Managing Raw Materials in the QbD Paradigm, Part 1: Understanding Risks - An initial assessment of materials must extend beyond the material specification to include the supplier's manufacturing proce


Managing Raw Materials in the QbD Paradigm, Part 1: Understanding Risks
An initial assessment of materials must extend beyond the material specification to include the supplier's manufacturing process, quality systems, and sourcing strategy.

BioPharm International
Volume 23, Issue 11, pp. 34-40


Figure 1. Raw material management approach in the Quality by Design paradigm
Figure 1 presents an overview of one approach that could be implemented for managing raw materials in the QbD paradigm.13,14 As illustrated in the figure, raw materials are initially selected during early-stage or platform development, before detailed characterization during late-stage development, they are then subject to continual evaluation throughout the product lifecycle. The initial risk assessment is performed early in the development process to prioritize areas of concern and focus further research, and is repeated as greater knowledge is obtained. Typically, knowledge is limited in the early stages to general information about the material and its performance in similar processes. The process typically is not fully characterized until process characterization is initiated (typically after end-of-Phase 2 clinical studies are successful). Stage-appropriate risk assessment practices are followed at each point, with the level of detail increasing as more knowledge becomes available. Based on platform knowledge and product-specific knowledge, the raw materials can be categorized into three categories: (1) critical raw materials, (2) key raw materials, and (3) non-key raw materials. A combination of mechanistic modeling and multivariate analysis can be used to analyze the effect of the various raw materials on the different process and product quality attributes. The approach could be used to identify raw materials that have the most potential to impact and hence need the most characterization.10–12,15

Critical raw materials are known to significantly affect product quality and these raw materials are therefore thoroughly characterized and their mechanisms of process interactions well understood. A relationship is developed among the relevant raw material attributes and the quality attributes that are being affected. For these raw materials, acceptance criteria must be developed within which their attributes can vary without leading to unacceptable product quality. Furthermore, analytical tests are developed to monitor raw material attributes to ensure that each raw material lot meets the respective acceptance criteria before its use in the process.

Key raw materials do not significantly affect product quality but do impact process consistency. These raw materials can be characterized as thoroughly as critical raw materials, but this is a risk-based decision and will depend on the platform and the product. They might or might not require routine monitoring based on the significance of their impact. If a new key raw material is added to the platform, it should undergo the thorough characterization of a critical raw material before being used in the platform.

Non-key raw materials include the remaining (and majority of) raw materials. These materials are handled through the internal quality system of the biopharmaceutical manufacturer as in traditional pharmaceutical manufacturing.

For all raw materials, the biotech company should have an internal quality system that would ensure appropriate raw material management. Some key aspects of this system would be:7,16,17

1. Review of the certificate of analysis from vendor and confirmation that the raw material lot meets the internal specifications. Materials specifications are set based on materials meeting the performance requirements of the process in question. In the vast majority of cases, material specifications are predetermined by the supplier. It is still up to the manufacturer to determine if they are adequate for their intended use, and in some cases it may become apparent over time that alternative or additional specifications are required.

2. Analysis of raw materials as necessary. The testing plan should ensure that while critical quality aspects are examined, superfluous testing that is not providing useful information is not performed.

3. Review of any changes to the vendor's manufacturing process with respect to change in raw material quality and its impact on process consistency and product quality.

4. Vendor site audits at appropriate frequency to ensure vendor qualification as needed during product lifecycle. These may include technical audits by subject matter experts to assess supplier capabilities and competencies.

5. Appropriate supply chain management system in place to avoid failure of incoming raw material lots in meeting specifications.

6. Ensure traceability of raw materials.

7. Raw materials of animal origin should be checked with respect to requirements with animal feed, animal age, manufacturing practices of the vendor, and other relevant aspects.

8. Custom-synthesis based raw materials need to be thoroughly characterized to ensure the process that is used to make them is well controlled and the raw materials are comparable across lots and scales that were used over product lifecycle.

9. A robust change control program should be in place to assess potential changes of the raw material to evaluate the potential to impact product quality.

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