Potent oral solid dosage APIs: containment fundamentals

The last 20 years have seen a significant increase in the need for contained handling and processing in the pharmaceutical industry, driven by the development of more potent APIs and a stronger focus on health and safety by the regulatory authorities

David Johnson, Sales Manager, Containment Technology, GEA

Containment issues have become a vitally important aspect of solid dosage form production. Active pharmaceutical ingredients (APIs) are becoming increasingly effective, with more than 50% of all new chemical entities (NCEs) being classified as potent (OEL <10µg/m3); at the same time, the health and protection of operators, all over the world, is being put under an ever more intense spotlight.

Containment is the separation of the product from the people — and from the environment — by a barrier. Containment is used to prevent any negative impacts (contamination) being transferred from one area to another, and vice versa. Why is the pharmaceutical industry interested in containment? For two reasons: operator exposure and the prevention or elimination of cross-contamination. In the event of exposure or cross-contamination, an operator could become sick, deformed or worse, making the employer liable to fines, FDA intervention, legal procedures and possibly even prison.

But how much containment is required? Navigating the maze of available hardware components and the huge variety of containment solutions has made it more and more difficult to select the most appropriate equipment for the specified task: suppliers of various hardware components have developed a wide range of containment solutions, making it difficult, even for experienced people, to decide on the optimal solution.

"A key point," says David Johnson, Sales Manager, Containment Technology, GEA, "is that the required level of equipment and containment performance is not simply a matter of measuring the Occupational Exposure Limit (OEL) of the product. This is a common misconception and, as a result, there is a tendency within the industry to over specify."

He explains: "Selecting an overly complicated solution means that the system is more difficult to operate, difficult to clean and maintain and, of course, more expensive to buy. It can be problematic to show that a particular solution is ‘good enough,’ but it can be done. By understanding containment and looking at the product, the operator and the equipment, we can create well engineered and better value solutions."

GEA has a long history of expertise in the field of containment. The company not only offers a comprehensive range of robust and compliant containment products, it also boasts unrivalled experience in identifying the most appropriate solution and a thorough understanding of containment risk analysis.

The regulatory position

Established standards and practices in western countries are now being adopted in emerging geographies as mandatory procedures migrate from using PPE (personal protection equipment) to maintain operator safety to practicing containment at source. The message has never been clearer: it is the first duty of the employer to protect the health of their staff. And PPE has been found to be inadequate during modern pharmaceutical drug production.

The employer company should implement additional personal preventive measures only when this cannot be guaranteed by suitable technical options, as described in the hierarchy of hazard control (Figure 1). In many countries, this is now the law.

Figure 1: The hierarchy of hazard control is a system used in industry to minimise or eliminate exposure to hazards. It is a widely accepted system, promoted by numerous safety organisations as standard practice in the workplace

PPE should be a last preference. It only protects the operator; the hazardous substance is not contained. PPE only provides limited operator protection and the problem of cleaning equipment and rooms remains. The use of PPE is an unpleasant and inefficient experience and they are plagued with hidden costs (filters, clean air supply, storage, etc.).

Furthermore, it is a common misconception that air suits provide total protection. In reality, this is simply not true.

In addition, it is becoming increasingly apparent to manufacturers that the implementation of seamless containment solutions offers considerable housekeeping benefits, such as

  • faster changeover times owing to reduced (room) cleaning
  • significantly decreased cross-contamination risks
  • substantial savings (air filters, air suits, contaminated cleaning fluid, for example).

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 ADE (Acceptable Daily Exposure) describes the absolute amount of a specific drug substance that an operator can absorb without any negative health effects. The OEL defines 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 (Figure 2). Dust inhalation is recognised as the biggest risk to operator health and safety. Both are based on an 8h shift.

Figure 2: How to calculate an OEL: for the pharmaceutical industry the product-specific limit for the accepted daily exposure to the operator of this product is the OEL (Occupational Exposure Limit)

On the basis that ADE = OEL x air breathed in 8h and a typical breathing volume = 10m3/8 h, then ADE= 10 x OEL (µg/day).

As exposure can’t be fully prevented, companies must ensure that the operator’s Real Daily Intake (RDI) of a hazardous substance — accounting for any dilution factor (if airborne dust is only 10% API, for example) — doesn’t exceed the product-specific Acceptable Daily Intake (ADI) by using suitable equipment. Thus, the most important numbers to describe operator exposure are ROI (Real Operator Intake) and RDI.

These numbers describe the amount of API that gets into the body of the operator while present for a specific period of time (ROI = 15min, RDI = 8h) 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.

Category systems

To categorise the high number of products with different OELs, industry has established certain Occupational Exposure Bands (OEBs). The intention was to facilitate understanding and establish certain containment technologies in accordance with the OEBs. However, non-specialist suppliers often try to promote their containment equipment with claims such as ‘3µg/m3’ or ‘better than 1µg’ or, even worse, ‘OEL 2µg/m3.’

All of these claims are meant to describe the containment performance of equipment such as extraction booths or containment valves. And, although the last claim is wrong (OEL is a product-related number), the problem with the other claims is that the test conditions are not defined. "Furthermore," adds David: "OEB levels differ from one company to another; they’re really only relevant internally and cannot be used to identify suitable containment technology. This makes it extremely difficult to compare figures obtained using different test materials, different samplers, different sampler positions or different analytical procedures."

Equipment parameters

After inventing split valve technology, GEA took the lead to form 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.

Formerly known as SMEPAC (Standardized Measurement of Equipment Particulate Airborne Concentration) and now published by the International Society for Pharmaceutical Engineering (ISPE) as "Assessing the Particulate Containment Performance of Pharmaceutical Equipment (APCPPE) – A Guide," the reference defines the repeatable test processes and parameters needed to assess the different levels of containment required throughout a plant and enable like versus like comparisons to be made.

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 Time Weighted Average) is defined as the containment performance during a longer period of time, such as one 8h shift. It is important to distinguish if there is an intermittent exposure, generated, for example, by the docking of a container with raw materials to a fluid bed, or permanent exposure from a tablet press that is not totally secure, for example.

In summary

Containment is determined by the characteristics of the product, equipment performance and operator function. Operator exposure depends on the type of equipment being used, product dilution levels and frequency of operation.

As exposure can’t be fully prevented, the employer must ensure that the operator’s RDI of a hazardous substance doesn’t exceed the product-specific ADE by using suitable equipment. The company should only implement additional personal preventive measures when this cannot be guaranteed by appropriate technical options, including

  • eliminating the source of risk
  • substituting the hazardous material with a less harmful one
  • modifying the process
  • using engineering controls to reduce exposure (contained handling)
  • improving administrative procedures (SOPs).

The selection, placement and implementation of suitable containment equipment can be a daunting task; it requires an in depth understanding of the overall process, primarily to ensure that the chosen equipment performs at the necessary level, but also, from a financial point of view, to prevent any expensive and unnecessary investment into an over-performing solution.

David emphasises: "Just because the product to be manufactured has an OEL of 0.5, it doesn’t necessarily mean that the equipment containment performance level should be 0.5; these are two different things and cannot be directly compared. Understanding how the product, the operator and the equipment work together is key to creating the right level of containment."

Keeping the real operating conditions of the final installation in mind, selecting and implementing the correct level of containment can play a key role in optimising the manufacturing process, making it efficient, safe and cost-effective.

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