Quality by Design (QbD) is by no means a new concept and has been adopted in a number of industries to continually improve product and process quality, most notably the automotive industry. Over the last decade the U.S. Food and Drug Administration (FDA) have taken the lead to encourage the use of QbD in the development and commercial manufacture of new drugs both at the active pharmaceutical ingredient (API) and finished product. This approach has many benefits namely minimising product variation and reducing overall business risk. It is not good for any Pharma organisation or CMO to encounter supply issues due to the manufacture or the quality of an API.
Have we not always practiced QbD to some extent?
How does QbD differ to more traditional methods of API development? In both practices the objective is to provide product that passes specification without fail. However the fundamental difference is how you get to this goal. Traditionally this has been achieved by carrying out the necessary testing at each key point of a process to ensure that the quality is being achieved and adopt the correct reprocessing or reworking if success is not achieved. A QbD approach is to design quality into a product through an improved scientific understanding and robust risk assessment for the manufacture of the API. It is also important to highlight that within the competitive global markets we all have to compete in the need to continually improve a process through life cycle management the QbD platform lends itself much better towards this objective than traditional methods.
Whereas QbD may have started as a regulatory initiative the benefits to industry has resulted with engagement with support provided by global regulatory agencies.
How do I sell this to my senior management?
Where for people with a technical background the concept of QbD can be reasonably straight-forward what are the benefits for the business as a whole and how can this be quantified. One of the biggest challenges for the industry is the “cost of poor quality” due to the failure to get it right first time (RFT) or really right first time (RRFT) depending on how you measure this. There are many factors that can contribute to cost of poor quality but as an industry our manufacturing technologies lag somewhat behind the FMCG and electronic industries. Where these industries can perhaps boast 5 or 6 sigma level the pharma industry is doing well to boast 2-3 sigma level. Working this through provides a staggering cost of poor quality and supports the recent FDA reports of quality being a major cause of drug shortages. This information in itself goes a long way in providing excellent justification for improving the approach to both development and manufacture.
When to implement QbD:
Ideally the QbD approach should start on day 1 of the process R&D phase of API development this may be seen as an added cost at a stage of the development cycle that can be avoided. There are some myths within the industry that believe QbD is a responsibility of the quality and regulatory affairs departments. There is also an assumption that QbD can be used only for new products and not products already on the market. Implementation of QbD is viewed as very expensive option for any Pharma organisation or CMO.
QbD should deliver a systematic approach documented within a structured framework which clearly reports the development pathway and information gained about the product and process. This should then ensure that the manufacture of product consistently complies with the specification with sufficient flexibility to manage small variation during the processing phase. It noteworthy to mention that the implementation of QbD should be carried out through-out the supply chain.
If QbD is not practiced within your organisation then there will be some barriers that will need to be overcome to achieve the competency level required for successful QbD implementation. This will require some form of training either in-house or external and the purchase of the necessary hardware/software to achieve the statistical modelling that will be required. There will also need to be a documented standard management procedure that is fully compliant with your existing quality systems and fulfil the regulatory requirements.
One might assume that at the go/no go decision process for QbD implementation budget constraints is the biggest barrier, it can in fact sometimes be the cultural change required within an organization to be the bigger obstacle to overcome. From a progressive perspective if this is new to an organization then it can only be viewed as an innovative step forward combining in a structured manner a science and risk based approach which ultimately improves product quality, process reliability and manufacturing cost. Over time process R&D work becomes a lot more focussed and where previously resource might have been spent in areas that turned out to be non-critical this could be achieved at the scoping phase within the QbD concept.
QbD and Lifecycle management
For a QbD approach to be successful it has three fundamental requirements to be fulfilled. The first of these is to understand the product in terms of target product profile. Supporting this will be the determination of the critical quality attributes (CQAs) which should be within an appropriate range limit, range, or distribution to ensure the desired product quality as detailed further within the relevant ICH guideline.
The next phase then switches the focus to the process required to deliver the product and will involve risk assessments. This will assess the impact of the raw material attributes and process parameters will have on the CQAs and as a result of this a laboratory program of work in most cases utilising design of experiments (DoE) to provide an efficient multivariate analysis approach will be undertaken. The culmination of this work should provide a design space in which the ranges have been defined for the various input variables and process parameters that has resulted in the target purity profile being achieved. At this phase the critical process parameters (CPPs) will be identified which will be linked to the CQAs. It is noteworthy to highlight that the risk assessment process should be repeated through-out the development process as more information and greater understanding is achieved.
The final phase is to devise a control strategy utilising Process Analytical Technologies (PAT) to ensure during processing final product purity will be achieved. This then feeds into the ability to conduct continual improvement as part of any lifecycle management program.
The QbD outlook
The fundamental theme of QbD is the combination of scientific findings and robust risk management to deliver a design space, process controls and specifications which builds quality into the overall process. The long term benefits of operating within a design space as opposed to the traditional proven acceptable ranges provides the freedom to move within this space as part of continuous improvement without triggering a regulatory post approval process change which can be a significant barrier in some cases. This provides immense flexibility for the manufacturer and it would be difficult to challenge the concept that in simple terms QbD relates to good development.
Dr Gary Reid of Aesica looks at the benefits of Quality by Design
Aesica Contact: Gary Reid; API Technical Director, Aesica Pharmaceuticals Ltd; Tel: +44 167 059 7294; E-mail: gary.reid@aesica-pharma.com; Website: http://www.aesica-pharma.com
For media enquiries, please contact Tristan Jervis at De Facto Communications on +44 (0) 735 8166 or e-mail: t.jervis@defacto.com.
Help employers find you! Check out all the jobs and post your resume.
