The International Conference on Harmonization guideline on quality risk management, ICH Q9, addresses active substances and
medicinal products, and was adopted by the European Union and Pharmaceutical Inspection Cooperation Scheme (PIC/S) in Annex
20 of their good manufacturing practice (GMP) guides. Drug manufacturers are gradually implementing quality risk-management
principles as introduced in sections 1.5 and 1.6 of the European Union's GMP Guide, Part I. However, the practical methods
for these new requirements are still perceived as difficult to interpret and apply.
In this context, a small, informal PIC/S working group is developing an objective and pragmatic example of methodology for
ICH Q9 that can be used by the widest audience. The methodology will meet the demands of operators and inspectors and comply
with all regulatory requirements. The main axes of this methodology are presented in this article; a complete description
with examples of how the methodology can be implemented is available on the PIC/S website (
The methodology example is meant to be used for training and will not be issued as a PIC/S recommendation or guideline. The
example will not influence the outcome of PIC/S inspections.
Primary methodological axes
The proposed methodology comprises an exhaustive review of the various stages that have an effect on the intrinsic quality
of the product. These steps include:
- The inventory and evaluation of primary risks
- The application of measures for the reduction of these risks
- The evaluation of residual risks.
For each recorded stage, risk is traditionally assessed according to potential severity and frequency of the risk occuring.
The manufacturer's ability to detect risk and the experience gained in performing the step in question also help determine
the risk involved.
Integrating a quantified experience factor in risk calculation with an objective scale serves as a major achievement in the
field of risk management. Calculated in this manner, the level of evaluated risk expresses the degree of technical mastery
acquired in the performance of each process step for the concerned perimeter, without having to take into account the specific
characteristics of the products involved. This is the first phase of the methodology and has been named System Risk.
The second phase of the risk-management methodology considers the integration of the particular properties of the products
themselves whose System Risk will have been previously assessed. This integration is done using a modulating factor, the P-factor,
which, multiplied with the System Risk gives the Total Risk.
The P-factor takes into consideration the intrinsic physicochemical and pharmaco-toxological characteristics of the product
as well as parameters expressing knowledge levels and experience gained by the manufacturer for the product concerned.
This dual approach makes it possible to significantly reduce the burden (i.e., resources) of risk management. For example,
the methodology avoids the needless repetitions of risk-evaluation steps that are typically conducted during the introduction
of a new product.
By implementing a risk-management policy that integrates the steps defined above, a manufacturer in the pharmaceutical area
can maintain the relevance of its risk levels and evaluate them for a total risk calculation. A risk-management policy should
also envisage provisions for the identification and inclusion of developments that could potentially modify the result of
an initial risk evaluation. Such developments may be internal or external to the company and may or may not be integrated
into the manufacturer's quality system.
Traditionally, these developments include the management of corrective actions and preventive actions, deviations, change
control, and internal and external information (e.g., GMP modification). Finally, a company's methodology of risk management
should be organized according to an iterative process.