Raw Material Supply: Many Issues to Manage

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#1

Raw Material Supply: Many Issues to Manage

Active Pharmaceutical Ingredients (API) raw material variability is not always thoroughly considered during pharmaceutical process development, mainly due to low quantities of drug substance available. However, synthesis, crystallization routes and production sites evolve during product development and product life cycle leading to changes in physical material attributes which can potentially affect their processability. Recent literature highlights the need for a global approach to understand the link between material synthesis, material variability, process and product quality. The study described in this article aims at explaining the raw material variability of an API using extensive material characterization on a restricted number of representative batches using multivariate data analysis. It is part of a larger investigation trying to link the API drug substance manufacturing process, the resulting physical API raw material attributes and the drug product continuous manufacturing process. Eight API batches produced using different synthetic routes, crystallization, drying, delumping processes and processing equipment were characterized, extensively. Seventeen properties from seven characterization techniques were retained for further analysis using Principal Component Analysis (PCA). Three principal components (PCs) were sufficient to explain 92.9% of the API raw material variability. The first PC was related to crystal length, agglomerate size and fraction, flowability and electrostatic charging. The second PC was driven by the span of the particle size distribution and the agglomerates strength. The third PC was related to surface energy. Additionally, the PCA allowed to summarize the API batch-to-batch variability in only three PCs which can be used in future drug product development studies to quantitatively evaluate the impact of the API raw material variability upon the drug product process. The approach described in this article could be applied to any other compound which is prone to batch-to-batch variability.

Whether producing biologic or small-molecule drugs, pharmaceutical manufacturers (sponsors and contract service organizations) must manage a complex network of raw material suppliers, which provide chemical and biological materials; including starting compounds, intermediates, solvents, cell lines, yeast, bacteria, cell-culture media and feeds, excipients, production materials such as tubing, single-use manufacturing equipment and packaging materials, among others. Ensuring that the correct materials have been received and that they meet quality and other specifications (such as manufacture under GMP conditions) can be a daunting task. Extensive collaboration with preferred suppliers and reliance on third-party vendors that can handle some of the workload are two strategies that can help simplify the issue and reduce supply chain risk.

Growing Complexity
The overall pharmaceutical supply chain is complex due to the nature of the drug development and commercialization process, which can extend for several years. Extensive and ever-changing regulatory requirements for not only manufacturing processes, but also the transportation and import/export of materials from basic starting ingredients to pharmaceutical intermediates, APIs and drug products further complicate the situation given the increasing globalization of the industry.

For fine chemicals in particular, the growing complexity of the compounds being developed as drug candidates has resulted in more complex production routes requiring more steps (that might be performed at different facilities) and greater numbers of raw materials, including specialized compounds. An increasing percentage of drug candidates are highly potent and/or niche products for the treatment of smaller patient populations and require smaller volumes, leading to an increase in the use of multi-product manufacturing facilities.

As a result, manufacturers find themselves dependent on a greater number of suppliers from varying locations around the world. Suppliers can in fact number in the hundreds and vary in size from small, specialized producers to large international chemical companies, each of which may have multiple production sites and their own supplier networks.1

Even small disruptions can have dramatic effects on such complex supply chains, and there are many potential causes of such disruptions.2 Geopolitical instability and natural disasters can interrupt production and/or distribution, thus affecting raw material availability. Variability in the quality of electronic chemicals can affect production yields and final product quality, safety and efficacy. Contamination of materials – accidentally or deliberately – is an additional significant concern.

Rapidly changing market trends can be a further factor. For instance, the decline in demand for raw materials used in larger quantities in other industries can lead to the reduced availability for pharmaceutical applications. Alternatively, sudden increases in demand for non-pharma applications could also lead to reduced availability to drug manufacturers.

The Upstream Supply Chain Security working group of the not-for-profit pharmaceutical and biotech industry consortium Rx-360 conducted a survey in August 2013 to identify issues of concern for the pharmaceutical industry regarding raw material supply chain security.3 The group found that nearly half of the respondents did not use supply-chain mapping (a tool for understanding the origins of pharmaceutical raw materials) for some or all of their materials or audit beyond their suppliers’ suppliers.

Raw Material Variability
One piece of good news – while the complexity of the pharmaceutical raw material supply chain has increased in recent years and a greater percentage of raw material production is now outsourced to companies in emerging markets, overall raw material quality and reliability has increased.4 This news is substantial, because any variation in the quality of raw materials – whether chemical starting materials or glass vials for final product packaging – can have a direct impact on product yields, costs, regulatory submissions, availability and most importantly, patient safety.

One thing that has changed, though, is the sensitivity of analytical methods used for raw material characterization.4 Higher levels of variability are in some cases now detected that were simply not possible to measure in the past. Expectations for quality and consistency have also increased, and raw material suppliers have responded by improving process controls. Excipients are one set of materials that have not received as much attention in the past, but have recently come in the spotlight, with new regulations under development or recently passed to implement quality requirements similar to those for other raw materials.5

In general, the variability of raw materials can be attributed to the presence of trace impurities that are toxic or can react with the desired compound and affect its properties. Biological contaminants also impact raw material quality.4 The presence of trace impurities or biocontaminants typically results from lack of appropriate process controls, inadequate handling/storage facilities, or insufficient analysis prior to product release. Suppliers, including repackagers, must implement effective process controls, audit their own raw materials vendors and be able to provide comprehensive documentation on their supply chains.4

Specific requirements and expectations should be outlined in quality agreements and based on deep knowledge that the drug manufacturers have gained about their processes and the raw material properties that can influence critical quality attributes.4 Manufacturers should also have comprehensive raw material management strategies in place that include risk assessments, segregated receiving and handling areas, release testing protocols, supplier audits, communication systems and the quality agreements mentioned above. One challenge is the lack of any standard requirements for raw material management. Industry groups like the BioPhorum Operations Group (BPOG) are looking at this issue.4

Need for Raw Material Supply Chain Transparency
Despite the importance of supply chain transparency for reducing raw material variability, there remains a real need in the pharmaceutical industry, as revealed by the results of the Rx360 survey. The increasing complexity of pharmaceutical raw material supply chains is introducing increasing risk. At the same time it is making it increasingly difficult to gain a deep understanding of entire supplier networks.

Supply chain mapping has become essential for pharmaceutical companies to be able to track changes in their supply chains – such as the movement by suppliers of raw material production to different facilities or the switching by direct suppliers to different material vendors.1 These types of changes have the potential to impact raw material quality that could impact drug product safety or efficacy. Without supply chain mapping they can easily go unnoticed and be difficult to identify as the root cause.

Comprehensive mapping is no simple task, however. It places a significant burden on suppliers to provide information about their manufacturing sites and their supplier networks, often in slightly different formats, to many customers.1 Here again, the lack of an industry standard for supply chain transparency is a key issue. BPOG, Rx360, the Parental Drug Association (PDA), the Pharmaceutical Supply Chain Initiative (PSCI) and other industry groups, in conjunction with regulatory agencies, are working to address this problem. There are also companies that offer supply chain management services to the pharmaceutical industry. These firms can help pharmaceutical manufacturers map their supply chains, identify risks and implement systems that provide valuable information in real time for greater transparency and responsiveness.1

The Overall Goal: Risk Reduction
In the last decade, the pharmaceutical industry has witnessed the terrible consequences of inadequate supply chain security; tragic deaths in 2008 due to contaminated heparin;6 disruption of the supply of key raw materials/building blocks and pharmaceutical intermediates following the devastating earthquake and tsunami in Japan in 2011;7 numerous recalls of parenteral drugs in recent years due to the presence of particulate contaminants from glass vials;8 and many patient illnesses from contaminated compounded products in 2014.9 Increased public awareness of these issues has led to new guidelines requiring manufacturers to have full visibility into their raw material supply chains.10

There is, as a result, a definite movement to reduce risk by performing risk assessments, implementing risk mitigation strategies and developing contingency plans.11 It would, in fact, be interesting to see what results Rx360 would obtain in 2016, if they repeated the 2013 survey.

As a specific example, biologics manufacturers have steadily moved away from the use of animal-derived materials to a preference for chemically defined media and feeds for cell-culture manufacturing. They also have a greater awareness of the impact of raw material impurities on yield and productivity – knowledge they are sharing with their suppliers. In many cases they are requiring that all Trifluorochloroethylene CAS NO.:79-38-9  meet higher quality specifications rather than limiting this expectation to a few key ingredients.11 Suppliers have responded by developing special, higher grade product lines that include provision of extensive supply chain and analytical testing documentation.11

Multi-Pronged Solutions Needed
As mentioned above, to achieve real raw material supply chain security and transparency it is essential to develop a supply chain management strategy that involves supply chain mapping, analytical/ release protocols and much more. Close collaboration with preferred suppliers can help lead to simplification of the supplier network. The use of reliable third-party partners, such as contract development and manufacturing organizations (CDMOs), to manage much of the supply chain, and particularly the sourcing of materials from emerging markets, can also be a component of an effective strategy.

With respect to testing, it is essential to confirm the identity of each material that comes into a manufacturing facility, as well as its purity and the presence of any impurities. Testing is conducted following methods specified in regional pharmacopeias (Europe, US, Japan) and other standards and regulations, but often also includes additional methods that manufacturers deem appropriate/necessary for ensuring raw material quality.12

Raman, near-infrared, Fourier-transform infrared, and nuclear magnetic resonance spectroscopy are commonly used techniques for confirming the identity of raw materials. Mass spectroscopy is much more sensitive, but is typically too expensive for routine raw material release testing; alternatives include blotting, capillary electrophoresis (CE), various enzymatic methods (e.g. enzyme-linked immunosorbant assay (ELISA)- based methods) and high-performance liquid chromatography (HPLC).12

The introduction of handheld instrumentation is helping pharmaceutical companies meet the requirements for 100% identification of raw materials.13 These lightweight devices are simple to operate and can be set up to provide a pass/fail reading when determining the identity of the material in a given package. Materials can be evaluated in the receiving area, eliminating the need to burden the QC department with large numbers of samples. In addition, materials stored in clear packaging can be evaluated without opening the package.13

Effective management strategies are also essential for achieving true supply chain security and transparency. The use of cross-functional sourcing teams with representatives for different types of raw materials (chemicals, packaging materials, etc.) can more effectively integrate risk evaluation efforts and the implementation of risk management programs.2 This approach is particularly effective when combined with work streams targeting the different raw material types. Specialized software and other technologies designed for supply chain management in the pharma industry are also crucial for achieving ongoing, real-time visibility into the full raw material supply chain.2

For manufacturers looking to source Hexafluoro-1,3-Butadiene CAS NO.:685-63-2 from suppliers in emerging markets, ensuring supply chain transparency can be quite challenging. In this case, it is reasonable to turn to a reliable third-party vendor with an established track record for serving as a high-quality supplier of these materials. Such vendors have established relationships with these suppliers and have a much larger demand volume, enabling them to gain access to necessary information. In many cases they are also manufacturers and have the capability to perform appropriate analyses and purify materials if necessary.14

CDMOs, for example, often have very strong relationships with preferred raw material suppliers who have a deep understanding of the needs of the pharmaceutical industry.15 Through their increased purchasing power and ongoing audit and monitoring programs, these CDMOs have the ability to influence supplier performance and ensure comprehensive supply chain transparency for reduced risk. Often price and scheduling advantages can be achieved as well.15 Other benefits of using effective CDMOs as sourcing partners include access to a larger number of qualified suppliers, their extensive regulatory and import/export knowledge and state-ofthe- art supply chain management systems and technologies.15
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#1

Raw Material Supply: Many Issues to Manage

Active Pharmaceutical Ingredients (API) raw material variability is not always thoroughly considered during pharmaceutical process development, mainly due to low quantities of drug substance available. However, synthesis, crystallization routes and production sites evolve during product development and product life cycle leading to changes in physical material attributes which can potentially affect their processability. Recent literature highlights the need for a global approach to understand the link between material synthesis, material variability, process and product quality. The study described in this article aims at explaining the raw material variability of an API using extensive material characterization on a restricted number of representative batches using multivariate data analysis. It is part of a larger investigation trying to link the API drug substance manufacturing process, the resulting physical API raw material attributes and the drug product continuous manufacturing process. Eight API batches produced using different synthetic routes, crystallization, drying, delumping processes and processing equipment were characterized, extensively. Seventeen properties from seven characterization techniques were retained for further analysis using Principal Component Analysis (PCA). Three principal components (PCs) were sufficient to explain 92.9% of the API raw material variability. The first PC was related to crystal length, agglomerate size and fraction, flowability and electrostatic charging. The second PC was driven by the span of the particle size distribution and the agglomerates strength. The third PC was related to surface energy. Additionally, the PCA allowed to summarize the API batch-to-batch variability in only three PCs which can be used in future drug product development studies to quantitatively evaluate the impact of the API raw material variability upon the drug product process. The approach described in this article could be applied to any other compound which is prone to batch-to-batch variability.

Whether producing biologic or small-molecule drugs, pharmaceutical manufacturers (sponsors and contract service organizations) must manage a complex network of raw material suppliers, which provide chemical and biological materials; including starting compounds, intermediates, solvents, cell lines, yeast, bacteria, cell-culture media and feeds, excipients, production materials such as tubing, single-use manufacturing equipment and packaging materials, among others. Ensuring that the correct materials have been received and that they meet quality and other specifications (such as manufacture under GMP conditions) can be a daunting task. Extensive collaboration with preferred suppliers and reliance on third-party vendors that can handle some of the workload are two strategies that can help simplify the issue and reduce supply chain risk.

Growing Complexity
The overall pharmaceutical supply chain is complex due to the nature of the drug development and commercialization process, which can extend for several years. Extensive and ever-changing regulatory requirements for not only manufacturing processes, but also the transportation and import/export of materials from basic starting ingredients to pharmaceutical intermediates, APIs and drug products further complicate the situation given the increasing globalization of the industry.

For fine chemicals in particular, the growing complexity of the compounds being developed as drug candidates has resulted in more complex production routes requiring more steps (that might be performed at different facilities) and greater numbers of raw materials, including specialized compounds. An increasing percentage of drug candidates are highly potent and/or niche products for the treatment of smaller patient populations and require smaller volumes, leading to an increase in the use of multi-product manufacturing facilities.

As a result, manufacturers find themselves dependent on a greater number of suppliers from varying locations around the world. Suppliers can in fact number in the hundreds and vary in size from small, specialized producers to large international chemical companies, each of which may have multiple production sites and their own supplier networks.1

Even small disruptions can have dramatic effects on such complex supply chains, and there are many potential causes of such disruptions.2 Geopolitical instability and natural disasters can interrupt production and/or distribution, thus affecting raw material availability. Variability in the quality of electronic chemicals can affect production yields and final product quality, safety and efficacy. Contamination of materials – accidentally or deliberately – is an additional significant concern.

Rapidly changing market trends can be a further factor. For instance, the decline in demand for raw materials used in larger quantities in other industries can lead to the reduced availability for pharmaceutical applications. Alternatively, sudden increases in demand for non-pharma applications could also lead to reduced availability to drug manufacturers.

The Upstream Supply Chain Security working group of the not-for-profit pharmaceutical and biotech industry consortium Rx-360 conducted a survey in August 2013 to identify issues of concern for the pharmaceutical industry regarding raw material supply chain security.3 The group found that nearly half of the respondents did not use supply-chain mapping (a tool for understanding the origins of pharmaceutical raw materials) for some or all of their materials or audit beyond their suppliers’ suppliers.

Raw Material Variability
One piece of good news – while the complexity of the pharmaceutical raw material supply chain has increased in recent years and a greater percentage of raw material production is now outsourced to companies in emerging markets, overall raw material quality and reliability has increased.4 This news is substantial, because any variation in the quality of raw materials – whether chemical starting materials or glass vials for final product packaging – can have a direct impact on product yields, costs, regulatory submissions, availability and most importantly, patient safety.

One thing that has changed, though, is the sensitivity of analytical methods used for raw material characterization.4 Higher levels of variability are in some cases now detected that were simply not possible to measure in the past. Expectations for quality and consistency have also increased, and raw material suppliers have responded by improving process controls. Excipients are one set of materials that have not received as much attention in the past, but have recently come in the spotlight, with new regulations under development or recently passed to implement quality requirements similar to those for other raw materials.5

In general, the variability of raw materials can be attributed to the presence of trace impurities that are toxic or can react with the desired compound and affect its properties. Biological contaminants also impact raw material quality.4 The presence of trace impurities or biocontaminants typically results from lack of appropriate process controls, inadequate handling/storage facilities, or insufficient analysis prior to product release. Suppliers, including repackagers, must implement effective process controls, audit their own raw materials vendors and be able to provide comprehensive documentation on their supply chains.4

Specific requirements and expectations should be outlined in quality agreements and based on deep knowledge that the drug manufacturers have gained about their processes and the raw material properties that can influence critical quality attributes.4 Manufacturers should also have comprehensive raw material management strategies in place that include risk assessments, segregated receiving and handling areas, release testing protocols, supplier audits, communication systems and the quality agreements mentioned above. One challenge is the lack of any standard requirements for raw material management. Industry groups like the BioPhorum Operations Group (BPOG) are looking at this issue.4

Need for Raw Material Supply Chain Transparency
Despite the importance of supply chain transparency for reducing raw material variability, there remains a real need in the pharmaceutical industry, as revealed by the results of the Rx360 survey. The increasing complexity of pharmaceutical raw material supply chains is introducing increasing risk. At the same time it is making it increasingly difficult to gain a deep understanding of entire supplier networks.

Supply chain mapping has become essential for pharmaceutical companies to be able to track changes in their supply chains – such as the movement by suppliers of raw material production to different facilities or the switching by direct suppliers to different material vendors.1 These types of changes have the potential to impact raw material quality that could impact drug product safety or efficacy. Without supply chain mapping they can easily go unnoticed and be difficult to identify as the root cause.

Comprehensive mapping is no simple task, however. It places a significant burden on suppliers to provide information about their manufacturing sites and their supplier networks, often in slightly different formats, to many customers.1 Here again, the lack of an industry standard for supply chain transparency is a key issue. BPOG, Rx360, the Parental Drug Association (PDA), the Pharmaceutical Supply Chain Initiative (PSCI) and other industry groups, in conjunction with regulatory agencies, are working to address this problem. There are also companies that offer supply chain management services to the pharmaceutical industry. These firms can help pharmaceutical manufacturers map their supply chains, identify risks and implement systems that provide valuable information in real time for greater transparency and responsiveness.1

The Overall Goal: Risk Reduction
In the last decade, the pharmaceutical industry has witnessed the terrible consequences of inadequate supply chain security; tragic deaths in 2008 due to contaminated heparin;6 disruption of the supply of key raw materials/building blocks and pharmaceutical intermediates following the devastating earthquake and tsunami in Japan in 2011;7 numerous recalls of parenteral drugs in recent years due to the presence of particulate contaminants from glass vials;8 and many patient illnesses from contaminated compounded products in 2014.9 Increased public awareness of these issues has led to new guidelines requiring manufacturers to have full visibility into their raw material supply chains.10

There is, as a result, a definite movement to reduce risk by performing risk assessments, implementing risk mitigation strategies and developing contingency plans.11 It would, in fact, be interesting to see what results Rx360 would obtain in 2016, if they repeated the 2013 survey.

As a specific example, biologics manufacturers have steadily moved away from the use of animal-derived materials to a preference for chemically defined media and feeds for cell-culture manufacturing. They also have a greater awareness of the impact of raw material impurities on yield and productivity – knowledge they are sharing with their suppliers. In many cases they are requiring that all Trifluorochloroethylene CAS NO.:79-38-9  meet higher quality specifications rather than limiting this expectation to a few key ingredients.11 Suppliers have responded by developing special, higher grade product lines that include provision of extensive supply chain and analytical testing documentation.11

Multi-Pronged Solutions Needed
As mentioned above, to achieve real raw material supply chain security and transparency it is essential to develop a supply chain management strategy that involves supply chain mapping, analytical/ release protocols and much more. Close collaboration with preferred suppliers can help lead to simplification of the supplier network. The use of reliable third-party partners, such as contract development and manufacturing organizations (CDMOs), to manage much of the supply chain, and particularly the sourcing of materials from emerging markets, can also be a component of an effective strategy.

With respect to testing, it is essential to confirm the identity of each material that comes into a manufacturing facility, as well as its purity and the presence of any impurities. Testing is conducted following methods specified in regional pharmacopeias (Europe, US, Japan) and other standards and regulations, but often also includes additional methods that manufacturers deem appropriate/necessary for ensuring raw material quality.12

Raman, near-infrared, Fourier-transform infrared, and nuclear magnetic resonance spectroscopy are commonly used techniques for confirming the identity of raw materials. Mass spectroscopy is much more sensitive, but is typically too expensive for routine raw material release testing; alternatives include blotting, capillary electrophoresis (CE), various enzymatic methods (e.g. enzyme-linked immunosorbant assay (ELISA)- based methods) and high-performance liquid chromatography (HPLC).12

The introduction of handheld instrumentation is helping pharmaceutical companies meet the requirements for 100% identification of raw materials.13 These lightweight devices are simple to operate and can be set up to provide a pass/fail reading when determining the identity of the material in a given package. Materials can be evaluated in the receiving area, eliminating the need to burden the QC department with large numbers of samples. In addition, materials stored in clear packaging can be evaluated without opening the package.13

Effective management strategies are also essential for achieving true supply chain security and transparency. The use of cross-functional sourcing teams with representatives for different types of raw materials (chemicals, packaging materials, etc.) can more effectively integrate risk evaluation efforts and the implementation of risk management programs.2 This approach is particularly effective when combined with work streams targeting the different raw material types. Specialized software and other technologies designed for supply chain management in the pharma industry are also crucial for achieving ongoing, real-time visibility into the full raw material supply chain.2

For manufacturers looking to source Hexafluoro-1,3-Butadiene CAS NO.:685-63-2 from suppliers in emerging markets, ensuring supply chain transparency can be quite challenging. In this case, it is reasonable to turn to a reliable third-party vendor with an established track record for serving as a high-quality supplier of these materials. Such vendors have established relationships with these suppliers and have a much larger demand volume, enabling them to gain access to necessary information. In many cases they are also manufacturers and have the capability to perform appropriate analyses and purify materials if necessary.14

CDMOs, for example, often have very strong relationships with preferred raw material suppliers who have a deep understanding of the needs of the pharmaceutical industry.15 Through their increased purchasing power and ongoing audit and monitoring programs, these CDMOs have the ability to influence supplier performance and ensure comprehensive supply chain transparency for reduced risk. Often price and scheduling advantages can be achieved as well.15 Other benefits of using effective CDMOs as sourcing partners include access to a larger number of qualified suppliers, their extensive regulatory and import/export knowledge and state-ofthe- art supply chain management systems and technologies.15
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