demand packaging and labeling addresses FDA's recent concerns about getting medical products to market in a more predictable, more efficient, and less costly manner, as detailed in its critical path initiative report.
By implementing on demand strategies, clinical supplies groups will not only save money and shorten timelines but also improve the overall efficiency of the critical path to new medical products.
Brian Moe, PharmD, is vice president, operations, with Clinical Supplies Management (CSM), 4733 Amber Valley Parkway, Fargo, ND 58104, (701) 235-8002, fax (701) 235-8014, email: firstname.lastname@example.org.
1. M. Eli, "Proactive Strategies for Matching Clinical Supply with Clinical Demand,"
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2. C.A. Carberry et al., "Challenges in Preparing Biologic Clinical Materials," Pharmaceutical Engineering, 19 (3) 1–7.
3. U.S. Department of Health and Human Services, Food and Drug Administration, "Innovation/ Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products," March 2004.