Setting Specifications for a Biotech Therapeutic Product in the Quality by Design Paradigm - Manufacturing using meaningful, science-based specifications will ensure that we attain the optimal balance

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Setting Specifications for a Biotech Therapeutic Product in the Quality by Design Paradigm
Manufacturing using meaningful, science-based specifications will ensure that we attain the optimal balance between manufacturing flexibility and product safety.


BioPharm International
Volume 23, Issue 1

Establishing Specifications for a Process-Related Impurity


Figure 4. Illustration of clinical and product design spaces for three host cell impurities chosen from Table 1. Host cell protein (HCP) and residual DNA data are plotted on the log scale (left axis) wheras the endotoxin data are plotted on a linear scale (right axis).
Process-related impurities are impurities that are derived from the manufacturing process.2 These could be extractables and leachables from the media or the additives such as cell culture media components and chromatography column leachables. Specification setting for many of these process-related impurities is driven by regulatory expectations. Figure 4 illustrates the clinical and product design spaces for three host cell impurities, namely HCPs, residual DNA, and endotoxin. It should be noted that HCP and residual DNA data are plotted on the log scale (left axis), whereas the endotoxin data are plotted on a linear scale (right axis). In comparison to the product quality attributes presented in Figure 3, it is seen that the product design space is significantly larger than the clinical design space for the host cell impurities. This is primarily a result of a better understanding of these impurities and their impact on product safety and efficacy, as well as the demonstrated excess capability of the process to remove these impurities. In addition, prior knowledge from other products expressed in the same host cell is very applicable for these impurities.

CONCLUSIONS

Setting specifications in the QbD paradigm will involve using product knowledge, process knowledge, prior knowledge, and appropriate statistical methods to define meaningful specifications. This approach also must include a continuous improvement element, so that the specifications are revisited and their appropriateness re-examined to reflect changes in process (process improvements, technology transfer, scale-up, equipment changes), analytical methods (novel techniques), and product knowledge (new clinical and nonclinical data).

Anurag S. Rathore, PhD, is a biotech CMC consultant and a faculty member at the Indian Institute of Delhi, India, 9650770650,
. Rathore is also a member of BioPharm International's editorial advisory board.

REFERENCES

1. Doblhoff-Dier O, Bliem R. Quality control and assurance from the development to the production of biopharmaceuticals. TIBTECH. 1999;17,266–70.

2. International Conference on Harmonization. Q6B, Specifications: test procedures and acceptance criteria for biotechnological/biological products. Geneva, Switzerland; 1999.

3. Rathore AS, Winkle H. Quality by Design for pharmaceuticals: regulatory perspective and approach. Nat Biotechnol. 2009;27–34.

4. Rathore AS. A roadmap for implementation of Quality by Design (QbD) for biotechnology products. Trends Biotechnol. 2009;27:546–53.

5. Seamon KB. Specifications for biotechnology-derived protein drugs. Curr Opin Biotechnol. 1998;9:319–25.

6. Murano G. International conference on harmonization—critical discussion of the biotech 'specifications' document. Curr Opin Biotechnol. 2000;11:303–8.

7. Schenerman MA, Axley MJ, Oliver CN, Ram K, Wasserman GF. Using a risk assessment process to determine criticality of product quality attributes, in quality by design for biopharmaceuticals: perspectives and case studies, Ed. by A.S. Rathore and R. Mhatre, Wiley Interscience, 2009, 53–84.

8. Apostol I, Schofiled T, Koeller G, Powers S, Stawicki M, Wolfe R. A rational approach for setting and maintaining specifications for biological and biotechnology derived products. BioPharm Int. Part 1: 2008;21(6):42–54. Part 2, 2008;21(7);32–40. Part 3: 2008;21(8):44–57.


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