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By Dawn Downey

Unique challenges arise in the development and scale-up of traditional sterile drug product manufacturing processes. During process development and again during commercial manufacturing, the scope of drug product batch size is often difficult to determine. This presents a great hurdle because key equipment such as tanks and mixing systems must be ordered far in advance to accommodate the long lead times needed to design, build, and qualify the systems. As a result, the project either slows to adjust for more accurate information, or equipment is designed and built based on vague assumptions. Unfortunately, designing and building equipment based on vague assumptions often results in equipment that is either oversized or undersized. A continuous formulation process, whereby the components of the batch are fed continuously until the desired batch size is achieved, can alleviate this dilemma. Thus, the expectation that the batch size is defined during process development or commercial scale-up is eliminated.

Continuous formulation in the context of the July AAPS Newsmagazine cover article, Advances and Challenges in Biologics Manufacturing: Innovation in Continuous Formulation, is the process used to combine and mix a monoclonal antibody (mAb) type active pharmaceutical ingredient (API) with a buffer solution continuously, as opposed to traditional batch addition and mixing. As shown in Figure 1, API and buffer are fed using peristaltic pumps through separate Coriolis flow meters and combined prior to mixing in an inline static mixer.

Figure 1 General Diagram of Continuous Formulation Process

Feedback control from the flow meters is used to control the pumps to maintain a defined flow rate. A back mixer (mixing element) attenuates concentration fluctuations as the result of pump pulsations. Drug product concentration is monitored using an online UV-Vis spectrometer, which is used as the primary process analytical technology (PAT) device. Drug product meeting acceptable parameters passes through a diversion valve and accumulates in a single-use accumulation tank, whereas drug product not meeting specified parameters is diverted to waste processing. A traditional sterile filling system in an isolator or restricted-access barrier system can be connected to the single-use filling accumulation tank used to supply filling operations.

Advantages of this approach include not only the scalability aspect, but also materials cost, flexibility, and ease of operation. The entire platform fits in a very small area near the filling line and does not require a room with large mixing equipment. API and buffer can be brought in through disposable, sterile, single-use equipment. The use of stainless steel parts is reduced so that minimal cleaning will be required.

The system we describe presents several distinct advantages to the traditional batch mixing process for formulation of sterile drug products prior to filling. Read the full article to learn more!

Dawn Downey is a currently a Senior Consultant Engineer at Eli Lilly &Company in the Engineering Technology Center. The AAPS Newsmagazine article is a collaboration with several departments at Lilly.
Authors Include: James Wiesler; Michael Walsh, Ph.D.; Beata Strubel; Bernard McGarvey, Ph.D.; Richard Shields; Garth Gathers, PE; and Jimmy Engle.