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How to Make Tablets from Potent APIs
Dr. Harald Stahl, Senior Pharmaceutical Technologist, GEA Pharma Systems With regards to production of solid dosage forms, often containment becomes one of the issues with Active Pharmaceutical Ingredients (APIs) becoming more and more potent along with stressing more on health and safety of the operator. The article deals with the introduction and details of the containment technology for potent APIs.

When talking today about solid dosage form production, often containment becomes one of the issues. The first is that Active Pharmaceutical Ingredients (APIs) are becoming more and more potent - meanwhile more than 50 per cent of all New Chemical Entities (NCE) are classified potent [Occupational Exposure Limit (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.

Regulatory Situation
It is the first duty of the employer to protect (the health) of its employees. The Control of Substances Hazardous to Health (COSHH) rules provide the following hierarchy of controls:

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.

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 Nominal Protection Factor (NPF) and Applied Protection Factors (APF) are as per 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.

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 (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.

How Much Containment is Required?
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, characterised either by the Occupational Exposure Limit (OEL) or by the Acceptable Daily Intake (ADI). 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; ADI = OEL [mcg/m3] x V[m3/day]

ADI = 10 x OEL [mcg/day]
ADI = NOEL [mg/(kg x day)] x BW [kg]

Additionally, it is common practice to describe the potency of a drug substance by an easy categorisation 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 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 per cent of a 'class 3 API' can demand higher containment levels than the handling of a mixture containing 5 per cent of a ’class 5 API’.

The Equipment
Suppliers 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’. 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 International Society for Pharmaceutical Engineering (ISPE)] an expert working group, consisting of 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. 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 Short Term Time Weighted Average (STTWA). 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 Long Term Weighted Average (LTTWA) is defined as the containment performance over a longer period of time, for example one shift of 8h.

Figure 1 shows two different scenarios. It is important to distinguish if there is an intermittent exposure as shown on the left side of Figure 1 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 Operator
Operator exposure is described by Real Operator Intake (ROI) and Real Daily Intake

(RDI). These describe the amount of API that 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.

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.

Selection of Appropriate Production Technology
A typical tablet production consists of thefollowing steps:
• Dispensing of API and Excipients;
• Milling of Raw materials in order to destroy lumps;
• (Wet) Granulation with subsequent Drying;
• Dry Milling;
• Addition of Lubricants;
• Tablet Compression;
• Coating;
• Primary and secondary packing;

The selection of the overall material handling system for potent APIs is of paramount importance as it determines more than any other aspects the containment performance of the entire installation. There are fundamentally two choices: systems based on stainless steel or disposable systems.

Intermediate Bulk Containers (IBCs) with split butterfly valves are the most commonly used material handling systems for dealing with potent APIs: the entire material required for a batch is loaded, e.g. under a laminar flow booth, into the IBC in the dispensing area. This IBC is then moved into the granulation area where it is docked using a split butterfly valve connection to e.g. a discharge station. The raw material is loaded either by gravity (if the room height allows) or via vacuum conveying into the granulator. A mill for breaking lumps should be integrated in between.

For granulation, various options exist. Typically these low dose recipes are best suited to wet granulation. Here there are four main options:

1. Integrated line consisting of a high shear granulator and a fluid bed;
2. Fluid bed spray granulator;
3. Continuous granulation and drying;
4. Single pot processing.

The advantage of option 1 is to combine the most effi cient granulator with the most effi cient dryer to achieve high throughput can be realized. Additionally the high shear granulation process avoids any issues with material separation. The process also creates material with high inter-granular porosity that demonstrates excellent compression behavior.

Using the FlexStream™ system developed by GEA Pharma Systems, granules also show excellent flow properties that are most important for a homogenious filling of the dies during compression. Continuous lines such as GEA’s Consigma™ offer a good alternative to conventional batch systems. The ideal solution for the granulation of potent API is offered by the Single Pot. It combines the process advantages of a high-shear granulator with a minimal surface area and the built-in possibility of cleaning in place to offer an extremely fast changeover. For compression of potent materials GEA's MODUL™ offers an unbeaten solution.

Case Stories
Over recent years several companies in India have used the experience and technical excellence of GEA Pharma Systems when installing containment systems for highly potent compounds. These include:

Zydus Cadila - Oncology solid dosage formulations
• Single Pot Processor - UP 75 & UP 10 (for R&D);
• Material Handling Solution: includes IBCs with Buck® MC 100 valve, Vibroflow™ & blending prism, Hicoflex®for discharging API from Isolator & charging into Single Pot Processor, IBC filling station at discharge of Single Pot Processor, Post Hoist Blender and Buck® MC Valve on Courtoy Tablet compression, IBC wash station, WIP drain frame;
• Tablet compression machine MODUL™P with HC ECM.

Cosmas - Oncology Solid dosage formulations • Flexstream™ size 3 in 10 bar execution;
• Material Handling system consisting of 100 L IBCs with Buck® MC 100 Valve, Vibroflow™ & blending prism, IBC filling station at discharge of Fluid bed processor, Post Hoist Blender, Buck® MC Valve on Courtoy Tablet compression, IBC wash station, WIP drain frame; • Tablet compression machine MODUL™P with C-ECM.
Natco Pharma - Oncology Solid dosage formulations
• Integrated line comprising of PMA 150, integrated wet mill, wet product transfer line from High Shear Mixer to FBD, Fluid bed processor Flexstream™ size 3, Integrated Dry mill & Vacuum transfer system for dried granules from FBP to IBC;
• Material Handling Solution: IBCs with Buck® MC 100 valve, Vibroflow™ & blending prism, Hicoflex® for discharging API from Isolator & charging into PMA 150, IBC filling station at discharge of FBP, Post Hoist, Buck Valve on Courtoy Tablet compression, IBC wash station, WIP drain frame;

• Tablet compression machine MODUL™P with HC ECM.
Project: Ranbaxy - Oncology Solid Dosage Formulations
• Single Pot Processor - UP 75 & UP 10;
• Handling Solution: IBC with Buck valve, Hicoflex® for discharging API from Isolator & charging into Single Pot Processor, IBC filling station at discharge of Single Pot Processor, Post Hoist Blender, Post Hoist, Buck® Valve on Courtoy Tablet compression m/c, IBC wash station, WIP drain frame;
• GPS Courtoy: Tablet compression machine MODUL™P with wash off line ECM.

The design of a line able to handle potent APIs in a save way requires an in depth understanding of the required level of protection. Here, the specifics of the API, the dilution with excipients, the containment performance of the equipment and the frequency of operation are the key parameters, which are linked by complex interrelations.