Contained Tableting for HPAPIs

APIs are becoming more and more potent: meanwhile more than 50% of all NCE (New Chemical Entities) are classified as potent (OEL <10 μg/m³). Furthermore, health and safety authorities all around the world are putting a greater focus on the protection of operators dealing with these substances. And, last but not least, suppliers of various hardware components have developed a huge variety of containment solutions, making it difficult to decide which is best, even for experienced people. Before we look at the factors defining the required containment levels, and discussing the possible hardware solutions, some fundamental thoughts about containment need to be covered.

Regulatory Situation

“It is the first duty of the employer to protect (the health of) his employees.” Even though the regulatory situation differs from country to country, the above statement (taken from the UK COSHH rules) should be seen as general guidance when handling potent substances. In fact, approximately 30% of all people in western societies will develop some form of cancer during their lifetime. If one of these had been exposed to a carcinogenic substance, whilst working for a pharmaceutical company, there is the potential for a legal claim against the company. This could result in high cost compensation and in very bad publicity, unless the company can prove that the employee had been protected using best available technology. Whereas the UK COSHH rules show a clear hierarchy of control measures:

• Elimination at the source
• Substitution with a less hazardous material or form
• Reduction of the quantity below critical limits
• Engineering controls to prevent intolerable operating staff exposure (contained handling)
• Administrative controls
• Use of Personal Protection Equipment (PPE).

In many other countries, no legislation enforces this hierarchy. Most western countries will monitor the conditions under which operators have to work in the countries from which they import, as it is seen to be highly unethical to support practices that create health and safety risks in other areas of the world.

There are good reasons for this order of preference, especially that PPE should only be used as a last resort (for maintenance; for necessary, but unforeseen interactions; or if any other method further up in the hierarchy has been considered without success). Why is this? First, PPE only protects the operator. The hazardous substance is not contained, which means that the associated problems are increased, such as changing filters, cleaning rooms and equipment, inside and outside, and become major containment issues. 

Additionally, depending on the PPE system used, the levels of protection are limited. For systems taking the air from the room via a filter system, the best filters (P3 according to EN 149) offer NPFs (Nominal Protection Factors) of 30. This means that if the dust concentration in a room is 3 mg/m³ (typical for open production), at best the concentration inside the system will be 100 μg/m3. Additionally, the lifetime of the filter element is limited because of the high dust load. The situation is different if air-fed systems are used. These systems can provide better protection levels, but there are still some areas of concern. The performance of these systems is very operator-dependent and, in most countries, it is not acceptable to put the responsibility for the health (or even life) of an operator into their own hands. The working conditions inside an air-suit are unpleasant: hot, humid with poor visibility and limited movement. This results in low levels of operator efficiency and the need to take frequent breaks, reducing efficiency even further.

It is also important to note the hidden costs associated with those systems, such as the large number of systems required, the limited lifetime of the suits and filters; the cost of the clean air supply and the 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 that they provide total protection; but, in reality, typical NPF and APF (Applied Protection Factors) are as shown in Table I. 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, the exposure level for an operator wearing a full air-fed suit will be 15 μg/m³ at best.

Containment Risks

During most of the manufacturing process, the APIs are inside machines or vessels that are more or less airtight. 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.

Cross-Contamination

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 as follows: 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 paracetamol tablets (4000 mg maximum 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 differs by a factor of 200,000 than in case 1. Common ways to reduce the level of cross contamination in multiproduct 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.

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 health effects . The OEL describes the maximum concentration of a drug substance that can be tolerated in the air of the production room without imparting any negative effect on the health of the operators. For established substances, these values are listed in textbooks such as ISBN 07176 2083 2 EH40/2002 OEL 2002 and ISBN 07176 2172 3 EH 40/2002 Supplements 2003. According to those, the OEL for paracetamol is 10 mg/m3, whereas 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 mathematically.

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.”

Thus, the concept of production lines suitable for the production of all class X compounds can be questioned. It oversimplifies the situation, not taking dilution into consideration (not every 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 the fact that operators might not be present all the time.

The Equipment

Suppliers who not specialists in the field often try to promote their “containment equipment” with claims such as “3 μg/m³”, “better than 1μg” or, even worse, “OEL 2 μg/m³.” All of these claims are meant to describe the containment performance of equipment such as extraction booths or containment valves. Although the last claim is wrong obviously (OEL is a product-related number), the problem with the other claims is that the test conditions are not defined. This makes it extremely difficult to compare figures obtained using different test materials, different samplers, different sampler positions or different analytical procedures.

After inventing split valve technology, GEA took the lead to form (under the umbrella of ISPE) an expert working group comprising experts from pharmaceutical companies, engineering companies and containment equipment suppliers. This group developed a guideline in which all of the variants discussed above are defined. The accepted test procedure uses lactose of a defined grade (other substances are possible), uses the equipment in a defined environment (humidity, temperature, number of air changes) and places the defined samplers in specific positions. The test includes performing the intended task and collecting air (via the filters of the samplers) for 15 minutes. Analysing the filters gives the quantity of lactose in a measured amount of air, which is the containment performance of the equipment. Using an average of 15 minutes, this performance is called STTWA (Short Term Time Weighted Average).

It is important to note that the total amount of powder escaping is measured. If dealing with potent APIs, often only a small percentage of a powder mixture is active, while the rest is excipient. The LTTWA (Long Term Weighted Average) is defined as the containment performance during a longer period of time, such as one 8 h shift. It is important to distinguish if there is an intermittent exposure, as shown on the left side, generated, for example, by the docking of a container with raw materials to a fluid bed, or a permanent exposure as shown on the right side, by a tablet press that is not totally secure, for example.

The Operator

The most important numbers to describe operator exposure are ROI (Real Operator Intake) and RDI (Real Daily Intake). These numbers describe the amount of API that gets into the body of the operator while present for a specific period of time in an area with a certain airborne drug concentration. If we know the breathing rate of the operator, and the dust concentration in the room, then the drug uptake can be calculated.

If the actual RDI is less than the drug-specific ADE, the situation is fine. If the RDI exceeds the ADE, measures must be taken to improve the situation. In our example, the most effective way would be to upgrade the granulator by adding a loading/unloading system with a better containment performance.