BioProcess Blog |

By Patti Seymour  (pseymourbptccom)  

With shortages of life saving medicines making headlines recently, President Obama signed an Executive Order on October 31 to ease pressure on health care providers and reverse this dangerous trend. Drug shortages, primarily involving generic sterile injectables, have been increasing in frequency and severity in recent years with roughly half of the approximately 80 manufacturers experiencing shortages in 2011.

FDA has reacted to this situation by issuing “A Review of FDA’s Approach to Medical Product Shortages,” detailing the existing drug shortage, summarizing actions FDA is taking both to prevent and respond to drug shortages, and the unique drivers causing these shortages. While the problem is complex and caused by a variety of contributing factors, quality issues at the drug manufacturing facilities seem to be a leading cause of the drug shortages, accounting for 43% of all shortages. As discussed in my previous post on this topic, FDA is focused on identifying and correcting supplier performance as part of their overall risk-based approach to inspections, which has translated into numerous 483 citations at sterile product contract manufacturers. The expectation is that Sponsors will be more proactive in managing these suppliers to ensure product quality, but clearly this is not happening. A leading manufacturer of sterile injectable oncology products, Ben Venue Laboratories, announced in August that the company was exiting the contract manufacturing business while it dealt with multiple FDA 483s at their manufacturing facility in Bedford, Ohio. Unfortunately for Sponsors and patients relying on medicines manufactured there, Ben Venue temporarily suspended all drug manufacture and distribution just before Thanksgiving, putting further pressure on already stressed supply chains.

Unfortunately, Ben Venue is not an isolated case. When using a CMO for any part of your supply chain, it is important to ensure that the CMO is operating in full compliance of all cGMP regulations to avoid supply disruptions. This diligence begins with the initial selection of the CMO but should continue through periodic GMP compliance audits. Without question, any quality issues identified either during a Sponsor audit or a regulatory inspection should routinely be addressed immediately and the CMO monitored to ensure appropriate corrective actions have been implemented and compliance is maintained or restored. Proactive supply chain monitoring can provide early warning signs of potential supply chain issues, enabling Sponsors to implement risk-mitigation plans to head-off potential catastrophes. For all links in the supply chains, a risk-management plan which identifies all elements that could contribute to a breakdown in supply and outlines risk-mitigation strategies, such as second source manufacturing for key links in the supply chain, that will ensure continuity of supply.

While some of the current drug shortages could not have been predicted, many of them could have merely by connecting the dots through vigilant supply chain oversight and robust risk-management plans. It’s not too late to thoroughly analyze your supply chain and inspect it for any chinks or weak links that could disrupt continuity of supply. Make this your New Year’s resolution.

Join Dr. Susan Dana Jones  (sjonesbptccom)   at the second annual Cell Culture World Congress to be held in Munich, Germany from February 28 to March 1.  At the conference, Dr. Jones will provide insights into the benefits of focusing on product quality early in cell line development in her talk entitled, “Enabling cost-effective product quality focus in early biopharmaceutical development.” Email  (sjonesbptccom)   Dr. Jones to set up a meeting.

By Alex Kanarek  (akanarekbptccom)  

If you still have concerns on how to implement the three key ICH Guidelines Q8, QA9 and Q10 into your company’s product development and manufacturing plans and quality management system, you can rest easy – help is at hand from ICH. The Quality Implementation Working Group (IWG) issued a “Points to Consider” Guide (PTC) for these three guidelines, which was published on the ICH web site in July. The document has considerable credibility, as it is based upon questions raised during 2010 training workshops held in the US, EU and Japan. It is intended to supplement ICH’s December 2010 Question & Answer document and the training materials that ICH has made available on its web site.

The most useful “Points to Consider” are those discussing the relationships between risk and criticality and between criticality and control strategy. The level of risk is determined by an assessment of severity, occurrence and detectability, and it can be altered by the application of risk management techniques. But the criticality of a quality attribute is primarily based upon the severity of the risk and is not changed by risk management activities. Since the criticality of a process parameter is linked to the probability of occurrence and detection, risk management may reduce the risks associated with this attribute. In other words, companies can use risk management to define the critical quality attributes, but they would use risk management to control the level of risk and determine the acceptable limits of the resulting critical process parameters.

This concept is crucial in the application of Q8 and Q9 and this highly relevant document can significantly increase understanding of the principals involved. Furthermore, the PTC guide discusses the concept of the Control Strategy Life Cycle. The document explains that control strategy is an essential tool in ensuring that CQAs are met in all stages of product development. Therefore, it has a life cycle that runs parallel to that of the product. As knowledge of the product and the manufacturing processes improves, the strategy will involve making changes to acceptance criteria, analytical methods and/or sampling points. Control strategy development should take into consideration the effects of scale-up and transfer of manufacturing to another facility, presenting yet another opportunity for the use of Quality Risk Management tools.

The Control Strategy discussion is taken even further in the introduction of Real-Time Release Testing. This technique may take some time to be implemented in the biopharmaceutical industry, but it needs to be considered now, in order to plan for the day when suitable analytical and control tools become available.

In all, this “Points to Consider” guide is required reading for anyone currently involved, or planning to be involved, in the implementation of the three key Guidelines in successful product development. But, remember, however you are applying the concepts of Q8 – 10 and QbD, compliance with the current GMP regulations is still required.

Dr. Sheila Magil   (smagilbptccom)  and Dr. Susan Dana Jones  (sjonesbptccom)   will be joined by Joyce Chiu of Sperian Protection to offer a short course on Ensuring Operational Excellence in Bioprocessing: PAT, QbD, DoE and Continuous Improvement – An Introductory Overview at the Bioprocessing Summit to be held from August 22-25, 2011 in Boston, MA. This short course is designed to impart the lessons learned from other industries to the application of Quality by Design, DoE, and PAT in biopharmaceutical production. Dr. Jones will also present a talk in the Optimizing Mammalian Cell Lines track of the main conference on Wednesday August 24, entitled Applying Quality by Design Principles to Candidate Selection and Cell Line Development, where she will demonstrate the advantages of evaluating product quality as early in development as feasible.