In a blog post on August 12, 2014 (here), I raised the question of why there have been so many recalls of parenteral products related to visible particulate matter. I also asked for suggestions and comments on the post. While we did not get a lot of feedback from the readers of the post (there were about 400+ readers), we did hear from a few of you. Although no one had a solution to the problem or specific suggestions to fix it, some of the comments pointed to what we had expected all along. There are a multitude of factors that lead to the formation of particulate matter, some of which have to do with formulation, some with storage, some with handling, some with manufacturing equipment and the like as was discussed in the blog referenced above.
One commenter noted that many of these facilities manufacture product for both the US and EU and wondered if there was a difference in the recall profile between the two regulatory regions. It was noted that the commenter did not think there should be a difference for parenteral products (presumably because visible particulates should be a high concern for each Agency), like there might be for oral dosage forms where the philosophical differences between the regulatory bodies are more “stark”.
Another commenter indicated that the standards that their contract manufacturer was using were different than what they used as their standards and, even through discussions with the contractor, they continue to agree to disagree! Still another speculated that, with all the facilities that got hit at the same time a few years back, and remembering back to their QA days and the old GWQAP (Government Wide Quality Assurance Program) inspection program, maybe FDA decided the “current” standard for particulate inspection should be tightened due to advancements in detection equipment or processes it became aware of and they launched a barrage of inspections to see where the industry stood.
Well, all good ideas and observations but still no definitive answers. In discussions with some of our compliance experts at Lachman, I was pointed to the work International Society of Pharmaceutical Engineering (ISPE) has undertaken with the FDA on the specific topic of drug shortages, of which the parenteral products is a large subset. In one survey, ISPE asked respondents: What is one type of [sterile] production equipment that likely contributed most to the [sterile] drug shortage or near-miss at your company? The response – aseptic processing equipment was the major piece of production equipment reported as posing problems, reported by both individual and company respondents, with lyophilizers coming in a close second. But, with this said, the multi-factorial nature of drug shortages and this specific parenteral problem is ever-so obvious. ISPE has identified the top 10 factors that firms that are the most successful in mitigating drug shortage problems report (which also relate to parenteral products) which are as follows:
- Strong Quality Systems → Ensure compliance to manufacturing regulations
- Avoiding drug shortages documented as Corporate goal
- Strong Quality System track record and GMP inspection history
- Corporate goals tagged to drug shortage prevention
- Ability to quickly react to drug shortages
- Strong relationship with Regulatory Authorities
- Strong communication link with Regulatory Authorities
- Dedicated Resources focused on preventing drug shortages
- Incentives tied to preventing drug shortages
- Metrics defined around drug shortages
They also identified strategies for mitigating shortages which include:
- Quickly react and respond to drug shortages
- Communicate and coordinate with Regulatory Bodies to bring resolution to issues in order to shorten time to re-enter the market
- Transfer products between facilities to provide back-up
- Re-introduce discontinued products
- Prioritize products for manufacturing, testing, and release
- Source alternate API
All of these are the “usual suspects” we think of relative to areas of concern in terms of mitigation strategies through postmortem analysis. The problem of identifying root cause issues are a bit more abstract and elusive. As the problem of visible particulate matter in parenteral products continues to surface, perhaps we will learn more as more data is collected and evaluation of the problem becomes more targeted.