QbD and Pharma 4.0. Interview for the VIVA BIO Team (Seoul National University)

A group of graduates from Seoul National University visited us to learn more about the implementation of QbD and the Pharma 4.0 concept in the european industry. They are sponsored by LG and on a European tour.

Under the motto “Innovating Biopharmaceutical Manufacturing Process” its objective is to obtain useful information to apply especially in the biotechnology industry in their country Korea.

We were delighted to receive them and answer their questions based on our experience.

Below we transcribe a summary of the interview (Question VIVA BIO Team, answers Alicia Tébar from QbD PS:

(1)   The details of assisting and teaching experience in QbD implementation

  1. I’ve heard that you’ve assisted more than 30 companies in QbD implementation. What were the difficulties in introducing and implementing QbD and how did you and the companies overcome this situation?

Everyone understands the advantages of applying the QbD methodology to obtain more robust and efficient processes, but during development the temptation to “take shortcuts” persists, especially if the pressure to reach the market is present.

QbD is a systematic process with well-defined stages that requires R&D teams have on time access to the knowledge that is being generated. Sometimes the major drawback is a lack of discipline and an incorrect knowledge management. In my experience, the most important thing is the change of mindset from a trial and error-based development to a systematic-risk based using DoE tools.

  1. After this project trip in Europe, we would like to introduce this paradigm, Pharma 4.0 and QbD to Korean students who have interest in pharmaceutical engineering and make a brochure relevant to our topic. Is there any necessary information that we have to include when we introduce Pharma 4.0 and QbD based on your teaching experience in Barcelona University?

I believe that QbD is the methodological basis for developing robust processes (PV Step 1 and 2) and Pharma 4.0 is the paradigm for the introduction of innovative technology in pharmaceutical manufacturing (PV Step 3). If the product / process design is not optimal, despite the automation and technology we introduce, the quality of the final product will not be guaranteed.

ICH Q8 and Q10 talk about the Control Strategy (as a result of the design) and at the ISPE 4.0 groups, we talk about the Holistic Production Control Strategy (considering the industrial level implementation). At this level PAT, AI, Big Data, cloud computing can be introduced, but the process definition, especially when advanced control strategies (RTRT) want to be used, must be defined with QbD during Step 1.

  1. Do you have any experience of assisting small and medium sized pharmaceutical company in QbD implementation? Are there any different approaches needed to assist them compared to big pharma? And we also want to know their capital procurement method.

My experience has been mostly with medium / small companies because large companies usually do not need too many consultants for this.

What companies of this size require, is adapting the QbD methodology in the most efficient way. This implies prioritizing. For example, focusing DoE efforts on the most critical process unit operations. Sometimes they are surprised that with a good previous analysis and DoE, results are obtained in shorter times than with the traditional test routine, and the most important, design space maps give a lot of information to choose the optimal process conditions, also to let it run smoothly if the variability sources have been well characterized.

The investment in QbD is small, it is basically training, DoE software and some more time during development. If you want to use PAT, the investment is somewhat greater due to the purchase of equipment and model development/maintenance.

(2)   The details of Pharma 4.0 and its Practice/Guideline

  1. It is hard to define and easily explain pharma 4.0, because it is a big paradigm which applies Industry 4.0 to pharmaceutical industry. Because of this reason, we’ve been trying to characterize Pharma 4.0 by these 3 aspects: Digitalization of pharmaceutical process, Conversion from batch to continuous process, and Implementing QbD ahead of GMP. Then, what are the most important three aspects that ISPE think to characterize pharma 4.0?

A short definition of Pharma 4.0 is:

Pharma 4.0 is the digitalized operations model of a pharmaceutical organization

ISPE has conceptualized pharma 4.0 in this scheme:

As you can see, we don’t just talk about technology and systems. The human factor is fundamental given the change in culture that it implies and the change in the organization. In a data-centric organization, information must be delivered to people to make decisions and not the way around.


  1. Were there any refusals or resistance to introducing Industry 4.0 to Pharmaceutical industry? If there has been any. how was ISPE able to overcome this situation?

Resistance is caused by regulation. It has been that way for a long time. The regulation of the pharma sector, the difficulty of introducing changes in the processes, makes that other industrial sectors have taken the lead for example in cloud computing.

The difficulty that may involve “a priori” to validate cloud-based systems with traditional standard criteria (e.g. infrastructure qualification) makes pharma still reluctant. Gradually, progress is being made, but it is a joint work of the industry and regulators in which global organizations like ISPE have an important role.

  1. Has ISPE worked with EMA or FDA to provide guidelines for Pharma 4.0?

We’re on that. In fact, in all the Conferences that ISPE organizes, representatives of the regulatory agencies are invited to favor the debate and the exchange of information. For example, in April 2020 the annual European ISPE conference will be held in Madrid, which will feature a track on Pharma 4.0 in which interesting user cases from the industry will be presented and in which we will also have representatives from the FDA and EMA.

  1. Do EMA and FDA take different approaches toward Pharma 4.0?

Well, in general we observe that regarding innovation in manufacturing, FDA clearly leads the way since the publication of the PAT Guide back in 2004. It’s surprising but 14 years have passed already It is known that FDA is giving strong support to continuous manufacturing. This will be ruled in a new ICH Guide Q13 dedicated to this subject. Since 2017 the FDA has a program to get some input from manufacturers who want to introduce emerging technologies into their processes.

In Europe we have also seen interesting initiatives such as including a chapter in the European Pharmacopoeia on Multivariate Statistical Process Control (MSPC) as well as the recognition of chemometric methods (machine learning) as valid for data analysis.

  1. We think that it is hard to guarantee safety and efficacy when the medicine is produced by digitalization process, because digitalization techniques like MES or digital twins have not been used before in pharmaceutical industry. Therefore, we wonder that are there any guidelines that can verify the safety and efficacy of medicine when using these digitalization techniques?

I am not an expert on this subject, but I know that work is being done to standardize a new way of “validating” that will surely be different from the classic one but equally safe.

(3)   The actual achievement after Pharma 4.0 implementation

  1. Is there any medical products is produced by digitalization process? And which benefit can be found when using this technology.

I do not know specific cases but what is certain is that greater efficiency is sought in manufacturing plants while maintaining quality standards.

  1. I’ve seen an article titled ‘Pharma 4.0: Hype or Reality?’ by ISPE. And there are certain doubts in Korea that it is too early to introduce Pharma 4.0 to Korean pharmaceutical industry. What do you think about these concerns about Pharma 4.0? 

Think big, start small, scale fast!

Cultural change is not easy and needs time. The process is unstoppable.