How to make tablets from potent APIs

Containment Fundamentals

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How much containment?

In an ideal world operators would not be exposed to a single molecule of a harmful substance, but in the real world, this is simply not possible. Three main factors dictate how much containment is required and, therefore, which method of containment is best: the nature, especially the potency, of the API handled is of paramount importance; the type of process to be executed; and lastly the working regime of the operators.

The product

The potency of a substance is, in most cases, characterized either by the OEL (Occupational Exposure Limit) or by the ADE (Acceptable Daily Exposure). The ADE describes the absolute amount of a specific drug substance that an operator can absorb without any negative effect on health. The OEL describes the maximum concentration of a drug substance which can be tolerated in the air of the production room, without any negative effect to the health of the operators. For established substances, these values are listed in textbooks such as ISBN 07176 2083 2 EH40/2002 OEL 2002 & ISBN 07176 2172 3 EH 40/2002 Supplements 2003. According to those, the OEL for Paracetamol is 10 mg/m³, while the OEL for Ethinyl estradiol is 35 ng/m³. It is important to understand that these values are based on certain assumptions. Also, the values might change during the lifecycle of a substance especially after more toxicological data is generated. If an OEL for a substance cannot be obtained from the literature, the value can be determined as follows: OEL = {NOEL [mg/(kg x day)] x BW [kg]} / {V [m³/time] x SF1 x SF2 x …}, with OEL = Occupational Exposure Limit NOEL = No Observable Effect Level BW = Body Weight V = Breathing Volume SF = Safety Factor

ADE and OEL are interconnected by the typical breathing volume of an operator (normally estimated as 10 m³/shift). Therefore: ADE = OEL [mcg/m³] x V [m³/day] ADE = 10 x OEL [mcg/day] ADE = {NOEL [mg/(kg x day)] x BW [kg]} / {SF1 x SF2 x …}

Additionally, it is common practice to describe the potency of a drug substance by an easy categorization system classifying all potent substances from 1 (less potent) to 5 (most potent). This allows production equipment to be classified as suitable for the production of a class X compound, plus it easily shows to operators the potency of the substance. However, when talking about this simple classification system, two important facts need to be considered: it is not totally universal, and nearly every company has its own classification system.

It also does not take into account the dilution of the API by excipients. The handling of a mixture containing 80% of a “class 3 API” can demand higher containment levels than the handling of a mixture containing 5% of a “class 5 API”.

As we will see in the following chapters, the concept of production lines suitable for the manufacturing of all class x compounds can be questioned. It oversimplifies the situation, not taking into consideration dilution (not all substance handled is pure API, especially when dealing with very potent substances often a large percentage of the mixture is excipient), the real number of operations, or also the fact that operators might not be present all time.