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Matt Bundenthal is direct sales and communications manager at Fette Compacting America, www.fetteamerica.com .
Risk levels should be considered when designing containment for pharmaceutical tableting equipment to enhance operator safety.
Tablet manufacturing is evolving, and the use of highly potent active pharmaceutical ingredients (HPAPIs) is increasingly prevalent. The inhalation of hazardous, airborne particulates can represent a real risk for those operating the equipment used to compress final tablets. It is due largely to these facts that the concept of contained tableting equipment is gaining prominence in pharmaceutical manufacturing facilities.
Any discussion of containment involving pharmaceutical tablet compression is likely to include a number of common acronyms. The following are some of those most commonly encountered:
Figure 1 depicts the various topics of consideration that come into play when operator safety is considered. A product should be initially assessed for the amount of dust it is capable of creating, as well as the amount of highly active substance it contains relative to its overall dosage (i.e., dilution). The manufacturer will also need to decide what protective measures to take with regards to the operator-which may well include the use of PPE-and how it will quantify the risk levels associated with a particular product (i.e., measurement protocols). Finally, after determining that a particular product does, in fact, constitute an exposure risk for the operator, consideration may be given to the use of specialized technology that includes features specifically designed to contain dust or allow for precleaning prior to breaching containment, for example, thereby mitigating the risk factors.
Different end users will employ different strategies for protecting their equipment operators, but what remains constant across manufacturers is a legal obligation for taking such measures. Containment solutions must ensure that established limit values for highly active ingredients can be reliably maintained during the manufacturing process. The International Society for Pharmaceutical Engineering (ISPE) Containment Manual acts as a guidepost for technical solutions pertaining to hazardous substance handling in pharmaceutical facilities and can provide further information (2).
Figure 2 depicts the relationship between OEB bands and OEL or PDE limits, illustrating how equipment users can identify the level of containment to be considered for various applications. It is important to mention that while the OEB and OEL categories do quantify limit levels, their interpretation and the way that various end users will seek to achieve operator safety can be highly variable.
Different containment requirements necessitate a wide array of equipment needs, and many tablet press vendors offer options that are suitably configurable. It is imperative to note that containment projects are inherently complicated, both from an equipment and facilities perspective. Consider the following steps.
Evaluate the API.
The first step is to determine if a particular active ingredient is potentially hazardous enough to those working with it, such that it warrants the use of contained equipment in the first place. There are differing philosophies on how best to approach such situations, which can include the avoidance of the ingredient all together (essentially a fool-proof approach), the use of PPE alone (the least effective approach), or something in between. Figure 3 illustrates this continuum.
Quantify the risk.
Once a determination has been made that an ingredient does have associated risks, it is time to define them. The OEB data shown in Figure 2 are the rule of thumb for pharmaceutical manufacturers seeking to quantify a risk level. These categories, when considered in addition to the drug load for a particular product (i.e., the ratio of active ingredient to the overall dosage or dilution), will lead to greater clarity in terms of what level of equipment containment is actually necessary.
Although the scope of this article does not allow for a detailed exploration of personal protective equipment (PPE), it should be noted that those having the most experience with compressing highly active substances generally elect to use some form of PPE, regardless of the efficacy of the contained system being utilized. PPE can be important given the fact that with virtually all contained systems, final cleaning will still include manual steps.
Choose a qualified vendor.
Identify equipment manufacturers that can meet your needs and who, ideally, have a proven track record with such applications. Asking for surrogate test results is a good way of vetting for this purpose. Qualified vendors will not only perform such testing, but also offer systematic methodology for scientifically matching a specific containment target (when one has been clearly stated) to a well-defined equipment system. This testing can bolster internal risk-assessment processes the end user conducts under ISPE’s Standardized Measurement of Equipment Particulate Airborne Concentration guidelines (3), as the methodology itself will result in a standardized, objective, and reproducible determination of a specific system’s capabilities.
Select containment-specific features and attributes.
Identify the level of containment the press will need to maintain and select the options necessary for reaching that goal. For example, an ingredient with an OEL level of 50 µg/m³ (OEB 3) will commonly require less containment than one with a level of 8 µg/m³ (OEB 4).
If a particular set of containment-related requirements necessitate dry-clean, low-dust production only, then a press fitted with glove- and rapid transfer ports, as well as need-specific process equipment, may prove to be the ideal fit. Glove ports typically utilize fail-safe technology that prohibits the operator from gaining access while a press is running. When the machine is in a static state, the ports provide access to the interior of the press for simple operations such as cleaning a punch tip or changing a fill cam, without breaching containment. A rapid-transfer port allows for either introducing a small component into the press or removing it, similarly without a breach. Utilizing split-valve technology for charging the press, in addition to high efficiency particulate air (HEPA) filtration and dust-tight discharge chutes, applicable models that are correctly configured can potentially provide containment levels of approximately 5 µg/m³ (i.e., the middle of the OEB 4 band).
Hazardous active ingredients necessitating wet cleaning, where the press will run itself through various wash and rinse cycles (i.e., wash-in-place systems), are often classified at the higher levels of the OEB 4 band and into OEB 5 or above. Such press systems are far more complex and are designed to introduce various forms of water and detergent into the machines. This set-up allows for the binding of airborne particulates with water molecules, which are then drained away before access doors are opened. Integrated, internal spray wands may be available, with which the operator can essentially pre-clean the compression zone prior to letting the automated wash system perform its function. For OEB 5 applications, process equipment such as de-dusters, metalcheck units, and quality control testers may be installed in separate but connected isolators, ensuring that the entire tableting system is fully contained and safe. When tackling these products that warrant higher levels of containment, sophisticated air management systems are available that provide automated safeguards against risk factors, such as power loss, and maintain predetermined set points (i.e., vacuum) across variable run conditions. The caveat to the latter approach is that project costs are generally much higher, as related equipment and facility considerations are proportionately more complex.
Due to this inherent complexity of containment projects, whether they necessitate dry- or wet-cleaning, they always present challenges extending beyond those of a non-contained endeavor. It is therefore strongly recommended that end users identify their equipment vendors as far in advance as possible. Making a selection early will allow for the commencement of project-critical dialogue between the end user and their chosen supplier. It should also be worth noting that contained presses often have lead-times of up to 50% longer than their non-contained counterparts.
The sole purpose of investing in contained compression equipment is to ensure the safety of one’s operators. Nothing else could, or should, be of more paramount importance. Take the time to properly identify potential risk factors, methodically match those factors to suitable equipment, and create a safer, more efficient working environment.
The author would like to thank Dr. Martin Schöler (author ofContainment, Fette Compacting GmbH, 2019) for his constructive insight and feedback during the creation of this article.
1. EMA, Guideline On Setting Health-Based Exposure Limits For Use In Risk Identification In The Manufacture Of Different Medicinal Products In Shared Facilities. European Medicines Agency, Committee For Medicinal Products For Human Use (CHMP), Guideline EMA / CHMP / CVMP / SWP / 169430/2012, 2014
2. ISPE, Community of Practice (CoP) Containment D/A/CH Affiliate: Containment Manual (English Translation) (ISPE, 2017).
3. ISPE, ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment (2012).
Matt Bundenthal is director of sales and marketing at Fette Compacting America.
Vol. 44, No. 4
When referring to this article, please cite it as M. Bundenthal, “Understanding Containment for Tableting," Pharmaceutical Technology 44 (4) 2020.