An overview into root cause investigation
Hisun Pharmaceutical (Hangzhou) Co., Ltd., Fuyang, China
One of the main goals of the pharmaceutical industry is ensuring the quality of its products. Science and quality are the cornerstones of any pharmaceutical industry. Against this backdrop, pharma industry members make substantial investments in manufacturing facility, critical building, testing infrastructure and operations to ensure product integrity, quality assurance and control. On the other hand in order to enforce all this, regulatory agencies worldwide implement and support strict enforcement of the most rigorous good manufacturing requirements as set and overseen by these regulators. Now to further support and enforce the tighter regulations and controls, a few years ago FDA had initiated the Quality by design (QbD) program. Effective 2013, all the regulatory submissions including and specifically abbreviated new drug applications (ANDA) will have to comply with QbD expectations and guidance.
All these initiatives and compliance driven requirements are in place and being enforced for the end consumer: patient safety and wellness. A consumer cannot determine whether or not the product he/she is taking is safe and effective and if it will work. Testing alone (as required by the cGMP) is not adequate to ensure quality either. This is because in most instances testing is done on a small sample of a batch manufactured from which the entire batch of product be made available for patients to use or not, depending upon the outcome of this small sample (e.g.100 tablets from a batch of 2 million units) analysis. Therefore, it is not only very important but rather a moral responsibility of organizations (anywhere in the world) that the products are being manufactured under strict controls and cGMP practices to its fullest compliance.
FDA Commissioner Margaret Hamburg in a speech recently urged companies to put out a greater effort to hit quality standards, noting that failures lead not only to costs for manufacturers but shortages for patients. The agency is also expanding inspections of manufacturing plants boosted by user fees, now being kicked in by API and generic drugmakers, but the sequestration law is limiting the FDA's access to those fees and thus the extent to which the agency can expand.
Globalization of industry
Now whatever said above in the introduction section is nothing new but rather age old expectations from the customer and the regulators, over and above the work ethics and moral responsibility of drug manufacturers. In light of economic downturn that started in the West (2007-2008) and after engulfing EU, it is coming over to Asia. The truth of the matter is that our health care system is struggling to establish control over escalating costs. It seems companies have tried different ways to reduce the cost of their products without sacrificing any of its quality controls. As the industry expands and consolidates, this is becoming a challenge for all drug manufacturers. With all these priorities in business, not only the incentive to foster innovation has been dampened but also the cost cutting and cost saving attribute has affected each and every aspect of the development and supply chain, from raw material through to the plants, API, manufacturing, and packaging including quality management.
Where are we heading with all this turmoil?
It is worthwhile to mention here that globalization in pharma industry is making the revolution. In that revolution, responsibilities and work allocation are spreading out in different territories and geographic locations but resources on the other hand are shrinking (rather than growing). Chronic underfunding has left us without the necessary and adequate scientific and human resources to evaluate and control the quality. But as we all know, that seemingly simple solution does not come without challenges. Here are a few of the most recent examples to review and learn lessons from:
Hospira, one of the leading drug manufacturers, last month issued three recalls of 5 products, some because of particles found in retained samples. GlaxoSmithKline has recently sued Hospira over some of the problems, seeking more than $25 million after Hospira was unable to fulfill a contract to make a vaccine for GSK.
A few weeks ago Hospira had been handed a Form 483 outlining 20 concerns, three of which were repeat violations since a 2010 warning letter from the FDA. The observations came after 5 inspectors spent three weeks going back over the upgraded plant that was part of a $375 million remediation Hospira launched at a number of its manufacturing sites. "It is like studying for a test for a year-and-a-half and suddenly it arrives, and the excitement had melted to disappointment and turns out the company failed the exam.”
Jubilant HollisterStier picked up some work recently when the maker of imaging agents needed to move production away from the beleaguered Ben Venue plant in Bedford, Ohio. As it turned out, Jubilant HollisterStier is having some issues of its own at a plant in Canada. In a Warning Letter, the FDA says the contract manufacturer released lots from its plant in Kirkland, Québec, where it manufactures sterile injectable products, even after some of the batches were out of specifications. The inspector was told during the March 2012 inspection that the company "only inspects lots once regardless of the number of defective vial rejection rate." Furthermore, the Warning Letter mentioned that the facility was not investigating every rejected batch as per FDA requirements and did not implement some kind of preventive action to keep the problems from recurring. The agency was unimpressed with the company's response that the "process is known to generate occasional out of limit in-process … aggregate particle density results." Why didn't the company get to the root cause and fix it, the FDA wants to know. An investigator was also troubled by the fact that the plant was not putting in place "corrective and preventive actions (CAPAs) in a timely manner." Some CAPAs were unresolved for 500 to 700 days. One was more than two years old, the Warning Letter says.
In an effort to cut cost and streamline manufacturing operation, Bristol-Myers Squibb reduced its manufacturing network to 12 facilities from 28 a few years ago.
Teva Pharmaceutical Industries indicated that the drugmaker can no longer operate as it did in the "good old days." Therefore, it is looking to cut US$2 billion in annual costs over the next few years, much of that from its extensive manufacturing network. The drugmaker has a network of 74 plants. Eight of those are in Israel, including two of its largest.
Sanofi last year cut 5% to 7% of its workforce of 28,000 in France after facing employee strikes and a public scolding by a top minister. The company made some cuts, but left the rest to attrition
Merck company's head count dropped to about 38,400 from 40,676 over the past year. The restructuring has so far squeezed out 115 million in costs. That puts it on track for the 300 million in cuts it's looking for by the end of 2014. And Merck now expects the restructuring to save 385 million a year by 2018. The cost-cutting drive is already paying off--and more quickly than the company had anticipated partly because of those job cuts and site closures. With all these measures in place the German company doubled annual profits to 789.8 million, or about US$1 billion. The path for business profits Merck is walking along does not stop here especially when they are seeing returns coming out of this tough task of cutting jobs. The company says lots of job cuts are still to come, and most of the "redundancies" will come this year and next.
Impax Laboratories has been struggling for two years to get its manufacturing practices down at a plant in California. The struggles persist, the company has confessed. In fact, a re-inspection of the plant was a train wreck, with Impax receiving 12 pages of Form 483 with a dozen observations, for 17 different products of which three of them were repeats. The FDA also noted that Impax released lots of drugs, even though the company should have known some of its test methods were inadequate. There were also problems with temperature during drying and problems with holding and warehousing of some products. The FDA said Impax was not thoroughly investigating complaints of broken tablets and that its computer systems lacked adequate controls. There were even problems with the basic cleaning of some equipment.
In search for greener pastures
The Middle East, with its political turmoil, has not drawn the same level of heated interest from drugmakers looking to place new manufacturing facilities at other parts of the world, but there are signs that is changing as there is a strong growth potential in Saudi Arabia and throughout the Middle East. Pfizer, the largest drugmaker in the world, is setting up shop there. The Saudi Press Agency reported that Pfizer executives also pointed to the growth potential in Saudi Arabia and throughout the Middle East as one reason to build there.
Pfizer has kicked off construction of a plant in Saudi Arabia, its first in the Gulf Cooperation Council area that also includes Kuwait, Bahrain, Qatar, the United Arab Emirates, and the Sultanate of Oman. The 32,000m2 facility is being built in Rabigh on the western coast of Saudi Arabia. It is slated to be operational in 2015, according to the Middle East North Africa Financial Network. The plant will make a number of Pfizer drugs, and production is slated to hit 18 million packs per year.
Pfizer is not the only drugmaker banking on the upside potential there. Indian generics maker Ranbaxy Laboratories is also building a plant in Morocco as a base for selling in North Africa. Merck Serono recently partnered with United Arab Emirates-based Neopharma. Jordan-based Hikma Pharmaceuticals last year noted it had suffered from the uprisings that have roiled the area since late 2010 but still planned to invest $300 million in the region. It said annual market growth should be about 12%, compared to the 2% forecast for Europe.
After-effects of Globalization
Here, we see all these healthy and big global pharma companies have even much bigger ambitions and they are doing whatever it takes to get to their goals and targets including possible job cuts, apparently. In addition, if we look at the above companies’ profile, capabilities and knowhow, there is no doubt that these are the few of the well-known established and seasoned pharmaceutical giants with the required muscles and strength to produce a quality product consistently and repeatedly. But the fact of the matter is that cost cutting initiatives are picking up the focus and driving these organizations to cut jobs, consolidate of manufacturing plants and move offshore in search for greener pastures. At the end of the day this is what business is and takes priority over everything and anything.
In our personal view and after speaking with a few of the experts in the field in Asia, North America and EU, here is the most probable and root cause of the quality problems that keeps appearing, at different places.
The cost pressure is eliminating jobs and putting pressure on the remaining lean team of professionals to speed up the work and produce same quality work with fewer resources. In addition, the procurement of professionals has the same amount of pressure and urgency as the reduction of the cost of incoming raw materials. The story does not stop here as moving offshore and outsourcing the development and/or manufacturing operation (including Quality) loosens direct control and supervision and relies upon CRO/CMO’s internal systems and controls. It is like getting into a never ending chain reaction engulfing everyone involved in the manufacturing supply chain. Up to some extent the lean organization focus and trend is healthy and is required for the healthy growth of the organization but after a while this may start working against your objectives and end results. This is because people come under so much intense pressure and stress that they can no longer focus on their key responsibility and become an inefficient mass and ineffective tool for the job.
Recent survey and experience sharing has also revealed that deviation investigation management and change controls have merely become a document to show to the management and to the regulatory agencies rather than to focus and use these as quality improvement tools. A poorly managed deviation investigation leads to poor root cause evaluation, therefore poor CAPA. Again due to same reason, root cause evaluation has merely become like a surface root cause evaluation rather than going deeper to find out the real cause. Often, systemic problem such as inadequate Preventive Maintenance Program is not brought to the surface as the root cause and therefore the preventive action and corrective action performed are incorrect and the problem still remains hidden and surfaces again after a while.
In a recent summary of the FDA findings it was mentioned that deviations management especially regarding process validation are the most frequent findings and cited observations. Change control and cleaning validation are the other frequent findings. The frequency of deviations relative to validation/qualification of water system, media fills and room qualifications keep on increasing.
All these recent happenings result from the lack of trust and fear of being blamed and this probably is the outcome of job loss and leaner organizations with heavier workloads and much tighter timelines associated with bigger expectations. The attributes such as fear of the unknown coming their way, job loss, and insecurity at the work place creates a culture wherein professional are not loyal and honest to their jobs and responsibility. This leads to the situation where workforce tend to avoid healthy discussions and professional attitude to solve the problems to the root cause but rather focus on the blame game and avoid confrontation. This is certainly not a healthy culture and atmosphere but this is what is happening around at work places. The motivation and professional environment is getting worser and unhealthy.
It is in everybody’s interest to invest in consumer confidence by making and showing high quality products repeatedly and consistently. To achieve and built that degree of confidence quality manufacturing is obviously is the key. But it is also important to take rapid, decisive action when problems arise and to conduct recalls where they are necessary. Studies have shown time and time again that companies benefit financially if they built in a culture of quality. All these mentioned above is not new to the industry especially to the global and reputed organizations that are facing the problems listed in this manuscript as above. So the question comes again, why we see the problems of quality and recall everywhere now and then. At the end, all this is making the general public to lose the confidence and trust in these reputed organizations
The analysis has again shown that the cost factor is playing havoc and forcing the senior management to cut jobs and enforce a tighter timeline with few resources. Moving offshore to gain on cost is again putting the quality at higher risks due to lose and indirect controls and systems of the CRO/CMO’s. The situation becomes more critical and important as the governments in emerging markets are still developing their standards and working to improve regulatory compliance. Another factor is that while the manufacturing capacity in these countries is improving, it is still limited. Whereas, the situation with regard to Contract Research and Manufacturing Service Providers (CRAMS) in North America and EU is a bit different as they are making extra effort to keep quality ahead of profits and work with complete transparency with their clients. This is one of the best ways to mitigate the quality issues throughout the supply chain and building confidence in internal, external stakeholders and finally gaining a larger satisfied customer base. In addition, more inspections need to be carried out to keep pace with the global regulatory agencies inspections and especially the quality of inspections.
Therefore, at the end, it is the sole ownership and moral responsibility of all the stakeholders/senior management professionals in the organizations to take a step back and revisit the declining morale and come up with the atmosphere and culture of security, trust, and respect, that will lead to the ownership and commitment attribute at work place. Once this path is carved out and is in place, we are quite confident and optimistic that the quality problems will decline and soon we will be able to win back the confidence of end user and regulatory agencies.
About the Authors
Fan Luying holds Bachelor of Science degree with specialization in Chinese Traditional Medicine from China Pharmaceutical University in Nanjing, China. China Pharmaceutical University is one of the reputed universities in China focusing on pharmaceutical education and training. Ms. Fan is currently working as System Engineer with Quality Assurance department of Hisun Pharmaceutical (Hangzhou) Co., Ltd. based in Fuyang, China. Ms. Fan's responsibilities include coordinating all the activities related to controlling and managing Quality functions. Hisun Pharmaceutical (Hangzhou) Co., Ltd. with Head offices located in Taizhou Zhejiang in southeastern China, which was founded in 1956. Hisun Pharmaceutical is state owned and one of the biggest research and manufacturing organization in China with a focus on antibiotics and oncology products, Hisun Pharmaceutical devotes to provide better service to global clients with its strong R&D.
Mortuza Bakshi holds Bachelor of Science degree with specialization in Chinese Traditional Medicine from China Pharmaceutical University in Nanjing, China. China Pharmaceutical University is one of the reputed universities in China focusing on pharmaceutical education and training. Ms. Fan is currently working as System Engineer with Quality Assurance department of Hisun Pharmaceutical (Hangzhou) Co., Ltd. based in Fuyang, China. Ms. Fan's responsibilities include coordinating all the activities related to controlling and managing Quality functions. Hisun Pharmaceutical (Hangzhou) Co., Ltd. with Head offices located in Taizhou Zhejiang in southeastern China, which was founded in 1956. Hisun Pharmaceutical is state owned and one of the biggest research and manufacturing organization in China with a focus on antibiotics and oncology products, Hisun Pharmaceutical devotes to provide better service to global clients with its strong R&D.
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