From quality risk management principles to the U.S. FDA’s recent proposals for quality metrics, industry faces pressure—both internally and externally from regulators—to ensure the quality of drug products. But quality is not just an endgame approach; it also begins at the bottom with the selection of raw materials.

ICH Q8 (R2), Q9 and Q10 provide complementary guidance on pharmaceutical development, quality risk management and quality systems, respectively, to improve product quality (1-3). A scientific and risk-based approach to quality product development has been outlined in these guidelines. Robust control strategy is the key for ensuring consistent process performance and product quality. ICH Q10 defines control strategy as:

“A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control” (3).

As described in ICH Q10, control strategy encompasses various sets of controls to ensure product quality. Process and product understanding is the foundation of control strategy. The scientific and risk-based approach outlined in the ICH documents is the basic principle for constructing robust control strategy and process parameter ranges (1-3).

Figure 1 provides a schematic of control strategy for a given critical quality attribute (CQA) of drug product. Process flow comprising of associated unit operations and various sets of control as defined in ICH Q10 are depicted. Raw material control is one of the controls shown in the figure. Raw material control strategy cannot stand alone—rather it should be part of the overall control strategy for the product.

Figure 1 Schematic of overall control strategy and how the raw material control strategy feeds into overall control strategy

The obvious question is “what should be the starting point for raw material control strategy?” The approach to material control strategy is no different than for any other control strategy. Understanding raw material attributes and their effect on product quality constitutes the first step. In order to develop a robust control strategy for raw materials, understanding of “how and what” (how material attributes affect the CQAs of product and what controls are needed to be in place) is critical to achieve consistent end product.

Understanding the Effect of Raw Material Attributes on Product Quality

Establishing the relationship between raw material attributes and product CQA is the key first step in designing control strategy. It is important to start thinking about control strategy for raw materials during early development and as product knowledge evolves. It is imperative that the rationale for having specific control strategy for excipients should be driven through risk assessment. Raw material risk assessment should be included as a part of process risk assessment. A clear, documented, team discussion on raw material risk assessment can result in robust control strategy.

Typically, material attributes of raw material are evaluated against the effect on CQA based on process and product understanding. Table 1 shows an example of a cause and effect matrix where the links between the raw material attributes and product CQA are assessed. This risk-based approach provides good insight into important material attributes. As shown in the example presented in Table 1, the impact on CQA is weighed on a low (1), medium (5) and high scale (9).

Table 1 Example of cause and effect matrix relationship for material attributes effect on CQA of final product

Cause and effect matrix assessment suggests that material attributes 1 and 3 do not impact any product CQAs. It is clear that material attribute 2 (MA2) has medium impact on CQA1 and CQA 3 in addition to strong impact on CQA 3. Hence, MA1 and MA3 can be classified noncritical material attributes and MA2 can be classified as critical material attribute. The impact of MA2 should be carefully evaluated on CQA and it should be assessed whether further control of MA2 is required.

Examples of a raw material attribute that may impact CQA would be particle size, bioburden, and pH. Process and product characterization can point toward essential control strategy. For example, if the CQA is not affected by MA2 within the incoming specification range, release of raw material as control strategy could be sufficient. If it is determined that significant changes in CQA are noted, narrow control of MA2 may be warranted.

Narrow Raw Material Control

If the narrow control of material attributes is warranted, this can be achieved by narrow specification on release of raw material through raw material manufacturing process/additional controls. Process understanding of the raw material manufacturing process and process parameters that impact MA2 are important inputs in determining the required control for raw material manufacturing process.

Bringing Control Strategy together for Raw Materials

Risk assessment and product/process knowledge (QbD or QbD-based approach) provide input in control strategy. An overall process and decision tree with an example of MA2 is demonstrated below. It is clear that the controls for raw material for MA2 could range from release and stability of raw material for MA2, control of process parameters that impact MA2 and possibly in process check for MA2.

Connecting Control Strategy to Process Validation Guidelines

Guidance from FDA and EMA on process validation stresses the importance of a lifecycle approach toward process validation rather than a onetime approach to demonstrate process consistency and control to manufacture a robust product (4). Control strategy forms the basis of this approach and feeds into a continuous process verification program (4). It is important that raw material control strategy is integrated in overall product control strategy.

Figure 2 Example of decision on control strategy for raw material

Summary

Product and process knowledge along scientific and risk-based approaches drives the development of control strategy. Various controls constitute overall control strategy for product development. Input raw material quality should be one of the considerations for overall control strategy and can be achieved through the basic premise of product/process knowledge space and scientific/risk based approach. It is imperative that the raw material control strategy be a part of overall control strategy.

References

1. ICH Harmonised Tripartite Guideline, Quality Risk Management Q9: 2005
   www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf
2. ICH Harmonised Tripartite Guideline, Pharmaceutical Development Q8 (R2): 2009
   www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf
3. ICH Harmonised Tripartite Guideline, Pharmaceutical Quality System Q10: 2009
   www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf
4. Mire-Sluis, A, et al. New Paradigms for Process Validation: A Practical Approach. Bioprocess International 11 (2013): 28-39
   www.bioprocessintl.com/wp-content/uploads/bpi-content/BPI_A_131109AR05_O_230181a.pdf

About the Author

Parag Kolhe is Group Leader-Senior Principal Scientist at Pfizer, Biotherapeutics Pharmaceutical Sciences. He has been working in the pharmaceutical industry for more than ten years. He has vast experience in development of monoclonal antibodies and vaccines.