How to make tablets from potent APIs
It is also important to notice the hidden costs associated with those systems such as: large number of systems required; lifetime of suits and filters is limited; cost for clean air supply; requirement for extra changing and storage areas.
These areas are most critical for the performance of the systems. After working in the contaminated area, the outside of the suit is contaminated with API. This contamination needs to be removed, which can be done either by air or wet showers. Whichever method is chosen, the remaining residuals, especially for very potent substances such as hormones or oncology products, can still be critical.
The effectiveness of air suits needs to be understood. It is a common misconception they provide total protection, but in reality typical NPF and APF (Applied Protection Factors) are as shown in table 1. APFs represent the reality of daily operation. Using the same example as above, this means that if the dust concentration in a room is 3 mg/m³, at best the exposure level for an operator wearing a full air-fed suit will be 15 µg/m³.
During most of the manufacturing process, the APIs are inside machines or vessels which are more or less air tight. The main risk of material escaping into the environment exists whenever a connection between those pieces of equipment needs to be made or broken, when a sample needs to be taken, and when the machines need to be cleaned at the end of a manufacturing campaign. Before the risks for the operators’ health are discussed we should also spend some thoughts on the risks of cross contamination. Even in the best designed multi-product facilities cross contamination will happen. The critical question is how much cross contamination is acceptable and how it can be ensured that the real levels of cross contamination are always below the acceptance limit.
How much cross contamination can be allowed is mainly dictated by the potency of the products handled. The most common definition of an acceptable level is: In the maximum daily dose of product 2 only 1/1000 of the minimal daily dose of the active of product 1 should be found. If we compare now Paracetamol tablets (4000 mg max daily dose) with typical oral contraceptives (containing 0,02 mg as a maximum daily dose) we see that the acceptable level of cross contamination in case 2 is by a factor of 200,000 higher than in case 1. Common ways to reduce the level of cross contamination in multi product facilities include separate production rooms, air looks and pressure cascades. These are fine for less critical products but when highly potent substances are handled, strict containment is the only way to protect both the operators’ health and the other products.