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Risky business: Establishing quality risk assessments

Heike Michaelis, director of the Emprove program at Merck, international developer of pharmaceuticals, and Frithjof Holtz, the company’s head of advocacy and surveillance for regulatory management explain how to make lighter work of risk assessments in biopharma manufacturing.

Suppliers have a vital role to play in helping drug manufacturers gain access to the comprehensive information needed in support of a risk assessment program.

In order to help ensure patient safety, biopharmaceutical companies must identify possible risks and mitigate exposure to those risks. Risk assessment programs are devised to do just that, helping to ensure safe and robust manufacturing processes.

Unfortunately, identifying and gathering the necessary data required as part of a risk assessment program can be incredibly time and resource intensive. Adding to the challenge is a lack of readily available, detailed information about consumables such as filters and single-use technology.

This article describes current processes and requirements for implementing such risk assessment programs, and offers recommendations for successful and robust quality risk management.

Building quality risk management programs

A good starting point for development of a risk assessment program is the International Conference on Harmonisation (ICH) Q9 Guideline on Quality Risk Management. This document is regarded as the “gold standard” for risk assessment worldwide. Widely referenced by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), ICH Q9 not only describes the steps that companies need to take to establish robust risk management systems, but also provides tools for success implementation of those systems.

ICH Q9 provides guidelines for many areas of risk management, from drug development to supplier management and drug production to packaging, labelling and storage. In developing risk management plans, companies can flexibly interpret and apply ICH Q9 guidelines depending on their specific activities, possible sources of risk and level of risk tolerance. For example, companies conducting sterile manufacturing must be aware of potential contaminants that can impact the safety of final drug products. As a result, these companies may have a lower tolerance for risk and therefore stricter adherence to ICH Q9 than other companies.

More guidance on enacting programs in accordance with ICH Q9 can be found in Technical Report No. 54, Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations from the Parenteral Drug Association.

Gathering data in support of risk assessment

Successful quality risk management depends on a strong understanding of the foundational science, components and processes of the risk under analysis. In the manufacture of drug products, this requires access to documentation and regulatory information describing all chemicals and consumables used in the manufacturing process. Such information facilitates qualification processes, selection of the best suppliers, supply chain transparency, preparation for approval and regulatory compliance.  

Information gathered from the suppliers of chemicals and consumables should include details on how these products are manufactured, how quality is managed and how the manufacturer manages their own suppliers. These details are essential for ensuring a robust, transparent and reliable supply chain. Additional information needed includes the effect chemicals and consumables such as filters or single use components might have throughout the production process and the final drug product. Information such as that regarding elemental impurities (regulated by ICH Q3D) for excipients is important input for the end user’s risk assessment. For consumables, a comprehensive extractables report will assist end users as they run leachables tests with their drug product.

How the information is used depends on the chemical or consumable itself. For raw materials such as excipients, the information is not only needed for the drug filing. For consumables such as filtration and single-use products or process chemicals, the information is used to qualify companies as suppliers, qualify the products for use in their systems, track and trace and better understand and characterise processes.

Obstacles to collecting risk assessment data

Drug manufacturers often experience considerable discrepancies between the information they need to ensure compliance and successful quality risk management and the information that is readily available. These companies often have their own internal requirements that are stricter than official guidelines.

This lack of clarity is especially challenging for consumables such as filters and single-use technology used in bioprocessing. Regulations around raw and starting materials provide relatively clear expectations of documentation expected from suppliers. In contrast, the regulatory landscape for single use is not as developed. As a result, when consumables are added to manufacturing processes there is no clear expectation for the type of information needed to complete risk assessment documentation.

At the very least, manufacturers need to know the risk of potential impurities from consumables – including extractables and leachables. Regulatory associations are working on establishing a common ground for assessing risk from filters and single-use technology. In the meantime, current methods rely on complex processes of evaluating toxicological risk by reviewing in-house studies, scientific publications to determine levels of acceptable exposure from extractables and leachables. Not only is this approach to risk assessment time-consuming, but it requires expertise and specific equipment to verify stability of plastics, integrity of bags and proper operator training among other considerations for risk.

Faced with this level of uncertainty, it is essential for biopharmaceutical manufacturers to partner with trusted suppliers to facilitate quality risk management programs. A strong manufacturer-supplier partnership for risk assessment is crucial.

Recommendations for risk assessment success

Suppliers have a vital role to play in helping drug manufacturers gain access to the comprehensive information needed in support of a risk assessment program. In the past, manufacturers had to contact multiple parties to collect the necessary information to support their risk assessment programs. We have created our Emprove risk assessment program to greatly simplify this process and save manufacturers time and effort associated with their own evaluation or testing. By providing extensive and detailed data about chemicals and consumables, the program addresses the challenges that manufacturers face in preparing for quality risk management.

Introduced in 2004, the program has been continuously extended and enhanced to encompass hundreds of raw and starting materials used by drug manufacturers. In June 2016, the program was further expanded to include products for filtration and single-use processing, making it the first program of its kind to include consumables for biopharmaceutical manufacturers. The program addresses current regulatory needs, anticipates future needs and delivers confidence, by informing risk assessment programs in a very effective way.

For drug manufacturers, it is important to understand the chain of custody of pharmaceutical raw materials. This aids in assessing the risk of falsification. For products in the Emprove program, we describe who produces, fills, labels, tests and releases the material. The original manufacturer is represented by a code. As original manufacturer data are confidential, customers can access this information through our online electronic original manufacturer tracking (eOMT) procedure. 

Drug manufacturers leverage the Emprove program by accessing information for over 400 products, which is available 24/7 through an online portal. Manufacturers can access individual dossiers covering qualification, risk assessment and process optimisation or purchase the entire suite:

Information about intentionally added elements and results from testing of different batches for twenty four elements in line with the ICH Q3D Guideline for Elemental Impurities.

The information provided by the Emprove program is beneficial to large, well-established manufacturers as well as small, emerging companies who may be overwhelmed by the burden of developing manufacturing processes and evaluating risk from pre-clinical to full scale-up.

Conclusion

While ICH Q9 provides strong guidelines for quality risk management, the success of these programs relies on access to documentation and regulatory information about all of the chemicals and consumables used in the manufacturing process. This process can become especially complex for consumables such as filters and single-use technology, where regulatory expectations are less defined and defining risk requires specialised equipment and expertise.

Faced with this potentially time- and resource-intensive process, biomanufacturers can greatly benefit from working with trusted suppliers who are in unique positions to provide risk assessment information. This type of supplier-manufacturer partnership can efficiently provide manufacturers with the information they require to implement risk management and assure safe products for patients around the world.

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