Quality by Design Approach in the Biotech Industry

QbD at a glance

The QbD approach has been implemented during these years in the management of different products and processes, and it is defined as a systematic approach to development, based on a predefined objective, aimed to achieve a process control based on sound science and quality risk management. 

Basically, the quality of the final product is no longer defined only by testing the final product, but by building the process and controlling the critical points throughout the manufacturing process by defining, upfront, the desired quality characteristics of the product; in summary, to build quality into the product. 

To guide pharmaceutical personnel in this journey and better define boundaries and rules to apply this approach, some guidelines have been issued. 

QbD basics are present in ICH Q8 (R2)1 in Part II – Annex, where the following minimum elements for pharmaceutical development are mentioned: 

• Definition of the Quality Target Product Profile (QTPP); 
• Identification of possible Critical Quality Attributes (CQAs); 
• Determination of CQAs of the drug substance, excipients and selection of the type and amount of excipient to deliver a drug product having the desired quality; 
• Selection of an appropriate manufacturing process; 
• Definition of a Control Strategy. 

QTPP is the basis of the design of the development of the product and it is defined as “a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy.” QTPP should include at least the definition of its intended use, route of administration, dosage forms and possible delivery systems, dosage strength, container closure system, therapeutic moiety release or delivery, and attributes affecting drug product pharmacokinetic and drug product quality criteria such as purity, stability, and sterility. 

CQA is defined as “a physical, chemical, biological, or microbiological property or characteristic of an output material that should stay inside a defined limit, range or distribution to ensure the desired product quality.” CQAs are associated with drug substances, intermediates, excipients and drug products.  

Strictly connected to CQAs are the Critical Process Parameters (CPP) defined as “a parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality.” 

Finally in order to monitor and control CPPs and CQAs, it will be necessary to put in place a Control Strategy defined in ICH Q102 as “a planned set of controls, derived from the current product and process understanding that ensures process performance and product quality.” Controls include parameters and attributes of the drug substance and drug product’s materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and associated methods and frequency of monitoring and control. 

Another important topic to be considered is the Design Space, designated during development, defined as “the multidimensional combination of interaction of input variables and process parameters that have been demonstrated to provide assurance of quality.” This topic has an impact on possible marketing authorization submission, as working inside the design space is not considered a process/product change from a regulatory point of view. 

All the above mentioned topics are part of an organized approach to product development managed by using quality risk management reported in ICH Q9 (R1)3.

Implementation of QbD Principle in Regulatory Dossier

Product /process development and its results are reported in a dossier presented to regulatory agencies in order to obtain the Market Authorization (MA). Since its introduction, it has been expected that this approach has been applied, especially for those products for which many variables are implicated, such as in the case of a biotechnological product. 

It would be interesting to understand the percentage and distribution of the implementation of the QbD development in Europe. Research4 has been performed considering all EU approved marketing authorizations in the period of six years, from 2014 to 2019. 

The research has been realized by consulting the European Public Assessment Report (EPAR) on the European Medicines Agency (EMA) website, by searching each EPAR for keywords “Quality by Design” or QbD. 

At first, the results were reported by ranking a total of 494 MAs according to the type of submission (i.e., full application, well-established use, etc.) and evidencing those classified as QbD. Only 151 MAs were developed using QbD, which is 31%. In Table 1, the individual percentage per year is reported, indicating that there was not a massive growth of the MAs presented with a QbD development approach but instead a somewhat steady state is evidenced: 

Table 1. Marketing authorization along 2014-2019 and percentage of QbD development approach 

A more detailed analysis was performed on the 271 MAs that were submitted with a full dossier; 104 of them were developed by using QbD, and an analysis regarding the percentage of small molecules versus a biotech product resulted in 78% small molecules developed by QbD and only 22% of biotech submissions containing the QbD approach. A small increase in biotech products using QbD for their development is seen from 2015 onwards. Of the biotech products, 48% used a QbD approach for development only during active substance (drug substance) development versus 7% if compared with the small molecules. On the other hand, a full QbD development is present in 36% of small products versus 13% in biotech product. 

Even if QbD development is not mandatory, it is expected that this approach should be used more frequently nowadays, more than 10 years since the adoption of ICH guidelines, as it should lead to an overall increase in the quality of the product. 

However, considering that the research may be incomplete, as it may be the case that some products were not classified as QbD because the full application was not put in place, but some of the principles of QbD could be actually presented in many dossiers which were not detected. 

Many concurrent causes can be the reason why pharmaceutical companies are not yet prepared to completely apply the QbD approach during product development. 

Conclusion

One important piece of information coming from this research is that QbD has been practiced more in small molecule realities than in biotech, which can be explained by the intrinsic complexity of the various steps of a biotech product. It has also been evidenced that most QbD-developed biotech products have used this approach during drug substance development, a critical and complex phase that includes steps such as the development of master and working cell banks, and the manufacturing process and its scale-up. 

Another major concern from pharma companies in general comes from the cost of the activities, mainly because the investment should be done in an early phase of the project, when still it is unknown if the target product would really be fit for the market and when no data from clinical studies are available yet. 

Some uncertainty and misunderstanding regarding the definition of the pillar of QbD could be the source of difficulties in applying this approach, especially in the first years in EU. Finally the regulatory benefits are unclear. 

One certain benefit in applying the rule of building quality into the product would be avoiding showstoppers when the project will be in an advanced status due to the use of materials, potentially affecting the quality of the final product. 

Reference 

1. ICH Q8 (R2) “Pharmaceutical Development”, 2009 
2. ICH Q10 
3. ICH Q9 (R1) 
4. J. P. ter Horst, S. L. Turimella, F Metsers, A. Zwiers, Therapeutic Innovation & Regulatory Science, 590 (2021)