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Supply chain traceability is essential in the manufacture of APIs to assure safety and quality.
Increasingly, regulators and consumers are pushing for improved information on how drugs are made and distributed, particularly as recent challenges, such as nitrosamines impurities and the vulnerabilities brought to light during the COVID-19 pandemic, have raised the profile of the pharmaceutical supply chain within global media. Therefore, full traceability of pharmaceutical ingredients, from the beginning to the end of the supply chain, is a progressively high priority for companies in the bio/pharma industry.
To find out more about the complex pharmaceutical ingredients supply chains, specifically that of animal-derived APIs, Pharmaceutical Technology spoke with Jaume Reguant, healthcare director, Bioiberica—a global life-science company, focused on the identification, extraction, and development of animal-derived biomolecules.
PharmTech: Could you highlight the importance of traceability in ensuring the security of pharma API and ingredients?
Reguant (Bioiberica): There are various reasons for increased supply chain traceability. For the manufacture of pharmaceutical APIs, traceability is absolutely essential as it ensures safety and quality. By implementing a robust set of processes and centralized way of working, manufacturers can ensure visibility from start to finish. This means, in the event of a problem, it’s possible to quickly identify the source—at any stage of production—preventing inadequate or unsafe products reaching patients.
These considerations are perhaps even more important when working with animal by-products. In fact, the quality assurance required for animal-derived APIs is particularly complex and goes beyond the pharmaceutical industry to the food industry—to the abattoirs supplying the large amounts of animal by-products needed to extract the APIs. This means that robust quality systems must be in place to verify the traceability is maintained through the supply chain. It’s for this reason that Bioiberica works with a vertically integrated supply chain model, allowing comprehensive control—from the collection of the animal tissues to the final API. This approach drastically reduces the risk of cross-contamination and transmission of animal-derived adventitious agents, while also making quality checks much quicker.
PharmTech: Have global regulatory bodies changed the way they approach APIs and other ingredients over the years?
Reguant (Bioiberica): The regulation of animal-derived APIs has dramatically changed over the last 10 years. Perhaps one of the most prominent changes was the response to the adulteration of heparin API in 2008 (1). Used for decades without significant safety events, US patients began suffering negative effects, which ultimately revealed weaknesses in the production of animal-derived APIs in certain countries where there were typically low standards in traceability and quality systems. Before then, regulatory oversight had been focused on the final API. The heparin crisis caused the revision of worldwide pharmacopeial monographs and led to the introduction of state-of-the-art analytical tests.
But the regulatory change that has had a key impact on the production of all animal-derived APIs, particularly in Europe, is the definition of pooled animal tissue as the starting material in the manufacturing process (2). This means that the complete supply chain, starting from the collection of the animal material, must fall under the good manufacturing practice (GMP) quality system. In addition, not so long ago, the application of good distribution practices for APIs became mandatory (3). The handling of APIs is, therefore, not only regulated under GMP scope at the manufacturing site, but also their distribution outside the site. Because of these changes, the whole supply chain is subject to strict controls, highlighting the importance of total supply chain traceability.
PharmTech: Do you foresee stricter regulations for traceability and quality of pharmaceutical ingredients coming into force in the future?
Reguant (Bioiberica): The regulatory landscape is always changing, and it’s possible that stricter controls are on the horizon, especially as developments in technology and processes are made. Over recent years, there has been an increase in regulatory requirements in several areas: how adventitious agents of concern (zoonotic diseases, cross-contamination with other animal materials, etc.) are monitored; how risk management principles are implemented in processes; and how the control and verification of GMP compliance throughout the supply chain is ensured. As the regulatory landscape continues to evolve, having total control of the supply chain, from the collection of the starting material to the final API, allows manufacturers of animal-derived APIs to be prepared to respond to stricter regulations.
A further consideration is that pharmaceutical companies are subject to stricter controls by regulatory authorities on how they address possible shortages of starting materials to ensure the availability of medicines. This results in additional challenges for the production of animal-derived APIs because their supply chain is dependent on herd size in different regions around the world and potential outbreaks of animal diseases that may lead to supply shortages.
PharmTech: Could you elaborate of some of the specific regulatory challenges facing manufacturers and suppliers of animal-derived (versus plant or synthetic) ingredients for use in pharmaceutical products?
Reguant (Bioiberica): Animal-derived APIs have a very specific set of regulatory challenges. They are a heterogeneous group of ingredients with variant regulatory frameworks depending on different health authorities. For example, heparin is considered a drug by the FDA, but a biological in Europe, which can present challenges. Regulations for chemical substances, however, are more globally harmonized. Unlike chemical substances, which have a consistent, characterizable chemical structure, regardless of how they are manufactured, animal-derived APIs have an intrinsic variability due to their biological origin. As such, this requires a control strategy across all stages of the supply chain—from the collection of the animal material to the final purification of the API. Otherwise, APIs with different safety and pharmacological properties could be produced.
What’s more, the optimization of manufacturing processes and introduction of new sources of the same starting material involve a significantly higher regulatory burden for animal-derived APIs. Comprehensive comparability exercises must be undertaken to demonstrate that the products have similar qualities and structural attributes before and after manufacturing changes have taken place, and that there will be no adverse impact on the safety or efficacy of the drug product. Several variations considered minor for a chemical substance are instead regarded as major for animal-derived APIs. For a multi-supplier, multi-customer system, post-approval changes can be a significant challenge and makes continuous process and supply chain improvement particularly difficult.
Guidelines specifically developed for biotechnological products are sometimes applied to animal-derived APIs. These have to be established in proportion to the risk and adapted to the particularities of each product, especially if the product of concern is not the same product for which the guideline has been developed. This message can be difficult to communicate to certain regulatory authorities.
PharmTech: What is the significance of a vertically integrated supply chain model and how can it benefit pharma companies in terms of supply chain security of ingredients?
Reguant (Bioiberica): A vertically integrated supply chain model offers significant advantages to pharmaceutical companies. Using Bioiberica as an example, which is part of the SARIA group, the way vertical integration works is that all source animal materials are collected from authorized and audited slaughterhouses, from animals that are deemed fit for human consumption. The animal collection, handling, and transport is carried out under rigorous hygienic conditions to prevent cross-contamination and adulteration. The APIs are manufactured under strict GMP conditions at state-of-the-art facilities. Each step of this process combined, under Bioiberica’s quality management system, results in high-quality final APIs and ingredients.
In addition to ensuring safety and quality, a vertically integrated company also helps to ensure supply chain security and cost-efficiency. Reduction in animal herd sizes due to diseases outbreaks may lead to animal by-products shortages. This issue results in competition to collect the animal starting materials, usually at very high prices, which generally increases the manufacturing costs of the API. Controlling the API supply chain from the collection of the starting material mitigates the risk of shortage. Moreover, there can be logistical problems when it comes to moving and exporting products that are of animal origin. The ability to control all aspects of the supply chain means that it is possible to proactively manage these challenges.
PharmTech: As sustainability issues and the environment are more prominent today than ever before, what measures can be taken by ingredients manufacturers to be ‘greener’?
Reguant (Bioiberica): As pharmaceutical manufacturers, along with every other company, look to be more sustainable, it’s key that they consider increased traceability capabilities as this allows them to ensure the necessary sustainability standards are met at each stage, including the collection of source materials.
For manufacturers looking to use animal-derived APIs, it’s understandable that there may be concerns around sustainability—particularly as high numbers of animals are necessary for their production. However, this is where vertical integration can make a difference, as it is the foundation of a truly circular bioeconomy. If you think about it a bit like a biorefinery—in the same way that petroleum refineries extract a range of products, such as liquid and gaseous fuels, tars, monomers for plastics, from crude oil—all of the animal matter used in animal-derived APIs are by-products of animals used in the manufacture of food. The aim is to utilize as much of the tissue as possible, which otherwise would have gone to waste, to create a useful and beneficial end ingredient.
PharmTech: What specific disruptions (if any) have you witnessed in the supply chain of APIs and ingredients for pharmaceuticals as a result of COVID-19? How can companies learn from the current global pandemic in terms of supply chain security, in your opinion?
Reguant (Bioiberica): COVID-19 has demonstrated the European Union’s, and other global regions, dependency on APIs and intermediates imported from other countries, highlighting concerns around possible drug shortages in the future. With animal-derived APIs, you need large volumes of starting materials to obtain the final ingredient, so—like any industry—there are potential risks in the face of significant disruption. The solution is to promote flexibility, diversity, and collection from countries worldwide, while also maintaining strict, traceable quality and supply chain models. There are plenty of industries, beyond our own, that could benefit from this model.
Providing people with medicine is an essential service—one that wouldn’t be possible without the manufacture of APIs. Like all businesses at this time, API manufacturers have taken the necessary steps to support and honor commitments to customers.
PharmTech: Are there any trends that you perceive will be important in supply chain security of APIs and pharma ingredients for the coming decade?
Reguant (Bioiberica): As mentioned, recent events have put increased focus on the need for diversity in source material, whilst also maintaining strict controls and standards across the board. I believe that there will be a continued increase in focus on source material diversity as a result of the pandemic. To secure the supply chain of animal-derived APIs, diversification is a must.
From a regulatory perspective, more flexibility is expected in implementing post-approval changes in the future when the [International Council for Harmonization] ICH Q12 Guideline on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management comes into force (4). It remains to be seen, however, whether the implementation of ICH Q12 will reduce time burdens and costs for regulatory authorities and the pharmaceutical industry that will have a positive impact on the supply chain.
Supplement: APIs, Excipients, and Manufacturing
When referring to this article, please cite it as F. Thomas, “Tracing the Supply Chain,” APIs, Excipients, and Manufacturing Supplement (September 2020).