New Technology | Quality Considerations Using Continuous Flow Chemistry In API Manufacturing

Continuous flow chemistry is a promising emerging pharmaceutical technology, which has the advantages of shortening the production cycle, high degree of automation, environmental friendliness, energy saving and emission reduction, etc. It is especially beneficial to reactions that are difficult to perform in batch mode. Active Pharmaceutical Ingredients, API) technology innovation trends. However, due to quality control and regulatory reasons, the adoption of continuous flow technology in the pharmaceutical industry has been slow for a long time. The promulgation of the ICH guideline “Q13: Continuous Manufacturing of APIs and Preparations” puts forward key points and control strategies for the process development of APIs, and regulatory expectations are gradually clarified. Based on the newly promulgated ICH Q13, this article summarizes the characteristics, application scenarios and quality considerations of continuous flow chemistry, and further explains the development points and control strategies of continuous flow chemistry through the sharing of literature cases, in order to promote the application of continuous flow chemistry in domestic pharmaceutical companies. Improve the manufacturing level of the industry and strive to achieve the country’s “double carbon” goal.

The supply of raw materials (active pharmaceutical ingredients (API)) is a prerequisite for ensuring the accessibility of drugs to patients, and it is especially important in the context of centralized procurement. With the formulation of the national “double carbon” goal, the National Development and Reform Commission and the Ministry of Industry and Information Technology issued a notice on promoting the high-quality development of the API industry in early November 2021. The innovation and upgrading of API production technology is moving towards Green and low-carbon transformation is an inevitable trend. Continuous flow chemistry is a chemical process intensification technology that uses micro-channel reaction, fixed bed, continuous stirring tank and other micro-reactors to achieve continuous production. It has the characteristics of intrinsic safety and rapid expansion of production capacity. The green pharmaceutical technology recommended by four ministries and commissions, including the Health Commission and the State Food and Drug Administration, is also a key technology to ensure the safety of the API supply chain.

Continuous flow technology has been used on a large scale in the field of large chemical industry, showing many obvious advantages, but the application of this technology in the production of raw materials has been slow, especially the variety of raw materials for multi-step integrated continuous production. In recent years, only 1 varieties are FDA-approved. WOODCOCK, the former director of the FDA Center for Drug Evaluation and Research, believes that the main barriers to the application of continuous manufacturing technology are the high cost of entry and the long review period. In order to help pharmaceutical companies understand the regulatory considerations and facility inspections of continuous manufacturing, and enhance investment confidence, the FDA released a draft of “Quality Considerations for Industrial Continuous Manufacturing” in 2019 for comments, but this guidance is only for oral formulations of small molecule drugs. In 2021, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, ICH) finally released the first regulatory document Q13 involving continuous manufacturing of APIs, namely “APIs and Preparations Continuous Manufacturing of “, including the continuous manufacturing of raw materials and preparations, provides a research guide for continuous manufacturing.

The ICH Q13 draft defines continuous manufacturing and its batches, guides the establishment of control strategies, and discusses research methods for process validation and process changes. The draft guide puts forward regulatory considerations for continuous manufacturing products in combination with reality, and helps applicants understand in the form of cases in the appendix, with a high level of writing and not dogmatic. This study sorts out the Q13 draft and related literature, and combines the research experience of the research group in the continuous flow synthesis process in recent years to make a review, in order to apply this technology to the production of intermediates and APIs, reduce manufacturing costs, save energy and reduce emissions , to promote the application of this advanced preparation technology in the production of chemical raw materials.

Part 1 Features Of Continuous Flow Technology

The most obvious advantage brought by continuous flow technology to the production of raw materials is that it can significantly shorten the production cycle, especially the multi-step integrated continuous production mode. Different from traditional batch production, uninterrupted continuous production generally requires the use of process analysis technology (process analysis technology, PAT) and equipment to monitor the quality online. Since there is no need to wait for each step of the intermediate to pass the test before entering the next step, it can reduce A lot of waiting time. Some other features are as follows:

① High degree of automation, less production personnel involved in the whole process, which can reduce the risk of human error and ensure product quality.

②The continuous flow reactor has small liquid holding capacity, fast heat transfer and mass transfer, and can be safely used in process conditions that need to be avoided in tank reactions, such as reactions at high temperature (high pressure) and ultra-fast exothermic reactions. In addition, reagents that are more dangerous and not suitable for tank reactions can be safely used in continuous flow reactions, such as some highly toxic and highly active reagents.

③The fluid in the microreactor is basically a flat push flow, which is easy to control by “three transmissions and one reverse”, and the amplification effect is small. The cycle from laboratory development to production amplification is short, and the production capacity can be quickly formed, especially suitable for contract customization of service innovative drug companies R & D and production institutions and contract custom production institutions shorten the cycle of process development and sample supply.

④The continuous flow facility occupies a small area, which can reduce valuable Good Manufacturing Practice of Medical Products (GMP) facility space, and greatly reduce the factory’s fixed asset investment and operating costs. The case of CONTINUUS Pharmaceuticals in the United States shows that with integrated continuous manufacturing, fixed asset investment can be reduced by 90%, API production and operating costs can be reduced by 33.6%, and tablet production can be reduced by 29.4%.

Part 2 Application Of continuous Flow Technology

For the pharmaceutical industry, the application of new manufacturing technologies is expected to enhance the stability of the drug supply chain, make it more efficient and adaptable, and ultimately bring benefits to patients. Applying continuous flow technology to the production of raw materials requires not only consideration of specific varieties, such as whether the process is suitable, whether special lines are required, innovative drugs or generic drugs, etc., but also a balance between production capacity and market demand, not simply between batch production and continuous production. Make a “binary” choice between production. It is generally believed that continuous flow technology is more suitable for small batches of specialty APIs or basic APIs with high demand.

Part 3 Quality Considerations For Continuous Flow Production

3.1 Batch range

The registered batch of the traditional batch production process is related to the feeding amount of the starting material. The commercial batch is determined according to the feeding amount and yield range of the registered batch, and the batch range is generally narrow. The Q13 draft has relatively flexible batch requirements for continuous manufacturing. Not only can it be formulated according to the amount of input materials and output materials, but also the running time (limited mass flow rate) can be specified, and the batch range can be determined by defining the minimum and maximum running time. It even allows other scientific and reasonable methods based on the characteristics of the continuous manufacturing process to define batches. The range of batches will be more flexible, and it will be more conducive for manufacturers to arrange production capacity according to demand and reduce storage costs.

3.2 Design And Integration Of Equipment

The production equipment situation is the content that needs to be provided in the API application materials. Traditional batch kettles only need to provide each equipment model and technical parameters, but continuous flow equipment is mostly customized equipment, and more content needs to be provided. The draft ICH Q13 requires a detailed description of any aspect of equipment design or configuration and system integration, and its Annex I provides an example of continuous production of APIs, including a mixture consisting of 2-step continuous reactions and 1-step batch reactions. Process continuous production case. This example is described and discussed in detail in terms of control strategy, process robustness, long-term performance, process validation, and regulatory considerations. It is easy to understand and will not be repeated here, but it should be pointed out that quality assurance (QA ) department should establish acceptance criteria suitable for the performance and stability of continuous flow equipment (such as including parameter variance and drift, and the occurrence of transient disturbances) to support the development and operation of continuous production processes. The continuous production method needs to run for a long time to reach the predetermined batch size, so the robustness of the equipment has a very important impact on the quality.

3.3 Process Control

Continuous flow technology is a dynamic process. At each time point of the process, the component ratios of the feed liquid at each point before and after the microchannel are different. For the multi-step integrated continuous flow reaction, the components at different points may be different. different. If the reaction degree of the previous site changes due to interference, it will definitely affect the quality of the next site. After continuous superposition, it will lead to a large deviation in the quality of the final product. Therefore, in a continuous flow reaction, a slight disturbance may cause Product quality has a large deviation. The Q13 draft clearly requires the establishment of a robust method for process monitoring and maintaining a controlled state, which is described in the appendix. It is required to add multiple PAT devices, accurately control the concentration and flow rate of the feed, and monitor the quality of each step. According to the previous step The quality level of intermediates, feedback control the flow rate of material addition in the next step, to achieve the purpose of controlling the reaction and maintaining a controlled state.

The management of disturbance is an important aspect different from the traditional batch process. Draft Q13 calls for the development of appropriate disturbance detection, corrective action, and material diversion strategies based on the equipment’s remain time distribution (RTD). The research on interference is generally in the later stage of process development. Through the method of dynamic simulation, the relationship between the kinetics of the reaction process and the properties of the input materials, process parameters and equipment parameters can be understood. This knowledge can help identify and evaluate risks. The case provided in Annex V of the Q13 draft can be used for reference. Through a series of RTD-based analysis of the magnitude and duration of the disturbance, the funnel diagram tool is used to evaluate the tolerance of the process to the magnitude or duration of the disturbance, and then formulate the material according to the evaluation results. The diversion point and diversion decision, and the material diversion decision tree is also given. The research results in this aspect are the key content to be provided in the process development section of the registration dossier.

3.4 Cleaning Validation

One of the biggest challenges posed by existing GMP systems is the cleaning validation of continuous flow equipment. Microchannel reactors are the most widely used in continuous flow chemistry, and the channel diameter of the reaction module is millimeter-scale; in order to maintain sealing, it is generally integrally formed, and the channel cannot be opened for cleaning. Commercial microchannel reactors often customize specially designed channels according to the mixing requirements of the process, which makes more types of components that may remain in the reactor, especially the components in multi-step continuous facilities are more complex, how to clean , How to take samples have brought confusion to manufacturers and regulators. The Q13 draft does not provide guidelines for the development of cleaning methods, and applicants are advised to refer to the “Draft for Comments on Quality Considerations for Continuous Manufacturing” released by the FDA in 2019. The guidance recommends that cleaning methods should first be developed and defined from knowledge gained from development and process scale-up (e.g. increasing production run times) studies, followed by periodic validation to confirm continued effectiveness. Cleaning procedures should be established based on the results of close monitoring of materials during operation and after dismantling. The following points should be considered in the formulation of the program:

① Check the retention and accumulation of materials on equipment, pipelines, filters and instruments, including online analyzers and sensors;

② Pay attention to material degradation, chemical film formation and microbial growth on the production line during operation;

③ The evaluation conditions during cleaning validation should consider potential failure modes (such as fouling and wear) under the worst expected conditions (such as extended production time).

3.5 Formulation Of Quality Standards

For varieties of multi-step integrated continuous production, intermediates are not separated during the process, acceptance standards and sampling plans for monitoring or control in the process need to be formulated during continuous reactions, methods and standards for real-time detection and release of finished products, and the establishment of these methods and standards Different from traditional production methods, new development based on PAT equipment is required. For example, online liquid chromatography is used to monitor the quality of intermediates, and the detection results are used for feedforward and feedback control. The method development of online liquid chromatography is different from the method development of traditional offline liquid chromatography. Firstly, the results are required to be responded as soon as possible. Secondly, in addition to the development of liquid chromatography methods, it is also necessary to develop online sample processing methods, such as sample quenching, dilution, and filtration methods. , and validated by methodology, these works pose new challenges to quality analysts.

In short, the formulation of quality control strategies for continuous flow production is a new challenge for domestic manufacturers and regulatory agencies. Both parties need to strengthen communication and work together to gradually improve regulations and guidelines.

Part 4 Case Study Of Continuous Production Of APIs

The advantages and challenges of continuous flow technology applied to the production of APIs coexist. Continuous manufacturing is still in its infancy in China. Although it has been developed for many years abroad, the continuous manufacturing products currently approved for marketing are mainly preparation products [14]. Only fluticasone propionate of Glaxo Company has been publicly reported as a continuous manufacturing API. Approved. In order to further understand the development and quality considerations of the continuous flow process, this study introduces two typical cases of API literature in the GMP stage for reference by colleagues.

4.1 Single-Step Continuous Flow Production

Vaborbactam is a boronic acid β-lactamase inhibitor developed by Rempex Corporation of the United States. In 2017, the FDA approved the combination of vaborbactam and meropenem for the treatment of complicated urinary tract infection and pyelonephritis, and the trade name is Vabomere.