In September 2014, the GMP world gathered in Washington for the annual conference held jointly by the PDA and the FDA. The main topics were the future of medicinal product manufacturing, product quality and management of the product lifecycle. Rapti D. Madurawe (Branch Chief ONDQA/OPS/CDER/ FDA) presented the FDA perspective on continuous manufacturing. This article provides a summary of her presentation.
The traditional approach to medicinal product manufacturing is batch related. The starting material is charged at the beginning of every unit operation and the finished product is discharged at the end of the process. In contrast to this approach, with continuous manufacturing the starting material is charged and the product discharged simultaneously (see Figures 1 and 2).
Figure 1: Example of traditional tablet manufacturing (source: Rapti D. Madurawe, FDA)
Figure 2: Example of continuous manufacture of tablets (source: Rapti D. Madurawe, FDA)
What is so special about continuous manufacturing? What can be done to ensure a successful project? According to Rapti Madurawe, anyone aiming at a continuous process must abandon the usual paths and dare to embark on something totally different, even though continuous manufacturing is basically nothing new. It is already the standard in other branches of industry such as petrochemicals, foodstuffs and the automotive industries. Thus, the pharmaceutical industry does not have to re-invent the wheel. It is only necessary to adapt the principles already in use. There are many sectors of drug production that are suitable for continuous manufacturing. Here are some examples (Figure 3):
|Areas Amenable to Continuous Manufacturing|
Drug Substance manufacturing
|Drug product manufacturing||
Figure 3: Areas amenable to continuous manufacturing
Continuous manufacturing offers many advantages in terms of quality, manufacturing and costs. Process knowledge is enhanced and process development simplified. Many different conditions can be tested within a short time in development screening. One particular advantage is that the same facility can be used for development and for the market product (virtually no scale-up issues). New chemical reactions can be used, such as highly exothermic reactions and reactions at ultra-high or low temperatures. Continuous manufacturing is especially amenable to quality-by-design products.
Manufacturing costs can be reduced significantly with continuous manufacturing, since smaller facilities and equipment are used. In addition, production times are shorter and enable greater flexibility. Efficiency is enhanced by lower solvent consumption and wastes and by the possibility of online monitoring and real-time release approaches.
There are no regulations specifically applying to continuous manufacturing. Since it represents a modern approach that embeds quality directly in process design, continuous manufacturing is rather more consistent with the FDA activities relating to quality by design. It can help to prevent possible supply shortages.
The definitions of “batch” and “lot” given in 21 CFR 210.3 are also fundamentally applicable to continuous manufacturing. However, it is imperative to define the batch prior to the production start, as key elements relating to GMP, such as documentation release and recalls, all relate to a specific batch.
According to ICH Q10, a quality control strategy should be based on understanding of product and process and it should assure the process performance and product quality. The control strategy for continuous manufacturing should particularly include the flow of material within the process in addition to classic parameters such as in-process controls and monitoring frequency. The important thing is to consider the impact of the instability of individual unit operations on the overall process.
“Is my process in a controlled condition?” was the question asked by Rapti Madurawe, a question which everyone should answer with “Yes”. For products that are manufactured continually over a long period of time, the following variabilities must be observed and monitored:
The control system should also be sufficiently robust to identify and isolate faulty material. Appropriate monitoring and sampling schedules that take the dynamics of the continuous process into account are also helpful here.
The FDA has been dealing with the topic of continuous manufacturing since 2009. To this end, it interacts with the European Medicines Agency (EMA), the academic world and the pharmaceutical industry. Together with the Center for Process Analytical Chemistry (CPAC) and the University of Washington, Seattle and Corning, the FDA conducts research on continuous manufacturing and microreactors.
The FDA is currently focusing on the following aspects (Figure 4):
|Areas of special interest to the FDA:|
Analytical tools to support automation
|Representative sampling to consistently assure product quality||
|Using multivariate analysis|
|Enhancing process understanding||
Figure 4: Areas of continuous manufacturing of special interest to the FDA
Rapti Madurawe stressed the fact that the FDA is keenly interested in scientific publications on continuous manufacturing.
The FDA Office of New Drug Quality Assessment (ONDQA) has already held both formal and informal meetings with various companies. At least eight pharmaceutical companies in the USA are actively involved in continuous manufacturing - not only for existing products, but also for new developments.
To date there have been very few requests for approval. Practical applications that have come to the attention of the FDA during meetings and in on-site visits include:
The FDA considers continuous manufacturing of medicinal products to have clear advantages for product quality and cost effectiveness. The FDA supports the scientific and risk-based implementation of continuous manufacturing.
Science and technology have matured to make continuous manufacturing a reality. There are no regulatory hurdles to overcome. However, to date little experience has been gathered either within the pharmaceutical industry or among the regulatory authorities.
The FDA advises companies to involve the authorities as early as possible when planning and developing continuous manufacturing.
Rapti D. Murawe, Ph.D., Branch Chief ONDQA/POS/CDER/FDA: Continuous Manufacturing of Pharmaceuticals – An FDA Perspective, PDA/FDA Joint Regulatory Conference, September 2014, Washington, D.C., USA
Dr. Sabine Paris
Maas & Peither AG – GMP-Verlag, Schopfheim, Germany