Quality by Design in the development of biopharmaceuticals – how Regulatory Affairs can mitigate bottlenecks

#Quality by Design in the development of biopharmaceuticals – how Regulatory Affairs can mitigate bottlenecks

If you are involved in (early) development of biopharmaceuticals, have you ever experienced serious delays because of problems arising from tech transfer? Or because of the first pilot scale batches not meeting important criteria of the specification that was adopted early in the program? Or because of a serious comparability issue between non-clinical, clinical and commercial scale batches? Or because the Agency does not agree with the proposed strategy, when your company finally decided to obtain Scientific Advice? A big chance you experienced not just one, but several of these “bottlenecks”.

Biopharmaceutical development necessarily requires a multidisciplinary approach, that is sometimes at odds with the realities of corporate structures and experience available in (smaller) companies. It is a challenging task to understand inter-dependencies between different pharmaceutical-technical aspects of a development program, together with the organizational aspects of a multidisciplinary approach. Once a development issue is noted by an individual, it can be difficult to translate this into action by the organization. Regulatory Affairs is arguably the single function where it all comes together; from technical CMC issues to nonclinical and clinical safety and efficacy studies, their interrelationships, and how to translate such issues in an efficient regulatory strategy.

When making an analysis of the many challenges in biopharmaceutical development four main bottlenecks can be identified: specific aspects of drug development that represent common root-causes for either delayed, over-budget or failed development programs. This blog will focus on these bottlenecks and how regulatory affairs specialists, working closely together with all relevant disciplines in the company, can offer advice and hands-on support to recognize and navigate through these successfully.

Manufacturing Process Development: tech transfer, scale-up and modifications

CMC development of a biopharmaceutical involves highly-experienced specialists that are very competent at their main task which is, necessarily, only a small piece of a complex puzzle. The first bottleneck regards the integration of the different pieces of the puzzle which typically requires involvement of regulatory specialists into the process.

Early involvement of regulatory people and thinking is essential to ensure that all aspects of the CMC development are integrated, aligned with nonclinical and clinical development and carried out according to an efficient regulatory strategy. For instance, regulatory specialists can enable a company to better manage tech transfer and scale up activities (which typically involves contract manufacturers and labs) by providing advice on the differing requirements from health authorities around the world for such activities, or to implement Quality by Design (QbD) concepts more efficiently by ensuring that the development is aligned with the regulatory strategy and QbD principles.

From QTPP to CQAs to Specification

The ICH Q8 Guideline describes the process by which pharmaceutical development progresses from concept to control strategy. According to the Guideline, a company first identifies a Quality Target Product Profile (QTPP) for the product to be developed and then identifies specific attributes that are critical to the quality of the product in accordance with the QTPP (critical quality attributes or CQAs). The essence of QbD (or the enhanced approach) described by ICH Q8 is the stepwise and iterative process needed to translate the QTTP to a product specification. According to this approach, first a risk assessment is expected to be carried out to systematically analyse all CQAs. Since the manufacturing process of biopharmaceuticals is complex, this necessarily involves many technical disciplines and can be a quite lengthy process. The risk assessment is followed by development studies to verify criticality and interrelationships of the many materials and process variables, normally using design of experiment studies. Based on the results of these DoE studies, the list of CQAs and the risk assessment is updated (reflecting the iterative aspect of the approach). As part of the DoE, a design space may be constructed, though the latter is not an essential part of the enhanced approach.

ICH Q8 covers a complex, multidisciplinary area that was identified as a common bottleneck due to the fact that many companies struggle to carry out their development projects in a focused and consistent way over the many years such a project takes. Instead they tend to operate more empirically and ad hoc. The concepts introduced in ICH Q8 (either the traditional or enhanced approach) are now seen as regulatory requirements in many cases. For instance, EMA biosimilars guidance states that “The QTPP should form the basis for the development of the biosimilar product and its manufacturing process.” Regulatory specialists can typically guide and drive these complex projects because they know what agencies expect and because they can communicate with all disciplines involved at a sufficient knowledge level. They can help establishing the (interrelated) development, control and regulatory strategies that adhere to global regulatory guidance.


Ensuring that your product remains comparable after manufacturing process changes during the complete product life cycle may be one of the most important challenges of drug development , and is the cornerstone of all CMC development and maintenance. (According to ICH Q8, development concerns the complete product life cycle, including the time that the product is on the market.) Comparability is a typical development bottleneck due to the fact that issues with it are a major source of Agency major objections to Marketing Authorisation, Extension and Variation Applications.

It is critical to prospectively determine acceptance criteria and design robust studies capable of detecting differences between pre- and post-change product. (Such a prospective approach would “automatically” follow from a QbD approach as described above.) Additionally, care should be taken to identify CMC changes that could impact product safety and/or efficacy, as it is well-documented that relatively minor changes can have serious effects. Regulatory specialists are well-placed to advise on the types of changes that alert the Regulatory Authorities.

Scientific Advice

When companies underestimate the importance of early Scientific Advice meetings with Agencies, this can often create a bottleneck in development if the outcome of such meetings means that a company needs to adapt a strategy/program that has already been initiated. This could have been avoided, had the meeting been sought earlier in development. In larger organisations there usually is sufficient experience in this field and it is common practice to prepare intensively and conduct rehearsals for these meetings. In contrast, this type of preparation slips by the wayside in smaller companies, to their potential detriment, as these meetings are a great opportunity to get valuable information about the viability of your development program, and thorough preparation enables a company to maximize the benefit they receive from the meeting.

Regulatory specialists are used to communicating with Agencies and, as a consequence, have the expertise to determine what questions are likely to elicit useful information from the agency, write the briefing book to the standards expected by the agency, to consult on meeting formalities, and to design rehearsals. 

The above examples illustrate four typical bottle necks that can seriously slow down development programs of biopharmaceuticals. But these examples also illustrate how strong involvement of Regulatory Affairs specialists early on in the project can make a big difference toward solving or preventing them.

Blog by:  Frank Hermens - Sr. Consultant at Xendo
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