Blinding into capsules: a specialist job

Most clinical studies are blind studies and therefore require that the patient or the physician (blind study) or both (double blind study) cannot identify the treatment drug, be it the tested active drug or the placebo or the comparator drug.

I shall focus this note on solid doses, particularly on tablets, which is the most common galenic form, being the easiest and most economical form.

Capsule is an easy form for early clinical test particularly for phase1or phase 2 studies because it requires limited formulation compared to a tablet. However, at commercial stage tablets are preferred because less costly than a capsule, unless the drug substance or the dosage does not allow for a tablet formulation. Therefore the much higher number of drug products in tablet form compared to capsule. As a consequence, most comparative clinical studies compare tablets with multiple possible combinations:

• Active versus placebo
• Active versus comparator
• Or further combinations thereof

It should be noted however that over-encapsulation permits blinding of most oral dosage forms: ½ tablet, several small tablets, capsules of different sizes or colours…

Protocol 1 above is the easiest from a formulation point of view. However, two possibilities are available if the active is in a tablet form. Either one formulates placebo tablets or, most often, the active tablet is over-encapsulated and a similar placebo capsule is formulated to avoid the development cost of a tablet formulation.

Over-encapsulation is done in different standardised size capsules. Similar standardised placebo (lactose) capsules are available. Creapharm holds stocks of such standardised placebo capsules.

Over encapsulation is a four step operation:

• Opening the capsule
• Introducing the tablet into the capsule
• Filling with excipient(s)
• Closing the capsule

These operations can be done separately with manual tools or sequentially on specific machines for capsule blinding.

Specific technical problems may dictate the choice between manual and automatic mechanical online filling. A common issue is the size of the tablet which does not fit a standardized swallowable capsule. Then, the tablet needs to be broken which usually leads to a manual process. Otherwise the choice is usually dependent on the batch size or run length. It is a common industrial trade off between lower set up and cleaning / clearing costs for manual operations versus higher performance for mechanical operations. It is our experience that the “breakeven” is around 50 000 capsules. An encapsulation workshop needs to have both types of equipment:

• Different capsule size manual fillers
• Machines with different capsule size tools

Over-encapsulation itself as described above is the core step. It requires prior and post operations:

• Preparation steps include weighing of excipients and possibly mixing
• Post encapsulation control is done either through weighing (100% or statistical) or through reconciliation

As the drugs are for clinical trials in human, all these operations have to be made in a pharmaceutical GMP environment.

It means that:

• A quality assistance system has to be in place with appropriate procedures
• The facilities have to meet the GMP standards and to be qualified for such operations. The suites where the operations are completed have to meet ISO 8/class D standards.
• The equipment has to be qualified and proper training needs to be demonstrated for the personnel.
• Because the facilities and the equipment are multipurpose proper cleaning methods have to be validated.

Finally: “the capsule does not stop there”. Over-encapsulation is a step in the supply of clinical trial material. Blinded capsules need to be primary packed usually in blisters or bottles. Then proper labelling, randomisation, secondary packaging of patient kits and pharmaceutical distribution to the investigation centres worldwide have to be completed before the trial starts.

All of this is clearly a specialist job. This is where Creapharm brings in its 15 years of experience with about:

500 batches over encapsulated,

5000 batches packed, and

5 Million units shipped to the investigation centres.

To offer one of the most powerful and versatile GMP’s capacity in Europe and abroad, Creapharm has recently extended its capacities by the construction of a new GMP area of 520 sqm, dedicated to:

• Bulk production and capsules filling
• Deblisterization
• Over-encapsulation/blinding of actives drugs
• Primary packaging in blisters or vials

This new zone, classified ISO8, consists of a weighting room and 4 booths with independentairlocks and air treatment systems to avoid cross contamination.