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Manual and Automated Filling of Powder in Capsules for Clinical Trials
The exploratory approach to developing formulations of oral solid dosage forms for first-in-human (FIH) studies is increasingly popular. This approach favors the simplest possible formulation, such as powder-in-capsule, sometimes without excipients. During the past several years, the emergence of systems that enable the automated and accurate filling of large quantities of active pharmaceutical ingredients (APIs) into capsules has expanded the popularity of the API-in-capsule dosage form. Filling APIs directly into capsules is probably the quickest option for entering clinical trials because it requires few or no excipients, thus saving three to four months that would have been spent on formulation development and stability testing.
A client asked Almac to provide supplies for an FIH study. The customer initially required fewer than 1000 capsules of two dosage strengths. To save time and API, the client decided not to conduct formulation studies. Almac manufactured these capsules manually using an analytical balance. The client subsequently asked Almac to resupply 25-mg and 100-mg capsules in quantities greater than 10,000 and 5500 units, respectively. Almac quickly decided that an automated process would be the best way to manufacture resupplies.
Because of the lack of toxicological information about the API, Almac treated it as a potent compound and assigned an operator exposure limit of 0.1–10 µg/m3. The company decided that its Xcelodose dispensing system (Capsugel), in combination with the potent-handling capabilities of its Xcelohood containment system (Capsugel), would be the appropriate equipment to execute this resupply project.
The solid-state characterization package provided the particle-size distribution of the batch of API to be used for the resupply (see Table I). This information, coupled with flowability data, suggested that the API possessed poor flow properties. Although poor flow does not affect hand filling, personnel thought that it might make filling with the Xcelodose difficult, particularly when using the high-throughput unit, in which the API must flow from the hopper into the dispense head. Fortunately, the API’s characteristics allowed operators to adjust the frequency of the equipment’s vibrations and the angle of the hopper to allow a reasonable flow of API into the dispense head.
Using a single-shift, 40-hour work week, Almac completed this project within three weeks. Less than one day was required to determine suitable processing parameters for the 25-mg and 100-mg strength capsules. The low-fill-weight capsules took approximately 76 h to complete, and the large-fill-weight capsules were completed in just over 36 h.
When Almac manufactured the initial clinical supplies by hand filling with an analytical balance, the average rates of production of 25-mg and 100-mg capsules were 30 and 50 capsules/h, respectively. Therefore, if the Xcelodose had not been available for the resupply, manual capsule filling of the 25-mg capsules would have required approximately 400 h to complete, and the 100-mg capsules would have required 110 h.
The lack of toxicology information about the client’s API is common in FIH studies. To ensure operator protection, the original clinical supplies were manufactured within a ventilated balance safety enclosure (VBSE). Because the analytical balance was in direct contact with the VBSE, however, any vibration from the latter unit made balance taring difficult. To manufacture the resupply, Almac used the Xcelodose within the specially designed Xcelohood. Because the Xcelodose was not directly in contact with the Xcelohood, the former’s microbalance was inherently more stable and resulted in much quicker taring than the hand-filling operation allowed.
Manufacturers can take various approaches to manufacture supplies for FIH studies. The increasingly popular exploratory-formulation approach allows firms to manufacture through hand-filling, capsule boards, and automated systems such as the Xcelodose. In this resupply project, the automated method resulted in direct cost savings by reducing labor expenses. The method enabled clinical supplies to be delivered approximately seven weeks earlier than a hand-filling operation would have done.
In addition, timelines for this project were shortened further because no cleaning method was required. Operators were able to develop the Xcelodose process parameters immediately. Only 5 g of API was required for development activities, and processing resulted in minimal losses. As a consequence, the automated method used less API compared with the hand-filling technique. If an exploratory-formulation approach is suitable, and speed to clinic is imperative, an automated method, such as the Xcelodose system, is a viable option for the manufacture of supplies for FIH studies.
Colin Lorimer is a senior formulation scientist at Almac Pharma Services, 22 Seagoe Industrial Estate, Craigavon, BT63 5QD, United Kingdom, tel. +44 0 28 3836 3363, fax +44 0 28 3836 3300, firstname.lastname@example.org.