Continuous Manufacturing (CM) – Is it a feasible approach to achieve QbD?

FDA issued a draft guideline on continuous manufacturing (CM) in Feb 2019 highly recommending firms to adopt it. ICH also endorsed the concept and have established a working group. Continuous manufacturing was proposed at about the same time when the QbD principles and expectations were being discussed, as it is an excellent approach for achieving QbD objectives. 

Let us delve on why the regulators suggest it to be a better approach. Although continuous manufacturing is an emerging concept, it has many advantages over conventional manufacturing, which have been highlighted in the guidelines, such as a reduction in production cost, improvement in quality due to better controls, higher flexibility, and higher product yields. Other advantages are - less manual handling and labour cost, lesser investment due to reduction in the capital as well as operating cost, fewer utilities, shorter processing time, easier scaling up to meet increasing demand and improved efficiency. It is suggested that all these advantages would result in lesser instances of drug shortage issues.

Most firms still prefer the conservative or conventional approach and are reluctant to shift to or adopt continuous manufacturing. So why are firms having an inhibition to adopt this approach? To find out, let us understand the difference between the two approaches with a brief overview of some of the pros and cons.

1)     Conventional manufacturing is based on the principle of a batch or lot processing approach which consists of many unit operations or steps during the manufacturing of a product. Continuous manufacturing is more of an integrated approach involving a single and continuous system of manufacturing. So, a CM is more seamless operation, which would result in shorter processing time and lesser wastage.

2)     The end-point variability, which indicates that the unit operation or a process is complete to give the desired output, is comparatively higher in the conventional approach. It is considered that the variability will be much lower, as it will be controlled better in continuous manufacturing by using in-line and on-line monitoring techniques such as Process Analytical Testing (PAT) approach/tools which will ensure real-time release while the process is on.

3)     The conventional approach is highly labour intensive and is largely dependent on the efficiency of operators as against in continuous approach where automation and use of the latest technology are employed to ensure both - processing and control measures.

4)     Continuous manufacturing is a process that requires a very high technical as well as process understanding and is complex system as compared to the conventional approach. It requires extensive development studies based on quality by design principles and a detailed study of risks.

5)     Conducting process validation for achieving integration as well as to meet the quality objectives throughout the manufacturing is much more challenging in CM. The goal to achieve the finished product specification as the material is being processed and tested on-line requires an extremely well-defined control strategy involving technically advanced tools for multivariate controls. This will also involve a lot of interactions with vendors and suppliers of API, excipients for controlling material attributes. Equipment qualifications and PAT implementation will not be an easy task and there will be constant interactions with the equipment manufacturers too.

6)     Managing deviation during processing is of utmost importance and hence the sampling plan will need to be devised in a manner that the variability is continuously monitored and controlled consistently. Corrective actions for any deviations would need to happen in real-time, as and when required, to avoid failures.

7)     One of the biggest challenges perceived by the firms to adopt continuous manufacturing approach is regulatory acceptance. Many firms either have none or limited experience of handling these kinds of complex systems, while they have been comfortably managing submissions and approvals based on the conventional approach. Firms are still studying and understanding the requirements for proving equivalency between the two approaches which is a big task and time consuming as well.

8)     Another big hurdle is that firms do not want to hamper their regular supplies by shifting their already approved process to a new one which would be a significant change and will require submission of a lot of data before approval.

Apart from the challenges listed above, there are other important aspects such as addressing the risk of cross contamination, cleaning validations, managing equipment shutdowns or breaks downs.

So in case of continuous manufacturing, while the cost of capital investment is low, labour cost is low, flexibility to scale up is high, resulting into a higher quality product, there will be a lot of activities during development and integration for understanding material attributes and process, conducting risk evaluations and developing a robust control strategy by employing advanced tools like PAT. It is obvious that the cost of shifting will be considerably high involving significant investments and may only make sense for high-value products that ensure a good return on investment (ROI). However, if this approach is adopted early on during new product development itself it would be far more beneficial. Hence every firm may need to do a case by case evaluation before adopting this strategy as it should also make good business sense. Few big firms have already adopted and implemented this approach managing all the above challenges, but how widely it shall be used in the pharmaceutical industry is still a big question. 

On the other hand, regulators like FDA are supporting this approach in a big way and are suggesting and urging the industry to discuss it with them before final implementation as they will be able to help and support by providing clarity in terms of regulatory expectations and approvals. On their part, the FDA has developed programs to help the industry in adopting the latest technologies to achieve modernization in pharmaceutical manufacturing. In the draft guidance, they have covered critical aspects such as quality considerations, batch definitions and its applicability, process validations, scaling up, stability and quality system requirements. They have also covered the data requirements for new ANDA, NDA submissions or handling it as a post-approval change for an approved product. The guidance provides a list of sections of eCTD where these data can be provided.

Industry commented on the draft guidance of the FDA and till the time this blog was published, there were in all 24 comments posted by firms and associations. They have raised questions on critical aspects such as non-conforming materials, risk-based equipment qualifications, lack of clarity in terms of differentiation between regulatory and GMP requirements, bioequivalence study requirements to establish equivalency, alignment of this guidance and its applicability when ICH issues their final guidelines and many more. They have urged FDA to make changes to the draft guidelines to provide more clarity. Industry comments are available under the public docket of website regulations.gov. I would recommend everyone to read the guidance and all these comments to get an insight on this topic. 

So, to summarise it has been a widely accepted fact that the advantages offered by continuous manufacturing make it an important approach to adopt. Feasibility of adopting this will depend on many factors, but despite all the challenges it still has lot of benefits. Deeper involvement and continuous interactions with the FDA and other health authorities will clarify things further and implementing this for global developments will happen only if more and more firms see the merits and gears up for the challenge. Making this choice will ensure long term benefits, cost savings and hence there is a need to invest upfront in a better technology that will ensure a higher quality product developed on QbD principles. In the current scenario, it is a wait and watch situation for many firms and only time will tell whether this will become the future of pharmaceutical manufacturing!!

In my next blog I will touch upon the quality metrics initiative by FDA. See you soon!!