PhM: What were the greatest challenges that you and your team encountered as you worked to determine the root cause of the heparin contamination? What do you feel are the key lessons that the pharmaceutical industry can learn from this case?
MN: There were several challenges involved. First, this is a very complex biological material, considerably more complex than some of the traditional biotech products
Secondly, available analytical methods, whether they are regulatory methods and applications or [compendial] methods in USP or [European] Pharmacopeia are very old analytical methods, and some of them have not improved since they were adopted some 60 years ago.
In addition, some of the bad batches of heparin did meet our regulatory and compendial standards, so there was no failing if you tested using these old-fashioned analytical methods.
Fourth is the lack of pharmaceutical development and detailed manufacturing information in the applications we have, what I will call the Quality by Design-type information. Because if we had Quality by Design type information on pharmaceutical development and manufacturing science, it would have been easier for us to identify the potential cause of the problem.
Instead, we had to start from scratch, conducting very detailed quality risk assessment of all aspects of the manufacturing process and the product characterization. So we had, in some ways, to redevelop or retrofit the information we have in the application, plus additional inspectional DMF [and] other information to restructure the type of information that we need and we expect nowadays. That was a major challenge to remap the entire development, manufacturing process, and the product characterization.
Once we restructured the manufacturing development and risk assessment of all these pieces, we started approaching the problem in a very systematic way, looking in different directions, looking in structural direction, looking at detailed structural analysis, using NMR and different methods, and also looking in the biological side, using more biological assay methods that may be more specific than the traditional anticoagulant assay that’s [accepted] by the USP.
So using biological investigation and structural, chemical characterization, we arrived at the fact that there was a heparin-like contaminant that exerts some biological activity but has some difference in the structure. And we identified this contaminant to be the oversulfated chondroitin sulfate.
Then we had to find the leading experts not only in the U.S. but in the world in order to confirm the earlier findings, because we had to go out and tell the public what had happened and develop the appropriate regulatory strategies, testing and other, to make sure that that contaminant was no longer present in any marketed heparin products.
PhM: How did you use risk management principles to prioritize the testing and rule out the options, and how did you connect clinical data to this investigation?
MN: As far as risk assessment, basically we have found, based on earlier survey and screening, that this was a quality issue. It had nothing to do with the medical practice in the clinics where patients had the adverse events associated with this heparin, whether a dialysis unit or surgical procedure.We were able to rule that out.
So we were able to focus that there is a quality problem with certain batches of heparin. So once we had done that, we had to follow good, quality risk management. We used a [fishbone] diagram, and looked at every possibility that could lead to a problem, whether it was in the raw material, in the reagents, equipment, the testing itself, or the manufacturing environment.
Results pointed to an external contaminant, so we started doing testing on the biological side and the analytical side. We needed to find a contaminant that acts like heparin in some ways and has some structural similarities and yet some differences. That then became the focus of our research.
PhM: Do you see a point where there might have to be a wholescale upgrading of analytical testing methods to avoid future cases involving other biomolecules or other molecules in general?
MN: Because of the challenges we had, not only the USP but the European Pharmaceopeia updated their monographs. Number one, I continue to believe that manufacturers have the primary responsibility for the quality of the product they manufacture. The FDA has to have an appropriate regulatory oversight to assure quality, safety and efficacy. But the primary responsibility is the manufacturer’s.
And that will mean different things. That will mean assurance of the quality of the product throughout the product life cycle and throughout the supply chain. So the manufacturer has the ultimate and the main responsibility to assure quality of all the raw materials, active and non-active ingredients purchased from suppliers in the U.S. or overseas, and to make sure that the quality system they have is capable and robust enough to assure quality throughout the process. That’s number one.
Number two, I also believe that incorporation of a Quality by Design type information is a key to better understanding and appropriate regulatory oversight.
Because based on the information we now have, and the risk assessment provided, we will have a better way to assure that the weak links in the supply chain or manufacturing are being addressed. If we lack this information, there will be knowledge gaps. We will then have to address some of these gaps when we have a crisis, and that’s not the way to do it. This is something that the American public will not tolerate or accept.
Thirdly, manufacturers should use modern analytical technologies, not only to satisfy regulatory requirements, but as a good business practice, to ensure the quality of all ingredients, active and inactive, throughout the supply chain to assure the consistency and robustness of the manufacturing process and the quality of the product. Manufacturers should use this whether or not it is required by regulators.
As regulators, we too must find a way to encourage, and in some cases, require the use of modern and appropriate methodologies to ensure the quality of the product.
[At some point], that may mean that we will have to find a way for periodic updating of compendial requirement of all pharmaceutical products, not only complex biologics such as heparin. We may need to find a way to interact with the USP to ensure that monographs of the public standards are updated and are adequate based on the current science rather than based on science that was available when the product was first approved fifty or a hundred years ago.
PhM: Do you feel that more explicit language is needed in the form of guidance for applying risk management and evaluating suppliers, because very often it’s the third or fourth link in the supply chain that gets completely overlooked?
MN: Right. I think our current [code] manufacturing practices require that. Existing regulations already requires manufacturers to ensure the quality of suppliers and so forth. This is already there. But we may have to find a better way to provide more clarity of what the Agency expects, and that could take the form of guidance, etc.
This is all spelled out in ICH Q10. There is language in ICH Q10 that addresses the responsibility of manufacturers and the Quality System to assure quality throughout the supply chain.
PhM: What QbD lessons can be drawn from the heparin recall?
MN: A QBD framework, first of all, would be advantageous from the cost perspective. When you have a systematic approach to development and manufacturing and quality control, and you do the appropriate risk assessment to guide the development and manufacturing and quality control, then you have a better way of knowing where is the area that poses the most risk, the investment needed and the appropriate testing that will be needed.
If you don’t do that, then you are spreading your costs in some areas where there is minimal or no risk, and yet treating those [lower-risk] areas as if they could pose maximum risk to the patient. So if you really do use a very sensible, systematic approach guided by good quality risk management, you will have development and manufacturing controls that can and will avoid many scenarios – I’m not saying every scenario – but many scenarios similar to what we encountered with heparin.
To be more specific, better characterization, modern technology on manufacturing and testing, using quality risk management and risk assessment to make sure that the quality throughout the supply chain and the product life cycle is assured, all these things are embraced by Quality by Design.
Then there’s that other piece of Quality by Design that’s very important, and sometimes misunderstood: Quality by Design does not mean less laboratory testing. It means [the most] appropriate testing.
In some cases, there may be more testing for certain attributes, and maybe less reliance on testing of other attributes. The quality control strategy that we are advocating under Quality by Design requires reliance on appropriate understanding during development, appropriate manufacturing controls, and appropriate analytical testing.