Clinical trials require low volumes of drugs produced to the same accuracy and cGMP standards as large production runs. Will Eaden, of CI Electronics, reviews checkweighers and sorters suitable for the job
For more than 150 years the two-piece hard gelatine capsule has been used as a means of administering controlled doses of powdered and liquid drugs. Hard gelatine capsules remain an extremely popular dosage form for pharmaceuticals that have reached full production, but they also have another important application: clinical trials.
Because of the versatility of the two-piece construction and the availability of various sealing techniques, small quantities of gelatine capsules can be filled by hand for Phase I trials, filled using hand frames for Phase II trials, or the process can be fully automated for larger-scale Phase II and Phase III trials. Furthermore, placebos can also be readily assembled using hard gelatine capsules.
The maintenance of quality assurance procedures in compliance with the appropriate pharmacopoeia is essential, which is why some form of checkweigher will almost certainly be employed alongside the filling processes.
Considering the substantial investment that will have been made in getting as far as clinical trials, and the critical nature of the trials to the product's life, every possible step must be taken to ensure success. It is therefore usual to weight-sort 100% of every batch. This has the effect of ensuring no out-of-specification capsules are delivered to patients and it gives statistics for the weight distribution of the capsules from which the fill weight distribution can be inferred.
For Phase I studies, where a relatively small number of doses and only a very limited quantity of the active pharmaceutical ingredient (API) are likely to be required, the capsule will be opened, filled and closed by hand. Following the adoption of the Clinical Trials Directive (2001/20/EC) in 2004, this must be carried out under cGMP conditions. Normally, the correct amount of drug will be determined by the capsule body being filled on a tared balance; as a further check, the closed capsule will be weighed and the result recorded.
A typical checkweigher for Phase I trials would be the SADE SP Benchtop tablet/capsule weight sorter from CI Electronics. This instrument has been developed specifically for weighing and sorting individual pharmaceutical tablets or capsules in smaller quantities and calculating statistical data that can then be printed or collected on a networked PC. One of the main advantages of the SADE SP Benchtop is that it is equipped with a bowl feeder that automatically loads each tablet or capsule onto the balance, allowing unattended operation, which saves valuable operator time and virtually eliminates the risk of operator errors; any out of specification capsules are extracted from the batch.
Phase II trials, studying efficacy, require greater volumes of product for administration to patients. However, patient-to-patient variability can be significant, so it is best to minimise all other sources of variation - including the pharmaceutical on trial. These two factors together mean that the most commonly used capsule filling technique involves the use of a hand frame in which approximately 100 capsules are processed simultaneously: the caps are all separated from the bodies together, the fill material (API and additives) is evenly distributed, and the caps and bodies are reunited.
While the above is true for powders, some drugs are more suitable for dispensing in their molten state, suspended or dissolved in a liquid.
Once again, cGMP conditions are necessary for the production of Phase II trial batches and 100% checkweighing is essential. The SADE SP 120 tablet/capsule weight sorter is also suitable for this type of work. It is very similar to the SADE Benchtop but it is equipped with a 60-litre bulk feed hopper to replenish the bowl feeder automatically and this enables larger quantities of product to be loaded. Weighing is then fully automatic, with statistics generated in the same way as for smaller-scale trials.
Batches of product numbering thousands or hundreds of thousands may be required for larger Phase II and III trials, which implies a need for an automated process. In addition, the formulation is usually the same as that planned for registration. Consequently, the encapsulation process and formulation must both be suitable for scale-up to full production. A SADE SP 220 twin-channel bulk weight sorter may be appropriate.
Whatever the phase, weigh sorters can help towards the robustness of trial data.