Criticality Management of a Drug Product and its Manufacturing Process - Pharmaceutical Technology

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Criticality Management of a Drug Product and its Manufacturing Process
Criticality management combines pharmaceutical product, process, and material knowledge and risk management in one approach, which is reflected in a single document.

Pharmaceutical Technology
Volume 9, Issue 32, pp. 6680

Knowledge and criticality in overview tables

Table VIII: Influential process parameters and material attributes.
Table II represents the parameters or material attributes that were evaluated for potential impact. Similar tables can be made to summarize the parameters or material attributes that have proven to be influential and highlight those that are critical (see Table VIII). The CCPs in the control strategy can be represented in a similar table (see Table VII). These tables can address questions such as which parameters or attributes across process steps or materials influence a given end-product CQA and which of those are critical.


Although chemometric tools such as design of experiments are essential in the realization of quality by design (QbD), development teams also need tools that lead them through the long QbD journey and keep them focused on what is critical to the patient. The authors believe that criticality management, as described in this article, can provide such tools. Criticality measurement starts as an empty template and is gradually filled out as the development team is guided through the effort. The criticality-management report is transferred to manufacturing operations so that what must be characterized on the full-scale equipment is clear. The criticality-management document is updated based on this characterization work, preferably before process validation.

In the postapproval stage, criticality management can help update and maintain all relevant product and process knowledge in clear, comprehensive, and easy-to-use overview tables. Such a documented understanding can facilitate innovative process improvement and corresponding change control.

Criticality management, as presented in this article, is more than a failure mode and effects analysis (FMEA) table. In contrast to FMEA, criticality management contains informative, well-designed tables that offer development-team members a quick and complete view of the current status of the product, process, and material understanding. All knowledge is documented so that one easily find detailed information if necessary.

The criticality-management process comprises all the steps from the generation of the target product profile to the development of a comprehensive control strategy. A formal criticality-management process should not start when the development work is already finished because it will most probably reveal gaps in product or process knowledge that are difficult to address in the short term. Criticality management should start when the late-stage formulation concept and manufacturing-process flow are selected to steer further development toward what is most critical for the safety and efficacy and to link it to the individual process parameters and material attributes that potentially influence these qualities.

The authors undertook criticality management for five products made using different manufacturing techniques and proved that it was useful. Completing all the steps of criticality management requires effort and perseverance. Development teams that start early and carry out the complete effort have a better view of their product and process, address more uncertainties early in development, and run less risk of missing an important source of variability. Criticality management is not part of the regulatory dossier because it can take more than 30 pages. But the fact that the cascade of influential and critical parameters or material attributes are clearly defined in the criticality-management document makes it easier to write a coherent and transparent development and control section in the common technical document.

The authors' approach can easily be updated when the International Society for Pharmaceutical Engineering's Product Quality Life Cycle Implementation criticality task team publishes a final guidance on the definition of criticality.

Filip Vanhoutte* is an associate director of drug-product development, and Guy Smans is a principal scientist in drug-product development, both at Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium, tel. +32 0 14 60 39 58, fax +32 0 14 60 5333,
. Luc Janssens is senior director of global regulatory affairs, and Marc Vanstockem is senior director and chemical–pharmaceutical team leader, both at Tibotec.

*To whom all correspondence should be addressed.

Submitted: June 10, 2008. Accepted: June 30, 2008.

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1. FDA, Pharmacetutical CGMPs for the 21st Century : A Risk-Based Approach (Rockville, MD, Aug. 21, 2002).

2. ICH, ICH Q8: Pharmaceutical Development, Step 4 (Geneva, Nov. 10, 2005).

3. ICH, ICH Q8: (R1): Pharmaceutical Development Revision 1, Step 3 (draft, Geneva, Nov. 1, 2007).

4. ICH, ICH Q9: Quality Risk Management, Step 4 (Geneva, Nov. 9, 2005).

5. FDA, "Submission of Chemistry, Manufacturing, and Controls Information in a New Drug Application under the New Pharmaceutical Quality Assessment System: Notice of Pilot Program," Fed. Regist. 70 (134), 40719–40720 (July 14, 2005).

6. W.P. Ganzer et al., "Current Thoughts on Critical Process Parameters and API Synthesis," Pharm. Technol. 29 (7), 46–66 (2005).


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