Igor Gorsky, Concordia Valsource10.11.17
In the last 10 years we are experiencing an unprecedented growth of biopharmaceutical therapies. They have shown to provide much more effective treatments to patients than traditional medicine, which has until now been dominant for several centuries. With advancements in mapping and understanding human genome, this trend will only increase and increase very rapidly. Analysis of the biotech market shows that if extrapolated to the year 2030 it will reach approximately 45%1 of all global pharma sales and by the middle of the century will definitely overtake all other pharmaceutical sales and become a therapy of choice for new generations.
Along with the growth of the biotechnology market, we are also observing the advancement of new technologies, new testing techniques, as well as implementation of risk-based lifecycle approaches based on knowledge management. Almost every company at this point in time is well aware and actively implementing some type of risk management strategy. Although future trends appear optimistic in general, unfortunately, some segments of the pharmaceutical industry remain conservative and adverse to change. Maintaining an attitude of, “If it’s not broken, don’t fix it,” changes and progress present considerable challenges for these segments of the industry.
This is especially visible in contract research organizations (CRO) and contract manufacturing organizations (CMOs). There are a great number of factors influencing development at CROs and CMOs. Among many of these factors are:
These times will be challenging and are approaching rapidly. It is discouraging to note that while reviewing recently issued FDA Forms 483 and Warning Letters we are still finding many firms are not up to par and compliant with elementary aseptic practices.
FDA observations
A recent Warning letter for one manufacturer states that, “During our inspection, we reviewed reports from multiple investigations that you conducted into complaints regarding the presence of visible particulates in several of your sterile injectable products. The presence of visible particulates in sterile injectable products is an indication of a significant loss of control in your manufacturing process and represents a severe risk of harm to patients. We documented that your investigations into these product quality defects were inadequate and failed to spur appropriate corrective actions and preventive actions.”
In another Warning Letter, the FDA depicts 1,500 complaints from 2012 to 2016 related to leaking, under-filled or empty bottles of a sterile solution. In its root causes investigation, the company has indicated issues with the bottle within the filling process—e.g. when the bottle isn’t correctly placed in the filling machine. Several manual interventions in the aseptic process were necessary, whereby defects haven’t always been detected, particularly when cracks occur in the glass bottle under the cap. Moreover, such cracks may develop a few days after the filling process, as noticed in the investigation.2
Yet another contract manufacturer failed to adhere to basic aseptic manufacturing practices and did not design and qualify its facility to aseptic process requirements. That Warning letter cites, “Failure to develop, conduct, control, and monitor production processes to ensure that [a product] conforms to its specifications, as required by code of federal regulation. For example: your procedure, ‘Aseptic Process Simulation Program’ is not adequately established. Specifically, there is no definition of what an intervention is for performing activities that are not considered routine and need to be assessed when performing an aseptic process simulation (APS). Interventions that were performed and approved during APSs are not written in a procedure; therefore operators do not know what interventions they can perform during routine production unless they review previous APSs.”
In addition, during this inspection regulators added that while products were filled in an aseptic fill room and area, “qualification of this room and area per ISO 14644-1, was not adequately performed. Key process parameters such as HEPA filter air velocities were not adequately established. The qualifications did not determine a specification for air velocities for the HEPA filters to adequately control the process. There was no evidence that unidirectional airflow was obtained through a smoke study. Total particulate air monitoring was only performed at a rest state. There was no monitoring at an operational state. There was no viable particulate monitoring.”
In a recent FDA Office of Compliance presentation,3 three regulators highlighted some key problem areas and trends in Warning Letters observations that included:
- Non-contemporaneous record keeping
- Deletion, falsification, alteration, or other manipulation of data
- Contract manufacturers issues
- Heparin supply chain challenges
- Aseptic technique failures, environmental monitoring failures, design and qualification of facilities
- Cleaning, equipment maintenance, basic sanitation failures
- Cross-contamination risks
- More often for non-application/OTC monograph drugs
As shown in the above list contract manufacturing and sterility assurance are among the issues cited by FDA, which is why it is more important than ever to re-emphasize to contract manufacturers the basic CGMP principles proclaimed almost 15 years ago in, described at the time as, “a significant initiative, pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century, to enhance and modernize the regulation of pharmaceutical manufacturing and product quality—to bring a 21st century focus to this critical FDA responsibility.”
This initiative was significant for many reasons, in which risk and knowledge management, process understanding, validation, monitoring and optimization would be playing a much more prominent role than formal data gathering. It would hopefully help manufacturers to establish sustainable cultures based on an understanding of risks to manufacturing processes as well as building of knowledge bases about their products and processes.
However, unfortunate examples such as those highlighted earlier still exist and tend to involve a considerable number of contract manufacturers. At the same time though, we also see a trend where some CMO firms are forward thinking and investing in modern designs and future technologies.
Recently there have been several mergers and acquisitions with the apparent goal of expanding contract manufacturing capacity and capabilities. This includes sterile pharmaceutical and biopharmaceutical expansion globally. We anticipate that these business moves will advance the ability of contract manufacturing of sterile products to meet the technological and capacity needs of the industry, with new facilities and technology as an answer to the issue of and problems associated with aging sterile product manufacturing facilities. This should also allow for contract manufacturers to better focus on efficiency and compliance. The challenge for the contract manufacturers will be to manage this growth while maintaining cost effectiveness, quality and compliance in a complex global environment.
Conclusion
Although we have seen increases in the issuance of Warning Letters by regulators, not all is bad in the world of sterile contract manufacturing. There are many firms that are investing in new facilities with newer designs, newer technologies and hopefully with an emphasis on:
References
Igor Gorsky is currently senior consultant at ConcordiaValsource, LLC. He has held multiple positions with increasing responsibility at Alpharma, Wyeth and Shire. He worked in production, quality assurance, technical services and validation, and was previously associate director of global pharmaceutical technology at Shire Pharmaceuticals.
Along with the growth of the biotechnology market, we are also observing the advancement of new technologies, new testing techniques, as well as implementation of risk-based lifecycle approaches based on knowledge management. Almost every company at this point in time is well aware and actively implementing some type of risk management strategy. Although future trends appear optimistic in general, unfortunately, some segments of the pharmaceutical industry remain conservative and adverse to change. Maintaining an attitude of, “If it’s not broken, don’t fix it,” changes and progress present considerable challenges for these segments of the industry.
This is especially visible in contract research organizations (CRO) and contract manufacturing organizations (CMOs). There are a great number of factors influencing development at CROs and CMOs. Among many of these factors are:
- Rapid growth of biological research by academia and start-up clinical research firms, which don’t have capabilities for commercial-scale production;
- Steady increase in grants and investments for biotechnology research and commercialization, which stands currently at approximately $300 billion and will rapidly more than double by 2030;
- General rise in therapeutic treatments for the world population, as the Baby Boomer generation ages and life expectancy increases; and
- Additional capacity for established pharmaceutical firms, especially for the products that may require aseptic production or special containment, such as many oncological products.
These times will be challenging and are approaching rapidly. It is discouraging to note that while reviewing recently issued FDA Forms 483 and Warning Letters we are still finding many firms are not up to par and compliant with elementary aseptic practices.
FDA observations
A recent Warning letter for one manufacturer states that, “During our inspection, we reviewed reports from multiple investigations that you conducted into complaints regarding the presence of visible particulates in several of your sterile injectable products. The presence of visible particulates in sterile injectable products is an indication of a significant loss of control in your manufacturing process and represents a severe risk of harm to patients. We documented that your investigations into these product quality defects were inadequate and failed to spur appropriate corrective actions and preventive actions.”
In another Warning Letter, the FDA depicts 1,500 complaints from 2012 to 2016 related to leaking, under-filled or empty bottles of a sterile solution. In its root causes investigation, the company has indicated issues with the bottle within the filling process—e.g. when the bottle isn’t correctly placed in the filling machine. Several manual interventions in the aseptic process were necessary, whereby defects haven’t always been detected, particularly when cracks occur in the glass bottle under the cap. Moreover, such cracks may develop a few days after the filling process, as noticed in the investigation.2
Yet another contract manufacturer failed to adhere to basic aseptic manufacturing practices and did not design and qualify its facility to aseptic process requirements. That Warning letter cites, “Failure to develop, conduct, control, and monitor production processes to ensure that [a product] conforms to its specifications, as required by code of federal regulation. For example: your procedure, ‘Aseptic Process Simulation Program’ is not adequately established. Specifically, there is no definition of what an intervention is for performing activities that are not considered routine and need to be assessed when performing an aseptic process simulation (APS). Interventions that were performed and approved during APSs are not written in a procedure; therefore operators do not know what interventions they can perform during routine production unless they review previous APSs.”
In addition, during this inspection regulators added that while products were filled in an aseptic fill room and area, “qualification of this room and area per ISO 14644-1, was not adequately performed. Key process parameters such as HEPA filter air velocities were not adequately established. The qualifications did not determine a specification for air velocities for the HEPA filters to adequately control the process. There was no evidence that unidirectional airflow was obtained through a smoke study. Total particulate air monitoring was only performed at a rest state. There was no monitoring at an operational state. There was no viable particulate monitoring.”
In a recent FDA Office of Compliance presentation,3 three regulators highlighted some key problem areas and trends in Warning Letters observations that included:
- Data integrity
- Non-contemporaneous record keeping
- Deletion, falsification, alteration, or other manipulation of data
- Supply chain
- Contract manufacturers issues
- Heparin supply chain challenges
- Sterility assurance
- Aseptic technique failures, environmental monitoring failures, design and qualification of facilities
- Rudimentary CGMP
- Cleaning, equipment maintenance, basic sanitation failures
- Cross-contamination risks
- More often for non-application/OTC monograph drugs
- Delay/Deny/Limit/Refuse
As shown in the above list contract manufacturing and sterility assurance are among the issues cited by FDA, which is why it is more important than ever to re-emphasize to contract manufacturers the basic CGMP principles proclaimed almost 15 years ago in, described at the time as, “a significant initiative, pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century, to enhance and modernize the regulation of pharmaceutical manufacturing and product quality—to bring a 21st century focus to this critical FDA responsibility.”
This initiative was significant for many reasons, in which risk and knowledge management, process understanding, validation, monitoring and optimization would be playing a much more prominent role than formal data gathering. It would hopefully help manufacturers to establish sustainable cultures based on an understanding of risks to manufacturing processes as well as building of knowledge bases about their products and processes.
However, unfortunate examples such as those highlighted earlier still exist and tend to involve a considerable number of contract manufacturers. At the same time though, we also see a trend where some CMO firms are forward thinking and investing in modern designs and future technologies.
Recently there have been several mergers and acquisitions with the apparent goal of expanding contract manufacturing capacity and capabilities. This includes sterile pharmaceutical and biopharmaceutical expansion globally. We anticipate that these business moves will advance the ability of contract manufacturing of sterile products to meet the technological and capacity needs of the industry, with new facilities and technology as an answer to the issue of and problems associated with aging sterile product manufacturing facilities. This should also allow for contract manufacturers to better focus on efficiency and compliance. The challenge for the contract manufacturers will be to manage this growth while maintaining cost effectiveness, quality and compliance in a complex global environment.
Conclusion
Although we have seen increases in the issuance of Warning Letters by regulators, not all is bad in the world of sterile contract manufacturing. There are many firms that are investing in new facilities with newer designs, newer technologies and hopefully with an emphasis on:
- Risk management implementation;
- Knowledge management;
- Personnel training;
- Aseptic process understanding;
- Smarter and more quality risk-oriented APS programs; and
- State-of-the-art cleaning validations.
References
- Deloitte 2016 Global life sciences outlook, Moving forward with cautious optimism, https://www2.deloitte.com/.../Life-Sciences.../gx-lshc-2016-life-sciences-outlook.pdf
- Indian Sterile Manufacturer receives a second Warning Letter, ECA 14-Jun-2017, http://www.gmp-compliance.org/gmp-news/indian-sterile-manufacturer-receives-a-second-warning-letter
- Paula Katz, Director, Manufacturing Quality Guidance and Policy Staff, Office of Manufacturing Quality Office of Compliance Center for Drug Evaluation and Research, FDA Compliance Trends, India Pharmaceutical FORUM 2017 – Towards Excellence in Quality Indian Pharmaceutical Alliance, Mumbai, India, Feb. 24, 2017
Igor Gorsky is currently senior consultant at ConcordiaValsource, LLC. He has held multiple positions with increasing responsibility at Alpharma, Wyeth and Shire. He worked in production, quality assurance, technical services and validation, and was previously associate director of global pharmaceutical technology at Shire Pharmaceuticals.
