Optimizing Package integrity operations for multiproduct CDMO facilities.

By: Tyler Harris, Application Engineer, PTI Inspection Systems

A growing pipeline of new and complex therapeutics has led to a monumental shift in business strategy across the pharmaceutical industry. The traditional approach of targeting one blockbuster drug to drive sales is a thing of the past, pushed to the wayside long ago by a combination of addressing unmet medical needs in smaller patient populations and an increased focus on efficiency and flexibility. Now, multiproduct manufacturing allows CDMOs to serve a wide range of clients and products, ultimately accelerating production and improving capacity utilization. Doing so successfully, though, while maintaining quality throughout the product’s life cycle until delivery can be challenging. A critical component to achieving this is container closure integrity testing (CCIT), which offers assurance of a package’s ability to prevent loss and maintain product sterility.¹ However, the effectiveness of any CCIT method is based on physics and the interaction of the product and package characteristics. Thus, with so many product and package combinations in use, how do you as a CDMO optimize operations in your multiproduct facility while also ensuring the technology you invest in can meet the needs of pharma manufacturers and their products? PROBABILISTIC VS. DETERMINISTIC:

A critical component to achieving this is container closure integrity testing (CCIT), which offers assurance of a package’s ability to prevent loss and maintain product sterility.¹ However, the effectiveness of any CCIT method is based on physics and the interaction of the product and package characteristics. Thus, with so many product and package combinations in use, how do you as a CDMO optimize operations in your multiproduct facility while also ensuring the technology you invest in can meet the needs of pharma manufacturers and their products?

PROBABILISTIC VS. DETERMINISTIC: IDENTIFYING YOUR PATH TO QUALITY AND COMPLIANCE

To understand the complexity of this issue, it is important to identify the key differences between the two categories of CCIT methods ? probabilistic and deterministic ? and what impact selecting one over the other has from both an efficacy and a regulatory perspective. Several guidance documents are available to help you with this task, yet USP <1207> provides one of the more thorough overviews, including what is available on today’s market and what the critical differences are between them.

Probabilistic methods rely on a series of sequential and/or simultaneous events, each associated with uncertainties, yielding random outcomes described by probability distributions.² They often require a large sample size and are only visually assessed by a technician, leading to qualitative and subjective results. While USP <1207> does not warn against using these methods, it does stress the need for reliable and accurate test data. Therefore, using probabilistic methods could put the manufacturers you serve at risk of facing scrutiny from regulators about why a method that offers more definitive results about package integrity wasn’t used instead.

The alternative is deterministic methodology, which follows a predictable chain of events, and leakage is measured using physiochemical technologies that are readily controlled and monitored, yielding objective quantitative data.² The investment in a deterministic method can be more significant, but the ROI this type of CCIT method offers is high when taking the benefits of deterministic into consideration, which can be particularly beneficial for a CDMO seeking increased efficiency in a multiproduct facility. This includes not only consistently reliable, science-based data but also several advantages, including a non-destructive approach to testing and easy changeover.

When faced with selecting a CCIT method to implement, you must weigh the difference between the investment and longterm benefits. Quality assurance has always been an investment that provides little measurable short-term ROI but always wins out in long-term performance. Ask yourself ? which option will help elevate your service above your competitors’?

SELECTING A CCIT METHOD WITH OPTIMIZATION IN MIND

If you’ve decided that an accurate, reliable, and repeatable CCIT testing method is the best way to maintain quality and differentiate your service from others’, then it’s time to gain a better understanding about CCIT and, most importantly, what deterministic method is the best fit for each application. The first question you will need to ask is – what is the level of detection required? This is identified through the customer’s own internal assessment based on the product and the risk associated with contamination. There are many types of breaches possible in a manufacturing environment and understanding what they are and how to prevent them offers manufacturers protection against a wide range of issues, such as lot-holds and costly recalls. Using the most appropriate CCIT method can help achieve consistent quality as well as sustainable compliance.

The next factors to consider are the products they want to manufacture and the package format intended for the application. As mentioned previously, the physics and the interaction of the product and package combination are critical. Other factors, such as the head space within a container and product viscosity and chemistry, can also impact how successful one method is over another. With this information in mind, you’ll then need to look at the options for deterministic methods available on today’s market, of which there are several.

For example, vacuum decay is a versatile deterministic method that works well for not only lyophilized products but also small molecule liquids in a wide variety of package formats. It offers defect detection of under 1 micron, making it the gold standard for package integrity testing in the industry today. The level of sensitivity used in a vacuum decay test is a function of the package design, the package test fixture, and critical test parameters of time and pressure, all of which are determined by the scope of the project and product needs. There is also the ability to have multiple test chambers in one instrument, with each test chamber designed to contain the package to be tested, offering the flexibility and efficiency a CDMO with a multiproduct facility needs to reduce costs but also maintain a high level of quality.

While vacuum decay can cover a large percentage of applications, it is not a fit for all. Project scope must remain the primary criteria for selecting the right CCIT method. There is never a one-size-fits-all solution, but there are inspection methods that can cover multiple applications without significant added investments. An experienced and knowledgeable technology provider can help you with your decision-making process, using only the most critical factors of a product’s needs as your guide. Be wary of decisions made on a price tag only and not the overall ROI, as this could result in selecting a method that leads you down a path toward high costs, poor results, and potentially, non-compliance.

RELIABILITY AND FLEXIBILITY FOR MULTIPRODUCT MANUFACTURING

The pharmaceutical industry today ? like the world it resides in ? is a fast-changing and unpredictable environment.Customers look to their outsourcing partners for an optimized manufacturing strategy that offers reliability and flexibility throughout the life cycle of their product. They want to be sure you can provide them the highest level of service and commitment, regardless of how many manufacturers you serve. One common pitfall that can deter this effort and push a company and its timeline off course is a reactive approach to quality control. However, by selecting a CCIT method that holds up to the quality standards of the industry, you can provide them with high-quality delivery systems that can withstand the rigors of the journey from the lab to the patient. As you continue to navigate the challenges of this evolving landscape, choose a supplier that is dedicated to helping you achieve your goals through all-encompassing solutions designed to deliver on the promise of science and your commitment to improving patient care.

REFERENCES

1. US Pharmacopeia. Chapter <1207>. Package Integrity Evaluation – Sterile Products. http://www.pharmacopeia.cn/v29240/usp29nf24s0_c1207.html
2. Stauffer, Oliver and Mullan, Juliet. (September/October 2019). Shifts in Container Closure Integrity Test Methods. Pharmaceutical Engineering.https://ispe.org/pharmaceutical-engineering/september-october-2019/shifts-container-closure-integrity-test-methods