Evolution and concepts
If you think back to the early 2000s, industry was very vocal about the challenges of operating a global business in an environment
where GMP regulations were regional. There was a strong desire to have some form of harmonized view of these practices. So
in July 2003, an informal ICH working group agreed on a quality vision: to develop a harmonized pharmaceutical quality system
(PQS) that's applicable across the life cycle of a product, emphasizing an integrated approach to quality risk management
and science. Q8, Q9, and Q10 have all evolved from the statement. Q8 is the science, Q9 is the quality risk management, and
Q10 is the quality system which all of this operates within.
In 2005, the ICH steering committee assembled another informal working group to come up with a concept paper on PQS. I led
the group, and we agreed that a quality-system guidance had to follow contemporary, modern principles, and align with the
International Organization for Standardization's (ISO) quality management-system principles.
The committee also agreed that a guidance had to focus on the product life cycle. GMPs were focused on commercial manufacturing,
but we have all learned that it's the linkage between development and commercial manufacturing that is critical to the successful
introduction of a product and successful transfer of the knowledge, or process understanding, around that product. The way
industry interpreted GMP back then was that once you had a process approved, you didn't change it. This interpretation inhibited
innovation and continual improvement.
In the end, the Q10 EWG wanted to augment regional GMP regulations and move from GMP compliance to robust processes and adequate
process understanding, which is where knowledge management comes in. Q10 defines knowledge management as a "systematic approach
to acquiring, analyzing, storing, and disseminating information related to products, manufacturing processes and components."
Knowledge management, knowledge transfer, and technology transfer are key aspects of the final version of Q10. Industry will
find very little reference to these concepts in GMPs, but they are critical to the success of each company.
For example, Q10 can help improve data management. Those in the industry that have adopted techniques such as Six Sigma have
found that they can convert their data into process understanding. At that point, they're well on their way to achieving the
kind of process control and quality that is called for in Q10. It's really about promoting the tools within Q10 to convert
data into knowledge you can do something with.
Within the ICH working group, there was always the fear that we were taking commercial GMP requirements and forcing them upon
development and clinical-manufacturing activities. So we made it clear that the elements of Q10 are to be applied in a manner
that is appropriate and proportionate to each product life-cycle stage, recognizing that the goal of development is different
than the goal of commercial manufacturing. Q10 is not meant to apply commercial standards to the development arena.
Q10 also does not replace regional GMP regulations but rather is to be used with the regulations. Regional GMPs don't explicitly
address all stages of the product life cycle nor do they promote innovation or continual improvement. So the quality system
that we defined in the final Q10 guideline, including its management responsibilities, encourages the use of science and risk-based
approaches at every stage of the life cycle and therefore promotes continual improvement across the product life cycle.
—Joseph C. Famulare
During the consultation and comment period for Q10 (Step 3), we received 300 estimated individual comments. One of the most
important issues was management of change in ownership of the product. It was noted that when product ownership changes or
certain transfers occur, that the change of ownership doesn't always follow the transfer of all the necessary things and responsibilities
to ensure quality.
So we added section 2.8, Management of Change in Product Ownership, to the final Q10 document. Section 2.8 states that when
product ownership changes, management should ensure "the ongoing responsibilities are defined for each company involved" and
"the necessary information is transferred." The hope for regulators is that this new section will address some past experiences
in which these issues were not well coordinated or addressed until quality concerns surfaced.
Another issue identified was management of outsourced activities and purchased materials. Everyone should be aware that the
process of manufacturing pharmaceutical products is more complex today than ever in terms of having many activities, operations,
and materials outsourced. Pharmaceuticals are manufactured globally and materials used in the manufacture of pharmaceuticals
are obtained from global sources. Section 2.7 of the Q10 document was expanded to address this, as follows [and is further
explained in the next section]:
"The pharmaceutical quality system, including the management responsibilities described in this section, extends to the control
and review of any outsourced activities and quality of purchased materials. The pharmaceutical company is ultimately responsible
to ensure processes are in place to assure the control of outsourced activities and quality of purchased materials. These
processes should incorporate quality risk management and include:
(a) Assessing, prior to outsourcing operations or selecting material suppliers, the suitability and competence of the other
party to carry out the activity or provide the material using a defined supply chain (e.g. audits, material evaluations, qualification).
(b) Defining the responsibilities and communication processes for quality-related activities of the involved parties. For
outsourced activities, this should be included in a written agreement between the contract giver and contract acceptor.
(c) Monitoring and review of the performance of the contract acceptor or the quality of the material from the provider, and
the identification and implementation of any needed improvements.
(d) Monitoring incoming ingredients and materials to ensure they are from approved sources using the agreed supply chain
The third issue identified during Step 3 called for a diagram that would illustrate the major principles of Q10 (see Figure
1). The diagram demonstrates some of the major features of the Q10 guideline, showing the relationship to GMP over the life
cycle of the product, and how quality systems extend even further back than development, further than GMPs. The important
elements are featured here, which include management responsibilities for the quality system, the actual elements in terms
of process performance and product quality monitoring systems, the corrective-action and preventive-action (CAPA) system,
the change-management system, and management review.
Figure 1: Diagram of the ICH Q10 Pharmaceutical Quality System model.
One of the final discussions we had in Portland involved suggestions for the IWG [to help carry out Q10 in all three ICH regions],
some of which included training. In terms of implementation within FDA, I think it will work very much in line with IWG. Certainly,
integration between the review, the compliance, and the inspection will continue here in the US, and...strong importance will
be placed on integration between assessors and inspectors.
Issues that will be discussed going across the ICH quality documents (Q8, Q9, and Q10) will involve a good integration of
design space, control strategy, and real-time release and criticality. Knowledge management will be important as to how it
will look in actual practice, and how we will understand that as regulators and be able to make, hopefully, better regulatory
decisions based on knowledge management and actual knowledge gained over the life cycle of the product and process. The opportunities
for both industry and regulators are summarized in Annex 1—the opportunity for industry to take ownership of quality and continual
improvement and better use of resources by regulators for more effective and efficient review and inspection processes (e.g.,
management of movement within the design space by the quality system). IWG is key to having these things implemented on a
regional basis and more harmoniously.