How CDMOs can Avoid Package Integrity Recalls through Sustainable Compliance.

Since announcing its initiative to modernize the regulation of pharmaceutical manufacturing and product quality over 20 years ago, the FDA has continued to reiterate its stance that establishing an effective level of quality control stretches well beyond meeting only the minimum requirements for cGMP; instead, it means utilizing advanced technologies that allow a facility to continuously operate above the bar through transparency and traceability. These investments drive what the agency describes as “sustainable compliance,” which is the state of having consistent control over manufacturing performance and quality. Without it, the industry will continue to experience quality-related recalls that have historically led to drug shortages and threatened public health. One way to work toward sustainable compliance is through container closure integrity testing (CCIT) methods that can accurately evaluate and analyze package integrity. However, their effectiveness relies on a clear understanding of the application and project scope and employing the appropriate technology for a specific product class. As CDMOs, you are faced with a wide range of customer products and needs. Therefore, it is imperative you understand what questions you should ask your customers to identify the right CCIT method for their product and secure access to technologies that can address the scope of services you need.

MITIGATE THE RISK AND FALLOUT OF DRUG RECALLS

Having the foresight and control to detect problems before they occur protects public health in myriad ways, especially when preventing quality issues that can result in costly recalls. This is more important than ever as innovations in science and technology are leading to exciting discoveries and novel drugs that stand to change millions of lives. The industry must be able to meet the moment by ensuring the integrity of these drug products as well as their container and closure systems is maintained at every phase of development and manufacture. This includes preserving their sterility and stability. Yet, a lack of sterility assurance is the most frequently cited quality issue for drug recalls. Review nearly any weekly Enforcement Report from the FDA and you are likely to see at least one recall related to this issue. Manufacturers facing a recall and, if applicable, the CDMO they partnered with - will need to identify what went wrong and where, all while the affected product(s) is removed from the market and production is suspended until the issue is resolved.

UNDERSTAND THE RISKS TO YOUR CUSTOMERS’ PRODUCTS

And although the financial fallout of a recall can eventually be calculated, what about a company’s reputation. In some cases, damage to both the manufacturer's and CDMO's brands could be too significant to overcome, leading to poor performance in the market and, eventually, lost jobs and other consequences. Thus, protecting your customers’ products is critical to their future success as well as your own. You can mitigate the risk of recalls by selecting a container and closure system based on the unique characteristics of a drug product and utilizing advanced CCIT methods that help detect package integrity issues before they threaten the quality and availability of these medications.

There are several factors that determine the effectiveness of a product and package combination. This includes, but is not limited to, the materials being used, the molecule, and even the structure and finish of a stopper. Adding to the complexity are breaches in sterility that can come from a number of issues, such as any crack or defect in the packaging that allows moisture, air, microbes/bacteria, or other harmful substances to enter the product, compromising safety and/or efficacy. Sterility issues can also be a result of fibers within the stopper or plunger seal surface or defects related to poorly molded stoppers, a change in material specifications (from new or existing supplier), improper fit, over crimping, or in-process issues.

While these breaches are possible in any manufacturing environment, CDMOs could face greater risks of packaging integrity issues due to the inherent challenges related to having to meet more than one client’s specific project needs. For example, CDMOs often rely on standard container and closure formats, such as a 5- or 10-milliliter syringe, and, as a result, they use a fill/finish system selected for that application. However, a sponsor may have a container and closure system design outside of these parameters for which the CDMO must still be able to properly fill and sanitize. Therefore, issues may arise if they are not utilizing a CCIT method that can aggressively and effectively test a container format and ensure the fill/finish process they’re using isn’t creating defects or an improper fitting of the components designated by the customer.

Given this diversity, there is no one test method that can be applied to all product packaging systems. The onus then falls on the CDMO to ask questions as early as possible about the customer’s process, their product(s), and their package system in order to identify the proper test method. The goal is to understand not just the product itself, but also any risks that would impede its ability to function as intended. Then, select a CCIT method that accounts for these factors. Traditional methods do not provide the granularity to truly assess sterility risk. As an example, a commonly applied CCIT method is the dye ingress leak test, which has a limit of detection of only 20 microns for rigid containers (or even higher for other package formats), meaning it cannot detect leaks lower than this level. However, defects below 10 microns pose a considerable risk for microbial ingress, and those below 5 microns can introduce oxygen, creating a high level of concern for products that are oxygen sensitive. By using advanced CCIT methods from a qualified technology provider, you can elevate the service you provide your customers, differentiating your organization from competitors and, most importantly, protecting patients.

SECURE ACCESS TO ADVANCED CCIT METHODS

The nature of the CDMO business is dynamic and flexible, so you must secure access to technologies that can accommodate the ebb and flow of this demand. While there isn’t one CCIT method that can be applied to every product, it is possible for one method to be used for most applications. And just as important as it is to ask the right questions of customers about their product and its needs, it is also essential to ask the right questions of an inspection technology provider. When vetting a solution, start with the question - what are the broad applications for which this technology can solve most issues?

For instance, PTI offers high voltage leak detection (HVLD), which is specific to vials and syringes that are liquid filled, i.e., large molecule products. If a client is filling a lyophilized product, though, they cannot use HVLD but, rather, will need to rely on vacuum decay. This approach works well for not only lyophilized products but also small molecule liquids. Although it is not ideal for large molecules, the CDMO and customer could talk through a control strategy where they may deploy vacuum decay under the right circumstances and have a vacuum-based solution that addresses the majority of the client's issues. This is just one example of how critical it is to have an experienced technology provider that can educate you on technologies and their uses.

In addition to mitigating the risk of integrity breaches, advanced CCIT solutions rely on deterministic testing methods, which follow a predictable chain of events, and leakage is measured using physiochemical technologies that are readily controlled and monitored, yielding objective quantitative data. And as described by the FDA, objective quality metrics data “may lead to higher levels of safety, efficacy, delivery, and performance” and “play an important role in supplier selection and can inform the oversight of contract activities and material suppliers, as well as help determine appropriate monitoring activities to minimize supply chain disruptions.” The data from these solutions also provides traceability, increases visibility into your manufacturing processes and, if necessary, is accessible for regulatory inquiries.

REIMAGINE THE SCIENCE OF CONTAINMENT QUALITY

Drug and medical device product failures that result in recalls are often costly and can delay delivering products to market or even completing a filing. Furthermore, a catastrophic issue such as this in today’s climate is even more challenging, as reaction time to a recall and/or any necessary corrective actions may be slower due to ongoing supply chain delays. Taking proactive steps with advanced CCIT methods can prevent these situations.

As the FDA continues its push to drive a culture of quality in pharmaceutical manufacturing, it is imperative to arm yourself with a partner that understands the science and the factors that drive its success and can develop methods to support your needs. PTI is focused on remaining this type of partner in today’s ever-changing industry landscape by reimagining the science of containment quality. We strive to achieve this through all-encompassing solutions that include IQ/PQ recipe creation, method validation, and excellent service that empowers you to deliver on the promise of science as well as those made to your customers and, ultimately, the patients who depend on them.