Thursday, September 30, 2010

How to make tablets from potent APIs

IntroductionWhen talking today about solid dosage form production, often containment immediately becomes one of the issues. Why? The first reason is that APIs are becoming more and more potent: meanwhile more than 50% of all NCE (New Chemical Entities) are classified potent (OEL < 10 μg/m³). Secondly, health and safety authorities all around the world are putting more focus on the protection of operators dealing with these substances. The third reason is that 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 first.
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.

Where as the UK COSHH rules show a clear hierarchy of control measures:
  1. Elimination at the source
  2. Substitution with a less hazardous material or form
  3. Reduction of the quantity below critical limits
  4. Engineering controls to prevent intolerable operating staff exposure (contained handling)
  5. Administrative controls
  6. Use of Personal Protection Equipment (PPE)
In many other countries no legislation enforces this hierarchy. Most of the western countries will monitor the conditions under which operators have to work in the countries from which they import as it is seen as 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? Firstly, PPE only protects the operator. The hazardous substance is not contained, which means that the associated problems are increased: changing of filters, cleaning of rooms and equipment, inside and outside, 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 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 loading.
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-dependant and in most countries it is not acceptable to put the responsibility for his health (or even life) into an operator’s 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 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:

Equipment Item
Air fed suit
10,000 200
Air fed half suit
2,000 100
Air fed hood
2,000 40
Filter air hood
500 40
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. Containment risksDuring most of the manufacturing process, the APIs are inside machines or vessels which are more or less ait 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. 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: 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 (4000mg 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.
How much containment is required?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 productThe potency of a substance is, in most cases, characterized either by the OEL (Occupational Exposure Limit) or by the ADI (Acceptable Daily Intake). The ADI 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 35ng/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 ……..
OEL     = Occupational Exposure Limit
NOEL  = No Observable Effect Level
BW      = Body Weight
V         = Breathing Volume
SF       = Safety Factor
ADI and OEL are interconnected by the typical breathing volume of an operator (normally estimated as 10 m³/shift). Therefore;-
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, as the attached diagram shows; 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.
The equipmentSuppliers 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. While the last claim obviously is wrong (OEL is a product-related number, it only has the same unit as the containment performance of a piece of equipment), the problem of the other claims is that the test conditions are not defined. This makes it extremely difficult to compare figures obtained by using different test materials, different samplers, different sampler positions or different analytical procedures.
After inventing the split-valve technology, GEA Buck Valve again took the lead to form (under the umbrella of ISPE) an expert working group, consisting of experts from pharma 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. Analyzing the filters gives the quantity of lactose in a measured amount of air, which is the containment performance of the equipment. As the average of 15 minutes is taken, 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 is defined as the containment performance over a longer period of time, for example one shift of 8h.
The diagram shows two different senarios:
It is important to distinguish if there is an intermittent exposure as shown on the left side generated e.g. by the docking of a container with raw materials to a fluid bed with subsequent operation of the fluid bed, or a permanent exposure as shown on the right side e.g. by a tablet press which is not totally tight.
The OperatorThe most important numbers to describe the exposure of the operator are ROI (Real Operator Intake) and RDI (Real Daily Intake). These numbers describe the amount of API which gets into the body of the operator, while being for a certain 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.
For example:
If the actual RDI is less than the drug specific ADI, the situation is fine. If the RDI exceeds the ADI, measures must be taken to improve the situation. In our example the most effective way would be to upgrade the granulator by a loading/unloading system with a better containment performance.
Conclusion of Fundamentals
This visualisation helps the concept to be easily understood. For real situations of course, a detailed risk analysis needs to be done in order to judge the containment performance of an existing installation, or to select the appropriate equipment for an upgrade of an existing facility, or the design of a new facility.

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