Performance validation: HPAPI containment testing in a risk-based era

Taking a more automated approach to validation testing paves the way to capturing more repeatable and reliable data, thereby improving levels of containment performance

In an industry that is seeing a surge in oncology and immune-suppressant therapies, and increasing demand for high potency active pharmaceutical ingredients (HPAPIs), there is a growing need for manufactures to look at more innovative containment strategies to meet high potency handling requirements. Subsequently, as these containment strategies evolve, so too does the role of containment verification and there is a clear need to understand the potential variations in testing and differing interpretations of results.

In this article, Michael Avraam, Global Product Manager at ChargePoint Technology, discusses the key considerations linked to containment performance testing, data collection methods and the interpretation of results. He also describes some technological developments that may help to ensure more efficient and consistent containment performance testing.

Industry landscape

Itís well documented that the biopharma market is continuously expanding, largely thanks to the global demand and growth in the oncology market. 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%.1 This has led to an increased need for the development of potent compounds and an increase in conventional drug manufacturing using HPAPIs.

The HPAPI market stood at a valuation of $2.64 billion in 2014 and, as a result of these trends, it is projected to be worth $25.11 billion by 2023 (Figure 1). Between 2015 and 2023, the market is expected to expand at a CAGR of 8.3%.2 Furthermore, the containment solution market is expected to grow rapidly by 2020, resulting in an increasing need for more advanced control strategies in high potency manufacturing that address both the quality of the final product and, critically, operator safety.

Market diversification has allowed more innovative technology development to safeguard drug products and the operator, including isolators, restricted access barrier systems (RABS) and split butterfly valves (SBVs), which are all now commonly used throughout the manufacturing process. In particular, closed transfer valves, such as the use of SBVs, are increasingly replacing traditional open transfer valves owing to the limited manual intervention involved, which reduces the risk of cross-contamination and the presence of airborne dust particulates, ultimately protecting operator safety.

Containment performance testing

All manufacturing equipment must be validated prior to its use in the manufacturing process. For example, before a manufacturer can implement a new control device within its process, it should be assessed according to the International Society for Pharmaceutical Engineering (ISPE) SMEPAC (Standardised Measurement of Equipment Particulate Airborne Concentration) guideline for its particulate containment performance. This is intended only as a guide for manufactures to enable them to demonstrate how a containment device will perform as part of a laboratory condition test, not within a particular process in the final manufacturing facility.

This guide was introduced in the 1990s, following the shift in focus from occupational health professionals on worker exposure measurement as the primary target to qualify containment equipment. It was formalised as SMEPAC and later adopted and revised by the ISPE. Although it is widely welcomed by the industry to ensure good practice within the validation of containment performance, the random nature of the guidance on sampling methods and distribution has been questioned by some who feel that it is challenging to achieve a specific measure of containment for equipment or devices. Some argue that the data lacks statistical validity and, more importantly, the method would be better suited if it provided a baseline dataset for future integrity testing.3

Data interpretation

There are many factors that can affect the interpretation of the SMEPAC test results, including the following:

Placebos: The SMEPAC guide recommends a variety of particle sizes and levels of detection of placebos during validation testing, including lactose, paracetamol, mannitol and naproxen. However, there are a number of questions that need to be addressed relating to how this could affect the interpretation of the results: how relevant is the test placebo to the real-life API that will eventually be used and has each supplier tested with the same placebo?

Test equipment: There is the possibility for test equipment with the same performance to show differing results ó owing to the considerable differences associated with various samplers when using the same test. Figure 2 is an example test table demonstrating the test material mass range used for each test cycle.

Testing protocols: As detailed by SMEPAC, the testing protocols allow for a certain amount of inconsistency. For example, referring to transfer quantity, the SMEPAC guideline notes that ďthe masses are intended to fully coat the exposed seal and operating surfaces and are suggestions,Ē so the very nature of providing a suggested weight range means that testing devices with volume variation will likely result in inconsistent results.

Data: Data is an integral part of any test, and manufacturers often use the data from this laboratory validation test to qualify the selection of the required containment technology for their process. However, this could prove to misrepresent reality, especially as the comparison isnít like for like. There are variations in the way the containment performance tests are done in the laboratory, and the interpretation and utilisation of the results obtained can be inconsistent with the real environment. Consequently, it is risky to presume that performance should be the sameÖ and itís important to consider the potential variables.

Contamination and operator intervention: During high potency manufacturing, itís essential to ensure full operator safety and reduced levels of contamination. As human intervention is present at almost every stage of pharmaceutical manufacturing processes, solutions must counter the potential risks. Critically, containment needs to be achieved while not hindering productivity and operability, which can sometimes be challenging.

Containment validation testing must also reflect operator intervention to ensure that the containment device is tested accordingly. Some of which, however, can be reliant on operator technique to achieve performance, thereby increasing variability even further.

Potential exposure: Validation must also be done 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 prior to being in the laboratory environment cannot be compared measurably with its normal application within the manufacturing area.

Preventive maintenance: Ensuring frequent monitoring and preventive maintenance helps to safeguard the reliability of the containment solution. Risk is limited if the identification and rectification of any damage has occurred prior to the test. By limiting manual intervention throughout the whole validation testing process, this will also help to maintain a more consistent result.

Technological outlook

The containment market has continuously adopted new design technologies, including SBVs, which have evolved during the last two decades to address more stringent containment demands when handling potent compounds. Other containment solutions such as isolators can be integrated with SBVs to enable the safer transfer of potent compounds and can be used in many applications when product flow, yield and sterility are important, as well as dust control and containment.

There are multiple ways to improve valve performance, including double gloving, enhanced wiping procedures and waste disposal. However, by further reducing human intervention and introducing an automated approach, could this be the answer to improved performance?

As the industry moves towards automation, the adoption of wireless monitoring technology will make it possible to receive vital equipment performance data and quickly generate an audit trail, thereby allowing maintenance, health and safety and compliance teams to make informed decisions to proactively manage their maintenance and validation programmes. Such innovative technologies promise to revolutionise traditional containment strategies, allowing manufactures to meet the most stringent regulations. There is also a real potential for an automated approach to enhance performance validation monitoring by providing a real-time, real-world method of validating and confirming equipment performance.

Final thought

Although widely adopted and welcomed, there are certain considerations to keep in mind when containment testing according to SMEPAC guidelines, and itís important for manufactures to understand the differences between laboratory and manufacturing environmentsÖ and the potential limitations of these guidelines. With the introduction of a more automated approach to validation testing, itís possible to capture more repeatable and reliable data, thereby improving levels of containment performance and, perhaps, even replacing the laboratory test in the future.

References

  1. www.persistencemarketresearch.com/market-research/sterile-injectable-drugs-market.asp.
  2. www.transparencymarketresearch.com/high-potency-active-pharmaceutical-ingredients-market.html.
  3. www.pharmtech.com/environmental-containment-performance-there-accountability.

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