Why are we seeing so many large-scale quality issues of late
from both in-house pharma and outsource manufacturers?
Another reason for high-profile systems failures may be linked to the fact that different Health Authorities can have different tolerances for the same observation. A facility may be operating under what it believes is a satisfactory state of compliance - until another Heath Authority, or even multiple Health Authorities, inspect the same facility with a different view. “All of a sudden” there can be findings of serious long standing compliance deficiencies. Further compounding the observation is that deficiencies of long duration can result in very broad and poorly defined investigational requirements, making resolution very difficult. Finally, once any competent authority takes a serious position on a violation, all others usually concur, making the failures “high profile” and multinational.
—name withheld by request
In my opinion, it's due to multiple reasons (these are all hypotheses):
- As Big Pharma has downsized its network of commercial manufacturing sites in a huge way, CMOs have taken on these sites, and this has caused enormous quality pressures on the CMOs, since they are not fully geared to assume full burden in a short duration.
- Regulatory agencies around the globe, including the FDA, have focused deeper and have gone deeper, magnifying glass in hand.
- More growth and emphasis on biologics — including vaccines by Big Pharma and Biotech — have brought in more sterile products for cGMP manufacturing; these have much stringent controls than those for the manufacturing of solid dosage or other non-sterile conventional products.
Eventually, this should reach a steady state and equilibrium!
—Mak Jawadekar
At the risk of sounding naive, I believe that the root of most problems on the CMO side is profitability of the organization. This multi-headed monster takes on several faces, not simply earnings per share.
For example, in a CMO, companies must continue to generate new projects in order to maintain a high degree of facility utilization. This means better throughput and rapid turnover of projects. As we've seen recently, validation and process qualification often suffer as corners are cut to get projects into a revenue-generating position quickly. Sponsors and suppliers alike may contribute to this pressure by wanting to push materials through the system quickly for use in trials or for filling the commercial pipeline. Speed to market has become the mantra of a number of suppliers and sponsors.
Competition in the CMO market is heating up, with companies trying to broaden the services offered to clients. This has resulted in expansion of services — formulation development at traditional fill/finish providers, for example — that are a bit outside the suppliers' comfort level. The added pressures of providing these services often takes away from the company's core assets, resulting in operating and quality difficulties.
—name withheld by request
We have seen that the global economy is going through a challenging and interesting transformation. In this painful and troubled environment the pharma world is not left alone, but rather faced with a tougher path and choices. Even though the user (that is, the end customer) and the FDA have not changed their requirements and expectations, the overall management did require some changes in operational strategies so as to improve efficiencies and thereby cut down the effective end cost while maintaining (or rather constantly improving) the quality under the umbrella of Quality by design (QbD) paradigm.
It is easy to say, but the actual execution is much more difficult and not short of challenges. While hanging in the troubled waters, the pharma companies are either putting increased pressure internally to improve efficiencies and/or are moving offshore and relying more and more on outsourced CRO/CMOs’ working culture, style, capabilities and a few other unknown attributes and factors. While working in-house, the increased pressure or stress is leading to cutting corners throughout the chain, starting from procurement to end quality testing.
On the other hand, while moving to external CMOs, pharma companies are losing control over their materials, processes and controls in the manufacturing and distribution chain. All these factors are leading to inferior quality standards of the end product and thereby increasing the risks of recalls and observations by the regulatory agencies during inspections. I believe this is the main reason for the high profile quality failures in recent years.
—Jack Aurora Ph.D.,
Hisun Pharmaceutical Co. Ltd.
I believe the increase in failures is due to a lack of oversight. Decisions are made at a lower facility level and signed off at higher levels in that facility, and often in the staff QA organization with responsibility for oversight at that facility. QA organizations have always been under pressure from a resource perspective — until a problem arises. Then management throws every resource at the problem, because a shutdown or recall has serious financial implications. As in many failures that have occurred, it had been ongoing for many years and rose to the surface during an inspection or recall. It’s easy to talk the walk, but much harder to walk the talk!
—Bob Calabro
Pharma Outsourcing Advisors
Current products seem to be taken for granted. They are making the company money, “and they always will,” after all. Why not squeeze out some of the costs and increase the margins? The current manufacture of products is not the sexy part of the business; R&D is. So spend on the latter at the expense of manufacturing. Needed investments for facilities and personnel are spent elsewhere.
The attitude of “making my boss happy” goes up the line and can come into conflict with getting out the news that dollars are needed to update the facility, for example. Warnings from the FDA may even be ignored in hopes that they will go away. (They never do.) There is great concern for the bottom line and making the investors happy as well. Somehow this must be balanced with real needs in manufacturing.
It is perhaps human nature to take for granted what we have. This is a mistake, whether in personal relationships or in running a company.
—Martin Steinman
I believe this problem has two root causes. From the small molecule perspective, I think we are seeing a slow erosion of quality control as companies try to reduce the overhead associated with the production of their products. On the large molecule side, issues like glass delamination are occurring in part because of the increase in the number of biologics on the market and the new formulations introduced resulting in interactions with the glass vials that were unexpected and not well understood.
—name withheld by request
The U.S. pharmaceutical industry is in the midst of a time like no other — incredible healthcare cost pressures, the expiration of key patents (the oft-mentioned "patent cliff") and relatively unproductive new product pipelines in many companies. At some companies, these factors can unfortunately drive short-term thinking and a relentless focus on cost control. As a result, companies are at risk of getting into trouble and, worse, putting patients at risk. Employees are spread very thinly and often do not have the combination of knowledge and experience to do their jobs effectively.
We see however a number of leading edge pharmaceutical companies that do their best to counteract these pressures. They continue to invest in the development of their people and knock down the traditional silos between Quality, Manufacturing, and R&D, while embracing initiatives such as Operational Excellence, Error Avoidance, and Quality By Design. While these cost pressures exist (and they will not go away), companies and employees need to hunker down, take a longer-term view, and ensure employees understand the “basics at a Ph.D. level” so they can excel in what they do and contribute to their company’s objectives each and every day.
—Jim Scull, NSF Pharmalytica
(with Jim Morris and Neil Wilkinson, both partners at NSF-DBA)