Development and control of manufacturing process of chemical raw materials in "Pharmaceutical Research Series"



1. API production process development - Core content

The purpose of the development of manufacturing process for apis: 1) Early stage is to develop the development process that can prepare the API in line with the stage quality standards; 2) In the later stage, a commercial production process that can consistently produce the expected quality apis must be established. Based on the above process development logic, some core contents and key tools in process development are listed.

➣ process development method

Manufacturing process development should include, at a minimum, the following elements: 1) identification of potential key quality attributes associated with the drug substance in order to facilitate the study and control of these attributes that affect the quality of the pharmaceutical product; 2) Determine a suitable production process; 3) Determine a control strategy to ensure process implementation and API quality; 4) Systematic methods for evaluating, understanding and improving production processes; 5) Use an enhanced approach combined with quality risk management to establish an appropriate control strategy, which may include, for example, suggestions for design space. In addition, the applicant can choose to use the traditional method or the enhanced method in the development of the API, or use both methods.

Key quality attributes of apis

Critical Quality Attribute (CQAs) : A physical, chemical, biological, or microbiological attribute or characteristic that should be defined to an appropriate limit, range, or distribution to ensure the desired product quality. The key quality attributes of an API typically include those attributes or characteristics that affect identification, purity, biological activity, and stability. Physical properties may also be designated as key quality attributes when they have a significant impact on the production or performance of a pharmaceutical preparation. Impurities are an important key quality attribute for apis because of their potential impact on the safety of pharmaceutical preparations.

➣ Correlation of material properties & process Parameters & key quality attributes

The process development procedure should identify which material properties (e.g. properties of raw materials, starting materials, reagents, solvents, process AIDS, intermediates) and process parameters should be controlled.

In the case of enhancement, the following steps are required to determine the appropriate material quality standard and process parameter range: 1) Identify potential sources of process change; 2) Identify the material properties and process parameters that are likely to have the greatest impact on the quality of the API, based on knowledge and risk assessment tools; 3) Design and conduct studies (e.g., mechanism and/or dynamic evaluation, multivariate test design, simulation, modeling) to identify and determine associations and relationships between material properties and process parameters and key quality attributes of the API; 4) Analyze and evaluate the data to set the appropriate scope, including the establishment of design space if necessary.

➣ Design space

The design space is a multidimensional combination and interaction of input variables (e.g., material properties) and process parameters that have been proven to provide quality assurance. Activities within the design space are not considered changes. An activity that goes beyond the design space is considered a change and usually requires initiating regulatory approval for the change.

The design space for each unit operation (for example, reaction, crystallization, distillation, refining) can be determined, or the design space for a combination of selected unit operations. The selection of unit operations containing such design space is usually based on their impact on key quality attributes and need not be continuous. A design space that spans multiple unit operations provides greater operational flexibility.

2. Production process development -- quality control

Whether developed by conventional means or enhanced means (or both), each API manufacturing process has a control strategy that includes, but is not limited to, the following: 1) control of material properties (including raw materials, starting materials, intermediates, reagents, inner materials in direct contact with the API, etc.); 2) Controls embedded in the design of the production process (for example, the sequence of refining steps, or the sequence in which reagents are added); 3) Process control (including process testing and process parameters); 4) Control of apis (e.g. release testing).

The development of control strategy can be combined with various methods, and some key quality attributes, steps or unit operations are developed in traditional ways. Apply enhancements to other areas. As the level of understanding of the process increases throughout the product life cycle, control strategies can be developed through multiple cycles. In terms of addressing variations in the operating range, the augmentation-based control strategy can provide flexible operating ranges for process parameters.

The control strategy should ensure that the key quality attributes of each API are within the appropriate range, limit, or distribution area to ensure the quality of the API. The quality standard for an API is part of the overall control strategy and not all key quality attributes need to be included in the quality standard for an API. The key quality attributes can be: 1) included in the quality standard and determined by testing of the final API; Or 2) included in quality standards and identified by upstream controls (e.g., through real-time release testing); Or 3) not included in the quality standard, but provided by upstream control. In some cases, process analysis technology (PAT) can be used to enhance process control and ensure product quality.

The information provided on the control strategy should include a detailed description of the individual elements of the control strategy and, where appropriate, an overall summary of the control strategy for the drug substance. It can be in table form or legend form, which is more intuitive and easy to understand. An ideal summary should explain how the various elements of the control strategy work together to ensure the quality of the drug substance.

3. Production process development - life cycle management

The development and improvement of manufacturing processes for apis usually continues throughout their life cycle. The performance of the production process, including the effectiveness of the control strategy, should be evaluated periodically. The knowledge gained from commercial production can be used to further deepen the understanding of the process and its properties, and to adjust the control strategy to ensure the quality of the API. Knowledge gained from other products or innovative technologies also contributes to these goals. Continuous improvement and successful process validation, or continuous process validation, require appropriate and effective control strategies.

Knowledge management should include, but not be limited to, process development activities, technology transfer activities to internal sites and contract manufacturers, process validation studies for the API life cycle, and change management activities. Knowledge and process understanding should be shared as needed to implement manufacturing processes and develop control strategies in the different locations involved in API production. For example, in the initial submission, the applicant may submit a plan for how specific future changes will be managed during the product's life cycle.