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Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
Collaborative efforts are underway between suppliers and drug manufacturers to address raw material variability.
Raw material variability can have impacts across the board, causing inconsistent processes and process yields, productivity/efficiency issues, and problems with quality compliance. Any one of these problems can ultimately impact drug efficacy and patient safety. While increased outsourcing of raw material manufacturing to emerging regions can contribute to greater issues regarding raw material consistency and traceability, overall raw material quality and reliability has increased in recent years. At the same time, the sensitivity of analytical instruments and the awareness of the impact of raw material variability on biologic drugs have also increased, leading to a need for further definition. Raw material suppliers and biopharmaceutical manufacturers both have roles to play in addressing this issue. The key to success will be open and transparent communication.
Manifold and significant impacts
Variability in raw materials from media to packaging can have an impact on the characteristics and quality of drug products that potentially impact safety and efficacy. More specifically, lot-to-lot variability of raw materials may impact drug product critical quality attributes (CQAs) such as identity, purity, quality, and stability and cause lot-to-lot variability of the drug product during its lifespan, according to Nataliya Afonina, president of AN Biologics Consulting. “Such variability may ultimately lead to out-of-specification (OOS) results for drug products and, in addition to impacting patient safety, affect the drug product clinical or commercial supply chain and regulatory submissions, which are all significant consequences,” she asserts.
“The impact of raw material variability can indeed be manifold and very significant,” agrees Raphael Gübeli, technical product manager for liquid formulation at Merck KGaA. Some effects, such as reduced overall yield of the biopharmaceutical manufacturing process, mainly have a negative economic impact. Unexpected raw material impurities can, in some cases, chemically alter the drug substance or remain in the final formulated drug product at elevated levels, potentially affecting efficacy and safety. “If not detected during final release testing by the manufacturer, there could be harmful consequences for the patient,” Gübeli says.
In some cases, minute quantities of an impurity can have a measurable effect. “For example, increasingly more information is being gained on the effect of variable elemental metal impurities on cell health and the yield of cell-culture processes. As more knowledge is gained, it has become clear that even at extremely low levels, a process can still be impacted by the presence of metal or other impurities,” observes Gary Perkins, head of process solutions customer relations in the quality services group of MilliporeSigma, the life-science business of Merck KGaA.
Consequently, all raw materials used to manufacture the API, plus any excipients and other materials used during formulation, must be fully characterized and monitored for changes in quality/properties. Packaging materials must also be monitored, as unexpected leachables or other impurities can also have an effect on product quality.
Better quality, but greater sensitivity
Concerns raised about raw material variability are not necessarily due to a decline in raw material quality, say the experts interviewed for this article. There have been some issues with increasing raw material variability due to outsourcing of raw material manufacture to China, India, and other developing countries and the use of repackagers, which can reduce transparency in the supply chain, according to Afonina. She notes that audits of even reputable vendors must encompass the complete chain of suppliers and repackagers.
In general, raw material variability hasn’t changed in recent years, but analytical capabilities have improved significantly, increasing the ability of both suppliers and drug manufacturers to analyze, characterize, and understand that variability, according to Perkins. These improved capabilities are a double-edged sword. “We encounter more variability as our ability to measure and analyze it is enhanced. In fact, variability that was previously invisible can now be identified, pushing manufacturers to further streamline processes to mitigate potential impacts of even the slightest variations,” Perkins explains. He adds that as detection limits continue to reach ever lower levels, the challenge becomes standardization, as it often does in the pharmaceutical industry.
It is also important to note, according to Gübeli, that expectations for raw material consistency and control of processes and final product quality have increased dramatically, and thus the variability has been reduced in many cases. Parag Kolhe, group leader and senior principal scientist with Pfizer Biotherapeutic Pharmaceutical Sciences, agrees that raw-material suppliers are providing consistently better quality materials. He provides one example in the primary packaging space; prefilled-syringe manufacturers have acknowledged the sensitivity of biotech products toward silicone oil and tungsten and improved their processes so that their primary packaging component specs are more tightly controlled.
Raw materials such as formulation excipients, however, which are present in drug products in high amounts, have received much less attention than active biopharmaceutical ingredients, according to Gübeli. “Many parameters defining the quality aspects of excipients are not yet routinely monitored or included as part of supplier certificates of analysis, and thus are not strictly under control,” he states.
Many sources of variability
Excipients are just one of many potential sources of raw material variability that can impact biopharmaceutical manufacturing. In general, variability can arise from inefficient/ineffective raw material manufacturing controls and residual impurity controls in starting materials. They can come from the basic starting materials (e.g., natural sugars and other plant-based compounds) used to manufacture biopharmaceutical raw materials or be an artifact of the manufacturing process itself (e.g., impurities in recycled solvents, chemicals released into the raw material process fluid from the equipment, etc.).
The most common types of raw material variability can be placed into three general categories, according to Gübeli. The first group includes trace impurities that alter the biopharmaceutical API, either by directly modifying it or by catalyzing its modification. Examples include peroxides, aldehydes, reducing sugars, and catalytically active metal ions. The second category comprises trace impurities that are themselves toxic to humans, such as lead and aluminum. The third class consists of microorganism contaminants (and their associated endotoxins) that lead to variabilities in the bioburden of raw materials and can cause severe immunological responses in patients.
As mentioned previously, raw material variability often occurs due to inadequate control of raw material manufacturing processes and/or analytical release testing by suppliers, and is most common at small outsourcing companies, according to Afonina. Specific problems to watch for include contamination with antibiotics or other foreign raw materials due to a lack of appropriate segregation of processing/handling facilities, equipment, or control of processes used for the manufacture of raw materials; poor GMP and analytical practices resulting in the approval of out-of-specification material; switching of suppliers for a given raw material; and deficiencies in the auditing of raw materials suppliers by biopharmaceutical manufacturers.
Vendors are responsible for controlling/minimizing raw material variability, according to Kolhe. They must control their own manufacturing processes and audit manufacturers of any raw materials they purchase. If manufacture of these materials is outsourced, they need to audit all facilities in the supply chain. If changes are made to manufacturing processes, comparability studies must be performed and the customer notified. “All these actions are important for all raw materials, but specifically for animal- and plant-derived materials for which properties are difficult to control,” says Afonina. “Overall,” she adds, “strong risk-based management and quality systems should be in place.”
Even repackagers must have the ability to trace specific raw material lots back to any changes that were made at their suppliers. “If a client asks a supplier for more information in order to investigate batch-to-batch variability in raw material quality, the supplier should be able to provide supply-chain documentation, including origins and analysis. If the answers are not there, more analysis should be done on the material,” Perkins says. All these key points should be covered in the quality agreement between the raw material vendor and the drug product manufacturer, according to Afonina.
To best aid manufacturers as they deal with raw material challenges, suppliers can, in addition to meeting specifications of pharmacopoeia monographs, provide in-depth raw material characterization data including customer-specific parameters and historical data that can be used for the prediction of future batch-to-batch consistency and information on appropriate handling and storage conditions, according to Gübeli. Trust can also be built by assuring independent supplier auditing and certification, such as is offered through the EXCiPACT voluntary international certification scheme for excipients.
Most manufacturers select raw materials that are excipient-grade or of similar quality due to the fact that the raw material or its impurities have the potential to be transferred to the final formulated biopharmaceutical product. For raw materials classified as excipients (e.g., according to US or European pharmacopoeia), the most important types of variability are part of the pharmacopoeia monographs and are controlled and specified in the certificate of analysis (CoA) by the supplier, according to Gübeli. Unfortunately, he also notes that the pharmacopoeia monographs generally lag behind state-of-the-art knowledge about raw material variability.
Communication is key
There is, however, a shared responsibility between the vendor and the client. “Clients need to be aware of their needs with respect to factors that are critical to the performance of their processes and make sure that suppliers understand these factors,” Perkins states. Biopharmaceutical companies also need to understand if the typical variability in a raw material is acceptable for a given process/product or if more controls are needed, according to Kolhe.
In general, it’s the responsibility of the manufacturer of a biopharmaceutical to select the appropriate raw material that fulfills the requirements for the production of a safe and high-quality biopharmaceutical under GMP. “Each biopharmaceutical and associated manufacturing process is unique and influenced by many raw-material associated factors to a different extent. These phenomena are only known by the manufacturers of the biopharmaceuticals. Therefore, we encourage manufacturers to cooperate with us as suppliers and exchange information on critical raw material parameters. Only then can we as a supplier assure consistency of these particular parameters by introducing them into custom CoAs,” Gübeli comments.
Biopharmaceutical manufacturers need to implement raw-material management strategies, including processes/systems for the release of raw materials for use based on specifications, quality agreements, routine audits, and raw-material change communications, according to Kolhe. Drug product manufacturers should also have segregated areas for receiving/handling raw materials to avoid the potential for contamination from other areas in of the manufacturing plant and have a system in place to monitor trends in the analytical data, according to Afonina.
Many drug companies are taking risk-based and science-based approaches to managing raw material variability. Such approaches require significant product understanding regarding the impact of raw-material attribute variability. “Formal risk assessment exercises are conducted to evaluate the potential risks associated with raw material availability with respect to final product quality, safety, and efficacy. The obtained results are then used to understand the risks and determine any actions needed in terms of raw-material quality attributes,” Kolhe explains. Integration of control strategies for final drug substances and drug products with raw-material control measures also help ensure consistent product quality.
“One of the issues here is that there is no standard or specific guidance on the management of raw material variability,” says Perkins. “In addition, the patchwork of regulatory guidance documents that are applicable make references to science-based and risk-based approaches to the minimization of raw material variability, but most are open to interpretation.” MilliporeSigma and other companies, as participants in initiatives of associations like the BioPhorum Operations Group, are opening up lines of communication, even across competitors. “A consistent industry approach to variability analysis will enable greater supply chain transparency, standardized process control, and key materials characterization,” Perkins asserts. “The general idea is that manufacturers would be accountable for a set of clear material definitions, so customers know that they are choosing the right raw materials,” he adds.
Transparency between a buyer and supplier is key so that manufacturers can understand and address variability issues with the potential to affect product quality and patient safety. “If the buyer provides information on the end use of a material, the supplier can then determine what information they need to know about where the material is coming from (if repackaging) or about key raw materials needed for its manufacture, as well as what analyses may be necessary,” states Perkins. Suppliers can in turn assist biopharmaceutical customers with risk assessment processes by providing streamlined documentation involving detailed raw material processing and characterization information, according to Gübeli. He adds that drug manufacturers will have the greatest success in obtaining raw materials that meet their detailed demands if they begin interacting with suppliers early in the development process.
MilliporeSigma is also working with customers and industry groups to develop an eData exchange format. The system will enable secure electronic sharing of comprehensive raw material production and test data. Not only are the data priceless; multi-variant analysis techniques provide a better understanding of variability and its impact on final drug products, according to Perkins.
Vol. 29, No. 3
Citation: When referring to this article, please cite it as C. Challener, “Biopharma Takes On Raw Material Variability," BioPharm International 29 (3) 2016.