Ruling Out Cross-contaminants: Rapid Delivery of a Validated Cleaning Method
Examining the importance of cleaning validation in supporting product integrity and regulatory approval
Michael Mrvos, VP, Sales & Client Services, Avista Pharma Solutions, Inc.
Eric Kesslen, Site Director, Avista Pharma Solutions, Inc.
Clean Slate: Eliminating contaminants prior to manufacture
Good manufacturing practice includes the prevention of cross-contamination of pharmaceutical starting materials and products with any microbes, microbial toxins, or residues from previously manufactured products. Adequate cleaning procedures are critical in preventing issues with contamination, which can stall regulatory approval or result in the failure of an entire batch of material. Validated methods are required to provide evidence to regulatory authorities that cleaning procedures adequately minimize the risk of contaminating products and ultimately ensure the safety of patients receiving them.
As drug manufacturers continue to strive for lean operation, demonstrating that all surfaces in contact with material meet acceptable criteria allows flexibility in leveraging space and equipment for multiple products. Preventing cross-contamination applies to drug producers of all sizes, from large manufacturing facilities to smaller compounding pharmacies. When drug products need a modification in concentration or an alternative delivery device, compounding pharmacies are key players to meet this need. This case study examines compounding pharmacies for sterile injectables (503B outsourcing facilities) to highlight the importance of cleaning validation as an integral component of meeting regulatory requirements during drug manufacturing.
Closing the gap: Regulations to safeguard product integrity
Compounding pharmacies can vary in size and capacity; they may support patients of a single pharmacy or they can be an outsourcing facility supporting an entire network of providers. State boards of pharmacy govern these facilities, but over the last several years, the FDA has increased scrutiny of compounding practices to ensure patient safety. Tight regulation of sterile injectables followed directly from a noteworthy tragedy involving contaminated products. In 2012, many thousands of vials of a compounded injectable steroid were contaminated with multiple species of fungi, which caused a widespread outbreak of fungal meningitis and resulted in 64 deaths.
The FDA provides a long-established infrastructure to regulate clinical trials and enforce rigorous manufacturing standards prior to approving new drugs. However, compounded drugs are not subject to FDA approval, and the state boards of pharmacy often lack resources or the infrastructure to provide comparable oversight. To close this gap in the regulatory framework, the FDA created the 503B designation for sterile compounding pharmacies to ensure compliance with cGMPs and with guidance set forth in USP General Chapter <797>. Most outsourcing pharmacies are dedicated to compounding efforts and are not equipped to perform cGMP analytical testing themselves. Avista Pharma supports this need by supplying the expertise and technologies to assist drug manufacturers of any size, including compounding pharmacies, in meeting high standards of product integrity.
Beating the clock: Rapid response to an FDA Form 483 observation
Alignment with the product approval process is part of a successful design strategy for any manufacturing process. Prevention of cross-contamination is one of many quality measures over which drug producers must demonstrate control. When confronted with an incident involving cross-contamination, manufacturers must be swift to deploy analytical resources to quickly address the issue and maintain production. Quality audits that result in a major observation by the FDA trigger a required response within a short time frame to address the issue. Quick resolution requires expertise in developing and validating methods, and this is best accomplished by dedicated experts. Avista Pharma is a leader in the industry to support clients in quality compliance with their broad experience and flexibility to support sudden urgent timelines. In the case discussed here, a 503B compounding pharmacy consulted the experts at Avista Pharma to assist them in complying with cGMP standards after a Form 483 was issued by the FDA.
Proper cleaning of a compounding area requires manufacturers to demonstrate that no residual material is left behind to prevent cross-contamination with future formulations. This case involved a Form 483 citing a deficiency for cleaning assays following work with a beta-lactam antibiotic, which poses a particular risk of contamination. Beta-lactam antibiotics raise a frequent concern among drug manufacturers because they represent a large segment of the antibiotic market despite their association with potential life- threatening allergic reactions. Because of the potential for severe health risk to patients, these antibiotics are considered contaminants that require specialized engineering controls for compounding pharmacies and manufacturing facilities. Production areas and equipment must be cleaned according to validated methods and then tested for cross-contamination to ensure patient safety.
Cleaning validation for beta-lactams provides a worthy proving ground for CDMOs such as Avista Pharma to demonstrate their ability to meet rigid acceptance criteria under tight timelines. Just as FDA guidelines include worst-case testing, demonstrating readiness to manage a high-risk contaminant that requires highly sensitive detection is evidence of Avista Pharma’s expertise in supporting this stage of drug manufacturing for even the most difficult contaminants.
Armed with the proper analytical expertise and instrumentation, and by dedicating resources around the clock, Avista Pharma delivered a validated assay in a fraction of the time this testing and development typically requires. The analytical method for cleaning surfaces and the quantitative analysis for a specific beta-lactam residue was developed within 8 days, expediting the progress of the next steps in validation. After optimizing the sensitivity of the cleaning assay to achieve a lower limit of quantitation for residual beta-lactams, our experts delivered a validated method. All activities were completed within 14 days to support the client’s quick response to the major observation.
Knowledge transfer: Integrating capabilities to educate the industry
The process of technology transfer is familiar to any drug manufacturer, and at its core, is the transfer of knowledge so that the process can be replicated. Similarly, leaders in the industry are called upon to transfer knowledge in order to replicate best practices. Avista Pharma is leading an initiative with counterparts outside the manufacturing realm to educate outsourcing pharmacies about managing multiple facets of cleaning validation. With partners in the legal domain and educational consultants, Avista Pharma will help establish a 3-tiered source of best practices for 503B facilities that includes education, analytical testing and consultation about the legal aspects of regulatory standards.
Based on the well-known steroid injection tragedy and other adverse events resulting from contaminated injectables, there is a clear need to raise the standards of practice among outsourcing facilities. However, the lessons learned apply to drug manufacturing as a whole, and ensuring product integrity early in any manufacturing process not only serves the patient, but also supports success in regulatory filings. When drug manufacturers of any size lack the means to perform cGMP analytical testing themselves, Avista Pharma can bridge the gap in supplying the expertise and technologies to carry out testing at the highest industry standard. Our experts draw upon broad experience to ensure that materials meet acceptance criteria that support patient safety, while delivering validated methods to assist clients in meeting regulatory milestones.
Success beyond science.
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