RAW MATERIAL RISKS
Raw material risk assessments are focused principally on the effect on the process in terms of quality and process performance,
but additional risk factors should be considered in selecting and a material and its source, such as material risk (e.g.,
toxicity, immunogenicity, viral safety), and risks posed by the supplier (quality systems, business, and technical capabilities).
This is presented in Table 2. Raw materials are required to meet industry standards where relevant, and should undergo testing
to confirm compliance with user specifications. Materials should be fully traceable to the site of origin and handling procedures
should be in place to prevent cross-contamination. Deliberate adulteration of raw materials for economic or other reasons
is a particular concern. Its detection and prevention requires a combination of analytical controls and supplier relationship
Table 2. Raw material risk categories
Process Risk Related to Raw Materials
Process risks arise from the stage in the process where the material is used and the effect the material has on product quality
or process performance at that point and at subsequent steps. The risk posed by the material, rather than by processing conditions,
is assessed. As in all risk assessments, the evaluation should be performed by a multifunctional team consisting of the development
team (experience of the specific molecule) together with subject matter experts with experience of similar molecules and unit
operations, or packaging and delivery devices as appropriate. Process risks can affect product quality, and process performance
(supply continuity, variability) and end-user satisfaction.
Risks Related to Material Properties
Certain risks arise from inherent properties of the materials used and from the processes by which they are made. It is therefore
necessary to have an understanding of material properties such as toxicity and their potential to cause harm should they happen
to be included in the final product, so that appropriate steps can be taken to protect the patient either by detection and
removal methods. In some cases, e.g., animal-derived materials (a potential source of TSEs), safety may be secured by a number
of methods such as sourcing from approved areas, by the processing of the material itself, or by demonstrating that the purification
process is capable of removing infectious agents by spiking studies. There are a number of materials where specific guidelines
or regulations cover their use and include, but are not limited to, residual solvents, residual metals, animal derived materials,
materials at risk for melamine contamination, and filters.1–6,18–22 Some materials may be complex and consist of multiple components (e.g., predispensed media or media additives in single-use
systems, prepacked columns) or themselves be components of drug product (e.g., prefilled syringes and delivery devices). In
such cases, it may not be practical to take apart the material for testing, and the user is heavily reliant on the supplier's
quality systems. Material risks are assessed by subject matter experts with the appropriate expertise, e.g., toxicology, immunology,
materials science, mechanical engineering, and environmental health and safety (EH&S).
All suppliers of materials used in pharmaceutical manufacturing must be audited. The supplier audit should have an effective
quality management system in place that is certified, where appropriate, to ISO9001:2008, ISO13485, or relevant industry standards
e.g., ICH Q10 guidance.23 Manufacturers of API and excipients have to meet the highest standards. The supplier also should have suitable audit procedures
in place for its sub-suppliers, with a strong preference for short, transparent supply chains, because of the increasingly
concerning emergence of economic adulteration, as mentioned above. Sourcing should be done from trusted suppliers and sub-suppliers,
and there should be evidence that the security of the supply chain in terms of safety has not been impaired. A more detailed
set of requirements is given in reference 24. Additional supplier concerns are for business continuity.
Suppliers should have adequate capacity to meet increasing demands and should have recovery plans in place in the event of
catastrophic events. Supply disruptions may not impact product quality, but they will impact patient wellbeing, which is also
a health concern. Lastly, the supplier's technical capabilities in terms of product and process understanding should be assessed.
Their understanding of the way their products are being used and commitment to service and support are fundamental to a good
supplier relationship. This is especially true as manufacturers become increasingly dependent on complex single-use technologies,
where the supplier becomes an integral part of the users manufacturing and quality systems. Some of the guidelines used for
systems verification can be applied to these complex consumables.25
Part 1 of this article presents an approach for managing raw materials in the QbD paradigm. It should be understood that risk
assessments are limited by what is known at a given point in time. Manufacturers should continue to monitor and correlate
product quality and process performance with process parameters (inputs), including raw material attributes, and refine specifications
and controls as appropriate, as part of continuous verification and improvement. Process analytical technology tools are highly
appropriate for this purpose.26 The effect of a raw material may not be fully understood even at a relatively late stage in development.
Part 2 of this article will discuss how to conduct risk assessments, and will give an example of the application of risk assessment
tools for raw materials in biotech processes.
The authors would like to thank Jennifer Mercer, Amgen Inc., Thousand Oaks, CA for her review of the manuscript and her helpful
Anurag S. Rathore, PhD, is a biotech CMC consultant and a faculty member at the Indian Institute of Delhi, India, +91-9650770650, email@example.com
Rathore also is a member of BioPharm International's editorial advisory board. Duncan Low is a scientific executive director in process development at Amgen Inc., Thousand Oaks, CA.