In recent years, regulatory agencies have changed the paradigm for the pharmaceutical industry in a number of important ways. Many of these changes have been aimed at innovating industry and the regulatory bodies, and have led to a much stronger focus on scientific knowledge within products and processes. A case in point is the change to the way the US Food and Drug Administration (FDA) approaches guidance creation. In the past, guidance was put in place primarily to address a specific issue or common requirements, for example: out of specifications (OOS) guidance or FDA meeting requests. Although important, this is an extremely tactical approach to sharing the agencies’ philosophical views on topics with industry. To be clear, this is not to suggest that these types of guidance have (or even should) be eliminated, rather that, in addition to these tactical documents, the FDA is approaching the overall process of issuing guidance from a more strategic perspective.

Nowhere is this more evident than the tripartite series ‘Q8 Pharmaceutical Development’, ‘Q9 Quality Risk Management’ and ‘Q10 Pharmaceutical Quality Systems’, and the synergy created with the 2011 process validation guidance ‘Process Validation: General Principles and Practices’.

Prior to the latest revision of the guideline, validation was seen more as an event than a process. Products would be validated generally with three lots (no matter how simple or complex the process may be and no matter what the state of understanding of the product was at that time) and, unless anything changed (equipment, process parameters, raw materials, etc.), one really did not need to do anything more than demonstrate the process could be revalidated, by a similar process, a number of years later. To be fair, this is very much an oversimplification, but it certainly is true that information gleaned over that period of time was really not much of a factor in the validation process for most organisations.

Important validation

In the new guidance, validation is seen as a continuous process, rather than an event, and the ongoing learning from a product is applied to the process in order to mitigate risks that are specifically identified. In order to better understand this concept, and to see the synergy with quality by design (QbD), there is a need to quickly review the elements of this approach. In the guidance, process validation activities are broken down into three stages:

process design: information from the development and scale-up activities are used to define the commercial process process qualification (PQ): the process design is evaluated to determine if it is capable of reproducible commercial manufacturing continued process verification: the process is continuously monitored to assure it remains in a state of control.

"It stands to reason that the better one’s understanding at the process design stage of one’s product and process, the less emphasis will need to be placed in the PQ stage in order to assure the process will be reproducible."

It stands to reason that the better one’s understanding at the process design stage of one’s product and process, the less emphasis will need to be placed in the PQ stage in order to assure the process will be reproducible. Conversely, the less one knows about the process going into process qualification, the greater the risk and, therefore, greater assurances will be needed in order to demonstrate the process is capable.

When one considers this approach in the context of ‘Q8 Pharmaceutical Development’, one quickly sees the synergy that is created. As a matter of fact, a closer look at section II in that guidance finds that the very first line states: "The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product". It goes on to then link this understanding, as well as knowledge gained during manufacturing, to the creation of the design space for the product, a critical element in QbD.

Clear guidance

If one’s understanding of the process can drive the validation strategy, the next question becomes: what is the critical data and where can that be derived? Here, it is possible to turn to ‘Q9 Quality Risk Management’ in order to help focus efforts. This guidance is very clear on the role of quality risk management in validation within section II.6 ‘Quality Risk Management as Part of Production’, which contains several sections, one of which is titled Validation, and reads as follows:

  1. to identify the scope and extent of verification, qualification, and validation activities (such as analytical methods, processes, equipment and cleaning methods)
  2. to determine the extent for follow-up activities (such as sampling, monitoring and revalidation)
  3. to distinguish between critical and noncritical process steps to facilitate design of a validation study.

Again, this fits perfectly with the validation guidance in supporting a scientific, risk-based approach for the determination of one’s critical process parameters (CPPs), validation strategy, continuous process verification requirements, etc. This also complements the ideals of the pharmaceutical development guidance as there tends to be less risk in variables that are well understood and could be statistically described (for example, mean and variability are well established) than those of which there is limited process understanding. This allows the focus of one’s efforts, not just on the parameters that there is limited knowledge of, but those that pose the greatest risk for product and, therefore, the patients.

Finally, when considering ‘Q10 Pharmaceutical Quality Systems’, all of these elements are combined in order to achieve a systematic, all-encompassing quality approach throughout the product life cycle. Certainly, in this context, validation plays an important role. Take into consideration the objectives of Q10, as outlined within section D:

  • Achieve product realisation (1.5.2): to establish, implement and maintain a system that allows the delivery of products with the quality attributes appropriate to meet the needs of the patients, healthcare professionals, regulatory authorities (including compliance with approved regulatory filings) and other internal and external customers.
  • Establish and maintain a state of control (1.5.2): to develop and use effective monitoring and control systems for process performance and product quality, thereby providing assurance of continued suitability and capability of processes. Quality risk management can be useful in identifying the monitoring and control systems.
  • Facilitate continual improvement (1.5.3): to identify and implement appropriate product quality improvements, variability reduction, innovations and pharmaceutical quality system enhancements, thereby increasing the ability to fulfil a pharmaceutical manufacturer’s own quality needs consistently. Quality risk management can be useful for identifying and prioritising areas for continual improvement.

In each of these objectives, one can see the role of validation and the associated stages. For example, how does one achieve product realisation without assuring (validating) one’s process is capable of producing a product that will meet the needs of the various stakeholders?How does one establish and maintain a state of control without identifying, monitoring and, when necessary, challenging critical parameters? How can one facilitate continual improvement without the benefit of continual monitoring to identify excess variability and potential parts of the process not fully in a state of control?


Although only a small number of examples are covered here, the message should be very clear: each part of the guidance supports and builds upon the next, and speaks to an approach that uses good science, statistical approaches and risk management techniques in order to obtain a product of consistently high quality. Within this framework, the process validation guidance is an important contributor to meeting the goals of quality by design. In considering the validation approach to be similar to other investment activities, one can understand how a strong understanding at early stages will allow the monitoring and control of the product, with less effort, as one moves down the product life cycle. If it is possible to change the view of validation from a set of discrete activities to one of an ongoing commitment, valuable knowledge can be gained and focus on continuous improvement efforts will be achieved in the most productive way possible.