Understanding QbD Requires Basic Fundamentals
Reading PharmTech’s October article on Critical Challenges to Implementing QbD gave me the impression that we might have the road map to Moksha or Nirvana. Unfortunately that was not meant to be. Somehow there is a belief that PAT in pharmaceutical industry is the roadmap to QBD, pharmaceutical industry salvation. In this article, blame of not achieving “pharmaceutical industry salvation” has been attributed to unfamiliarity with the used equipment and corporate culture. I do not believe either of these is completely true.
If a company is authorizing installation of equipment that is not understood by the operating personnel then we have a two-fold problem. 1) Personnel do not understand the basics of the process needs and have installed a wrong equipment, and 2) Authorizing managers have not asked right questions to challenge the expenditure. This is a clear case of “lack of understanding of the fundamentals.” It is a case of trying to climb Mount Everest without understanding the challenge and proper gear.
Corporate culture has nothing to do with QBD or PAT. Companies have a basic goal (i.e., deliver the expected profit to their stakeholders). They have been able to deliver the profits using inefficient processes. They do not see any need to change. Consumers have paid for these inefficiencies, as they want to extend their life.
Unless we totally understand the fundamentals of active pharmaceutical ingredient (API) manufacturing and API-excipient blending process (i.e., chemical interaction and operating parameters), we will not have command of the process (i.e., first time quality will be elusive). Complete understanding of the interaction and the right instruments will tell us where we have gone “off-course” and how to command the process. Until we have the understanding of fundamentals and use them properly, we will not have a perfect process or close to it that will deliver quality. Innovation will automatically come, as it is a human trait.
Innovation has to evolve at the profit making company rather than at an external agency, an expenditure body. Regulatory bodies can demand quality and the operating companies have to deliver quality. However, any expenditure that will reduce their profit margins like now, will meet resistance.
I have to ask a question: “Does anyone really understand QBD and PAT” and if so, can the answer be written in one sentence not exceeding 25 words? If we can, we have simplified the definition of pharmaceutical innovation and we will meet the quality objectives.
I have done a deep dive into this four things that define QBD below such as :-
- Design of a process that is consistently capable of meeting critical quality attributes.
- Thorough understanding of the impact of the starting materials and process parameters on product quality.
- A strategy for identifying, understanding and controlling critical sources of variability are identified, understood, and controlled.
- Process monitoring that enables continuous, consistent quality.
PAT , multivariate analysis , modelling and simulation tools like FMEA, HACCP , risk assessment programs are a few methodologie sof getting there.
Does this definition help better your understanding. Pls let me know
Thanks and great if that helps you. Is this for API or for formulation? However, it is too complex for me. We need to simplify.
I think there is a general misunderstanding of Janet Woodcock’s intention from the Critical Path Initiative. CDER studied other sectors and found they were designing products that could be manufactured robustly – they did not push forward to trial prototypes just to get through safety trials, they were at pains to design their products to be manufactured. This meant they had to spend time and resources fixing problems early on that would otherwise cause issues. Culturally, pharma dose not have time for this. The psyche is rush for the clinic and get some data to prove efficacy. If automotives did that there would be many more deaths on the road.
Some of the confusion, i think, is because module 3 is called the ‘Quality Section’ in regulators common parlance. As you know, module 3 is about CMC and this is basically manufacturing. So QbD is really Design for Manufacture (this is well known in other sectors).
I totally agree also that the industry should be driving this, not the regulators – but old habits die hard!
Hedley
QbD and PAT: Tools for better understanding production processes in order to make them more robust, to reduce standard deviation, to increase efficiency. ( only 20 words! ). Good luck Girish from Budapest !
Hedley and Miklo’s:
Thanks and I am delighted with your input. By having discussion we might be able to get to the goal sooner than later. We do have an opportunity. Thanks.
Thanks, Girish, for fostering this dialogue. The sooner the industry can develop a common understanding of what is meant by QbD and PAT, the sooner we will be able to leverage the efficiencies brought to bear by greater system integration, feedback loops, and communication to continuously improve our understanding of the design space and critical-to-quality attributes.
Our customers are increasingly looking to integrate business processes and data across CMC, Manufacturing and Quality organizations to lay a foundation for QbD. There are also many that are taking a “wait-and-see” approach to avoid rework once requirements are more pinned down by the regulators, which is unfortunate since they will not be able to partake in the benefits of greater product and process understanding.
Thanks.
The joy of achieving QBD and PAT in one stroke is exhilarating. It can be done.
We should not have “wait and see” approach as problem “A” is different from Problem “B”. We have all of the knowledge. We just have to piece it together one step at a time. Each win is big.
Again, the joy is tremendous. We might remember byline from an advertisement “Try it, you will like it”. Believe me, this is contagious. Thanks and good luck.
I think our industry is not willing to apply PAT because of regulatory concerns. It is really unfortunate that FDA need to promote PAT, because if we start using PAT it is going to reduce our own headache.
FDA is very clear about their idea that Quality must be built in to the product and not to be tested. this is the basic thought behind QbD.
Please provide some more thoughts on it.
Swagat Sangamnerkar
Pharmaceutical Manufacturing Graduate Student,
Stevens Institute of Technology,
New Jersey.
Believe that everything can be improved. Use one visual methodology that everyone in the company can understand from the first formulation through to realtime production control.
Precise and profound process planning produces predictably perfect products.
John
W.r.t. Qbd: By implementing quality systems from the development of formulation.Systems have to be implemented to have control over the each unit stages of development activities( preformulation, analytical method development, formualtion development, …) so that none of the necessary optimization steps are missed out, and possible critical quality attributes are monitored and controlled before the process is transferred to scale- up(or PE) and at scale- up level it’s again monitored for variations at higher scale..Again CQA are scrutinized at scale- up levels and process is optimized and finalized for Exhibit batch. As for as my knowledge and experience is concerned I believe, this definitely helps in avoiding possible exhibit batch failures to reasonable extent.
It is true that basic fundamentals have to be known for all who involves in performing , monitoring these activities. QA who implementing system for monitoring all these needs to have knowledge in both analytical and formulation research and in processing. And it is a team work of all interdisciplinary department along with quality department.
Sir,in short i have tried to write some points, plz suggest me if u have some more ideas.
FDA has been giving presentations and issuing guidance on this topic for literally years now. This started at the top of the agency and understandably needed to trickle down.
Will industry change as a result of the guidance? It already has!
Overall, It’s only an opinion, but QbD = keeping an understanding of development in the forefront of development efforts, via providing the coherence and continuity that one off trial-and-error approaches lack.
Eventually this is what will save money and work, providing the business benefit. By introducing the QbD principles with regular risk assessment sessions early in the drug project, many potential future problems can be avoided.
How to improve R&D with QbD?