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ISPE SMEPAC Guidelines Driving High Potency Facilities And Equipment

By Michael Avraam, Global Product Manager at ChargePoint Technology

ISPE SMEPAC Guidelines Driving High Potency Facilities And Equipment

Indeed, the containment solution market is expected to grow rapidly by 2020 and with this increasing need for high potency handling capabilities, more advanced control strategies in HPAPIs are vital to both the quality of final products and critically operator safety.

We have already witnessed the market diversify with technologies such as isolators, restricted access barrier systems (RABS) and split butterfly valves (SBVs) now in use to safeguard drug products and operators throughout the manufacturing process. Closed transfers, such as the use of SBV, are growing in popularity as they limit manual intervention, reducing the risk of cross contamination and limiting the presence of airborne dust particulate to meet operator safety targets.

ISPE SMEPAC Guidelines

The increase in drug manufacturing using HPAPIs means that pharmaceutical manufacturers are having to invest in high potency facilities and equipment to deal with the associated risks, and these have to be implemented and validated. For example, before a manufacturer can implement a new control device within its process, it should be assessed in line with the International Society for Pharmaceutical Engineering’s (ISPE) Standardised Measurement of Equipment Particulate Airborne Concentration (SMEPAC) guideline for its particulate containment performance. This is a guide to demonstrate how the containment device will perform as part of a laboratory condition test, not in a particular process in a real-world manufacturing environment.

‘The guide aims to define current good practices providing information to allow organisations to benchmark their practices and improve on them. Specifically, the guide provides a methodology to derive data associated with handling of pharmaceutical ingredients that is useful in the assessment of potential risks.’

In the late 1990s, occupational health professionals focused on worker exposure measurement as the primary target to qualify containment equipment through workflow outcomes, regardless of the source. The method was formalised as SMEPAC, later adopted and revised by the ISPE. While widely welcomed by the industry, the random nature of this guidance on sampling methods and distribution makes it challenging to achieve a specific measure of containment for equipment or devices. The data lacks statistical validity and more importantly, the method would be better suited if it provided a baseline dataset for future integrity testing.1

Key considerations

There are many factors that can affect the interpretation of the SMEPAC test results, including the testing protocols, the placebo, test equipment and the data analysis.

The testing protocols detailed by SMEPAC allow for a certain amount of inconsistency. For example, referring to transfer quantity, the SMEPAC guideline notes ‘the masses are intended to fully coat the exposed seal and operating surfaces and are suggestions’. For example, as there is a suggested weight range documented within the guide, expecting consistency in results between devices tested with volume variation will no doubt result in inconsistent results.

There are various types, particle sizes and levels of detection of placebos that the SMEPAC guide recommends during validation testing, for example, lactose, paracetamol, mannitol and naproxen, but how relevant is the test placebo to the real-life API eventually to be used and has each supplier tested with the same placebo? These are two questions that could affect the interpretation of the results. Equally, there is the potential for some considerable differences from various samplers when using the same test — it is possible for test equipment with the same performance to show differing results.

Within the industry, manufacturers often look at the data following this laboratory test and use it to qualify the selection of the required containment technology for their process. However, comparing these tests like for like could prove to misrepresent reality. There are variations in the way the containment performance tests are performed and the interpretation and utilisation of the results obtained can be inconsistent, so there is a risk to presume that performance should be the same, whether it’s in the laboratory or the manufacturing environment. But should it? In a risk based era, we need to consider the areas of variability and how these could eventually lead to issues, if not addressed.

Growing demand for high potency active pharmaceutical ingredients (HPAPI) and the rising prevalence of specific therapy areas, such as oncology, immune-suppressants and hormone, are fuelling the need for high potency handling capabilities. As the use of high potency containment systems is rising, manufacturers are looking at more innovative containment strategies and containment verification has never been so important. However, it’s critical to understand the variations in testing and the challenges posed by potential differences in the interpretation of results.

Industry and regulatory outlook

As the biopharma market is continuously expanding, including global demand and growth in the oncology market, there is growing need for the development of potent compounds and an increase in conventional drug manufacturing using HPAPIs. By the end of 2024, the cancer segment is projected to reach close to $100 billion in value, expanding at a CAGR of 6.5%.

Ensuring operator safety and reducing levels of contamination is essential during high potency manufacturing. As human intervention is present at almost every stage of pharmaceutical manufacturing processes, solutions to counter the potential risks are vital. This needs to be achieved in a manner that does not impede on productivity and operability, therefore identifying an appropriate solution can be a challenge. Validation testing also needs to reflect operator intervention to ensure that the containment device, some of which can be reliant on operator technique to achieve performance, is tested accordingly.

The containment should also be validated at each step where potential exposure is present in its normal environment, including full risk assessment for the whole process. For example, a charging application that has not undergone contained dispensing operation prior to being within the laboratory environment, cannot be compared measurably to its normal application within the manufacturing environment.

Questions should also be considered around preventative maintenance. The condition of the device and the identification and rectification of any damage, before it is used, introduces further risk. Frequent monitoring and preventative maintenance helps to safeguard the reliability of the containment solution. By limiting manual intervention, this will also help to maintain a like for like result.

Using technology to address containment requirements

New design technologies such as SBVs have evolved over the last 25 years to address the more stringent containment demands when handling potent compounds and remove the risk of airborne exposure. These valves can be integrated with other containment solutions such as isolators to enable the transfer of potent compounds and are used in many applications when not only dust control and containment is a concern but where product flow, yield and sterility are also important.

It has been a common perception that containment performance is directly associated with the levels of particulate residue visible after separation of the containment device, but performance tests have proven that the containment performance is not directly linked to the level of visible residue. Nonetheless developments in extraction methods have led to the recovery of potentially airborne particulates, thereby reducing and eliminating these visible particles. Extraction offers an excellent, robust solution to achieving repeatable performance.

Other ways of helping to improve valve performance include double gloving, enhanced wiping procedures and waste disposal. However, by further reducing human intervention with an automated approach, may it offer an alternative option for reducing risks further?

As the industry is moving in this direction, by incorporating wireless monitoring technology, it will be possible to receive vital equipment performance data and generate an audit trail; allowing maintenance, health and safety and compliance teams to make informed decisions to proactively manage their maintenance and validation programmes. By removing the risk from human intervention, such technologies will add a new dimension to traditional containment strategies to allow manufacturers to meet the most stringent regulatory requirements. With the potential to enhance performance validation monitoring they also provide a real-time, ‘real-world’ method of validating and confirming equipment performance in situ.

Conclusion

There are several considerations when containment testing. Due to the clear differences between laboratory and manufacturing environments, it is important to understand the potential limitations of the SMEPAC guideline, which is based on a laboratory test.

As the industry continues to move forward with technological advancements to capture more repeatable and reliable date, there is an opportunity to improve the levels of containment performance and validation testing to maybe eventually replace the single laboratory test.