Safe Handling of Highly Potent Substances
For many years now, the number of Highly Potent Active Pharmaceutical Ingredients (HPAPIs) has been increasing in formulation and administration. The successful development of new cancer therapies and the growing number of women worldwide using the contraceptive pill are two main reasons for this phenomenon.
At the same time, more and more countries are placing greater emphasis on employee health protection. When it comes to marketing authorisation, the laws of the country in which a pharmaceutical product is to be sold apply; but when it comes to health and safety, the location of the manufacturing site determines which rules and laws must be observed. And despite a global character of medicinal product manufacturing, many multinational companies are unwilling to work with "overseas" companies if the level of protection offered to the local workforce is lower than that offered at their own site.
Most Western countries, as well as a growing number of emerging nations, have enacted laws that give employers full responsibility for protecting the health of their employees. In most cases, they also specify what measures should be taken to protect personnel and products: For example, in most cases, protective clothing and other personal protective equipment (PPE) are considered only a last measure. Apart from legal obligations, the protective performance of these PPE is very limited.
State-of-the-art containment provides a [physical] barrier that separates agents or highly potent substances from manufacturing personnel. This concept is well known and has its roots in the aseptic manufacturing of sterile dosage forms. Although a key aspect is to keep microorganisms and foreign particles away from the product, the main focus of containment is to protect operators from exposure to the API.
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Even in so-called "closed facilities," there is always some risk of exposure. "If you find 0 exposure, your analytical method is not accurate enough," commented Dr Andreas Flückiger [formerly Head of the Occupational Health Services of the Roche Group] during his presentation at PharmaCongress 2023 in Wiesbaden. An analogy that also applies to cleaning equipment in multiproduct facilities. No matter how much effort we put into cleaning the equipment, we will always find traces of the previously manufactured product. If not, we have not measured accurately enough or the method is not sensitive enough.
Therefore, we need to know what the operator's acceptable daily exposure or Acceptable Daily Intake (ADI) may be. Acceptable Daily Exposure (ADE) is very similar to Permitted Daily Exposure (PDE), a limit recently introduced by the European Medicines Agency (EMA) for cleaning validation.
The main difference is that the second point (PDE) is aimed at preventing overexposure of patients due to cross-contamination resulting from inadequate cleaning, whereas the ADI/ADE concept is aimed at operator safety. ADI values range from sub-microgram levels to several milligrams per day. For comparison, the weight of a fingerprint is about 10 micrograms. In addition to the substance-specific ADI value, the frequency of use and the dilution of the API in the formulation (medicinal product preparation) must also be considered to determine the required level of protection.
Wiesbaden, Germany19/20 March 2024
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Equipment cleaning and, especially in solid dose manufacturing, powder transfer operations are the most critical steps. The current standard for powder transfer is the use of split butterfly valves, which are available from several suppliers in both stainless steel and disposable versions. The containment performance of these systems is tested after installation according to the SMEPAC protocol - an ISPE guideline widely recognized as the gold standard. Micronized lactose is commonly used as a surrogate test material in this process. Thus, instead of a highly potent APIs, the leakage of the surrogate is measured.
The type and position of the measuring equipment are specified, as are the test environment and the analytical methods to be used. Only after these tests have confirmed that a safe level of exposure or the required containment level is achieved can the system be used for the safe handling of HPAPIs.
However, it is often criticized that these tests only validate the performance as-is. Even if they are checked every two years, each batch processed in between poses a potential risk to operators as, for example, the seals within the containment age; there is a risk of mechanical damage or that someone simply forgets to install a seal properly. In this respect, a SMEPAC test could be compared to a media fill in sterile manufacturing: essential for an overall review, but insufficient for a timely evaluation of the runs that occurred between assessments.
Attempts were made to address these concerns by having operators wear a mobile version of a modified SMEPAC test, but these are expensive, inconvenient for daily use, and most importantly do not provide a result until several days later, which would be far too late in the event of a serious containment breach.
An alternative idea was to place light scattering devices near the butterfly valves and/or in other critical areas. The problem with this, however, was that false alarms could occur, as often the movement of operators was enough to create enough dust in the air to trigger an alarm.
GEA Pharma & Healthcare and Pallas have jointly developed the Digital Canary to ensure employee health protection. Based on the concept of miners taking a canary underground, this 21st century equivalent is a real-time continuous monitoring system designed to detect product leaks from closed pharmaceutical production lines and eliminate the need for routine workplace health monitoring.
The patented "Canary" consists of an aerosol spectrometer-based sensor that provides a constant reading (compared to a baseline) for each dust exposure at the sampling point. The information is relayed to a control system that triggers an alarm if the data is out of specification.
Dr Flückiger also discussed the available results and experience with the system to this point during his presentation. For example, the system cannot be used without further consideration for all conceivable products or product dusts. Depending on product properties such as porosity and particle size, product-specific correction factors may be required, which must be determined in advance. One advantage of the sensor used is that it can also measure particles up to a size of 100 µm. According to Dr Flückiger, these 'large' particles are particularly relevant for containment measurement because they carry the mass into the airways. Many smaller particles are also simply exhaled again. Containment measurement in a real environment with a real, highly potent API has not yet occurred. But the values obtained by SMEPAC measurements using surrogates are generic, Dr Flückiger concluded.
About the Authors
Dr Harald Stahl
...is Head of Application & Strategy Management at GEA, responsible for the evaluation and integration of new technologies.
Dr Robert Eicher
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy around pharma technology.