Quality counts

The last few years has seen the FDA steer industry further in the direction of a quality–by–design (QbD) approach, and away from the quality–by–testing (QbT) approach traditionally taken by the pharmaceuticals sector. This move has largely been lauded by business as a sensible move likely to ensure consistent quality of the end product. Crucially, it hopes to encourage far more innovation in the industry, which has traditionally lagged behind other manufacturing sectors such as semiconductors in its understanding of the science and engineering behind quality manufacturing. Furthermore, the approach ties in well with the PAT initiative, a regulatory framework backed by the FDA, which many forecast will have a big impact on the sector.

QbD verses QbT

Both QbD and QbT are fundamentally different to one another, and there are good reasons for the emerging focus on QbD. The traditional QbT approach is wasteful and inefficient, and some have been critical of the approach for failing to evaluate the quality of the product until it has already been produced. “The basis of quality by testing is that the finished product is tested for quality. Quality is assessed by testing and rejecting lots that fail to meet its stated specification,” explains Ali M Afnan, Process Analytical Technologist, FDA/CDER/OPS (Office of Pharmaceutical Science). “This approach therefore results in a great deal of waste and thus is costly to the manufacturer and in turn the consumer.”

Delivering quality is, of course, crucial – particularly as it is often out of the hands of the American public to evaluate product quality. “Because the American public is the ultimate customer of pharmaceutical manufacturing and because the public is often unable to judge the quality of a product, the goal of our regulatory system is to make sure that patients do not have to worry about the quality of their medicines,” stresses Afnan.

Astonishingly, the wastage cause by the quality by testing approach can inflate production costs by as much as 10 percent. FDA regulations that require approval of every change to manufacturing process have been a hindrance in encouraging an alternative approach to manufacturing. However, the tide has turned and the FDA has now reconsidered its traditional approvals procedures to rectify the concerns that overly restricting regulations may in fact have a detrimental effect on manufacturing innovation. One of the big restrictions was the regulatory framework in which pharma production has been embedded, with rule–based process specifications (SOPs) that cannot be changed after the submission to FDA, etc. Regulations have now been lowered to allow for improved progress.

The basis of the alternative approach is that “quality cannot be tested into a product; it has to be built by design”. Afnan argues that:

“Within QbD, processes are understood at a mechanistic level, design reflects this knowledge and quality is inherent in the product. This design incorporates knowledge of the product and the process to ensure all critical quality parameters are adequately controlled.” Proponents of QbD such as Afnan are quick to emphasize how this approach will guarantee that a product will be produced to guarantee quality each time. As such, each batch will therefore be right the first time.

A change for the better

The shift in focus is expected to bring about a well-needed modernization to the sector and allow new ideas the breeding ground needed to flourish. “As pharmaceutical manufacturing evolves from an art to a science and engineering based activity, application of this enhanced science and engineering knowledge in regulatory decision–making, establishment of specifications, and evaluation of manufacturing processes should improve the efficiency and effectiveness of both manufacturing and regulatory decision–making,” enthuses Afnan.

Delivering an effective framework to ensure that risk is mitigated whilst encouraging the continuous improvement and innovation is a key public health objective according to the FDA. The Administration has recently changed its review system from the CMC system to a new risk–based pharmaceutical quality assessment system within their Center for Drug Evaluation and Research’s Office of New Drug Quality Assessment. This new switch will “encourage the implementation of process analytical technology (PAT), Quality by Design and facilitate continuous manufacturing improvements via implementation of an effective quality system,” according to Afnan.

Process and Analytical Technology

A Process and Analytical Technology (PAT) initiative has been initiated by the FDA and designed to revolutionize and improve many pharmaceutical processes. A regulatory framework, PAT discusses possible routes and opportunities to promote and encourage opportunities for innovation.

The FDA has outlined the guidelines of the initiative in a document entitled “Guidance for Industry PAT – A Framework for Innovative Pharmaceutical, Development, Manufacturing and Quality Assurance."

The framework enables manufacturers to actually understand the effects of the chemical and physical properties of raw materials so that they increase their knowledge to be able to improve formulation and processing.

‘The PAT Guidance is not intended to be a “how to” guidance. It is written for abroad industry audience in different organizational units and scientific disciplines,” explains Afnan. “To a large extent, the guidance discusses principles with the goal of highlighting opportunities and developing regulatory processes that encourage innovation.”

Afnan believes there are numerous benefits the initiative can bring to the industry and help achieve the desired future state of pharmaceutical manufacturing

These include:

• Product quality and performance achieved and assured by design of effective and efficient manufacturing processes.
• Product specifications based on mechanistic understanding of how formulation and process factors impact product performance.
• Continuous “real time” assurance of quality.
• Regulatory policies and procedures tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability.
• Risk-based regulatory scrutiny that relates to the level of understanding of how formulation and manufacturing process factors affect product quality and performance and the capability of process control strategies to prevent or mitigate risk of producing a poor quality product.

Any firm that sees innovation as one of its priorities will find the initiative beneficial and applying the guidelines can lower production and monitoring costs and while mistakes cannot be ruled out entirely by following the PAT guidelines, they will be spotted far sooner rather than at a much later stage nearer the completion of the product. This way it will avoid any catastrophic problems that fail regulatory requirements.

Providing the catalyst

Manufacturing quality analysis is one area that the pharmaceutical industry has some serious catching up to do. The PAT initiative is likely to provide the catalyst so urgently needed by the industry. Prior to the introduction of the initiative, regulations already in place made the industry very reluctant to change to new technologies and process in case they defied them. Now though moving towards following the PAT–based manufacturing process might be the way forward.

Certain concerns have made some companies reluctant to embrace the PAT initiative. For instance, one of the biggest worries is that adapting processes may reveal new problems that will then have to be reported to the FDA. Rectifying this new problem can be a time consuming and costly business. Rising costs resulting from updating processes is especially off putting for many companies. Through identifying key processes parameters theses imagined costs can however be avoided.

Data overload is also a major concern for many companies who assume that the amount of data analytical technology will generate will be unmanageable. According to the FDA “real-time or near real-time measurement tools typically generate large volumes of data”. This can be combated by only targeting the most essentially important data.

Overall, although initially apprehensive, the industry does appear to moving closer to embracing the initiative, and recognizing the beneficial impact that it can have. Indeed, uptake seems to be spreading throughout the sector – the initiative has been embraced by many ranging from non-application products (Over-the-counter products), generic products, new products, and biopharmaceuticals. Encouragingly, it appears the initiative has interested most firms that the FDA has dealt with. With a renewed focus now on quality, the industry is looking to leave its testing times well and truly behind.