First, we need to determine the Quality Target Product Profile (QTPP), which includes clinical conditions of use, route of administration, dosage form and delivery system; dosage specifications; the release or delivery of the active ingredient of the drug, as well as affecting the pharmacokinetics of the drug The attributes of the product; the product quality standards (such as purity, stability, and drug release, etc.) of the drug within the validity period; and the production cost. for example. For an injection, you need to consider: whether it needs to be dissolved in the solution and then administered after clinical use? Will the pH of the diluted solution affect the stability of the drug? If the drug is administered by infusion, how long can it be placed to ensure the drug Stability? Also consider: if the hospital bed is close to the window, under the sun, the infusion sample still needs to be stable. QTPP usually needs to be discussed and approved by all departments of the company. In addition to the formulation development department, it also includes clinical research and development departments, preclinical research (pharmacokinetics and toxicology research) departments, pharmaceutical regulations and industrial production departments.
After the QTPP is clarified, it is necessary to query relevant information or conduct experiments to determine the physical and chemical and biological properties of the drug (ie, pre-prescription research), and then combine with medical, market, operational, and regulatory requirements to determine the production of stable quality and reliable efficacy products. Critical Quality Attributes (CQA). The key quality attributes reflect a certain physical, chemical, biological and other properties or characteristics of the output material (intermediate) including finished products. Only when this property or characteristic is within an appropriate limit, range or distribution can we ensure Expected product quality. Whether the attribute is critical depends on the degree of harm caused to the patient when the attribute exceeds the acceptable range. For example, identification of active ingredients, content, content uniformity, degradation products, residual solvents, moisture content, drug release, particle size, dissolution, etc. In this process, a CQA report will be formed, and the identification of key quality attributes needs to be approved by the entire development team (pharmaceutical company departments). Based on these key quality attributes and pre-prescription research reports, the formulation development team will draft the formulation product development strategy and enter the product development stage after being approved by the formulation department management.
Small trial development
Product development must first be carried out on a small scale. Due to the very limited sources of APIs during this period, formulation development is usually dominated by formulation studies, accompanied by manual preparation. Mainly based on the concept of physical pharmacy, exploring the nature of raw materials, the nature of excipients and different formulation concepts will have a significant impact on the key quality attributes of the formulation products, and at the same time tackle the technical bottlenecks. For the functional requirements of some new formulations, it is also necessary to consider adding functional excipients. It should be noted that the selection of functional excipients must be within the scope of “quality” and “quantity” published by the FDA.
After the small trial development basically meets the development requirements and the prepared products basically meet the requirements of the product’s key quality attributes, the formulation development work enters the process development stage. In this process, the production process route is mainly determined according to the key quality attributes of the product, and the auxiliary materials are adjusted according to the needs of the process. The main result of process development is to confirm the key process steps and the range of process parameters. It is worth mentioning that the feasibility of industrialization needs to be considered at any time during the formulation development process. For example, formulation developers should try to use mature, reproducible, simple, and low-cost processes. The selected process and equipment need to be confirmed by the production department, and the selected auxiliary materials must be consistent with the production department. The author’s experience is that the formulation development department is best to use the auxiliary materials of the production department for prescription development and process development. The selection of production technology and equipment needs to consider the feasibility of the production department. For example, the author has experienced the situation. Because Japan and the United States have different definitions of PEG6000, different departments within the same company use different auxiliary materials, which causes confusion during technology transfer. Therefore, if you do not pay attention to the source of the auxiliary materials, it will inevitably affect the quality difference between the R&D stage and the mass production after the market.
After the process route of the preparation product is determined, product development enters the process amplification stage. At this stage, the key process parameters are mainly optimized according to the scale of the pilot production and commercial production batches, and the auxiliary materials will be further adjusted according to the needs of the process; mathematical models, statistical methods, etc. (if possible, use an online analysis system PAT) to confirm the key process steps and their parameter ranges. In this process, it is also necessary to produce batches at the edge of the key process step parameter ranges; confirm the risks that may arise from the key process steps and establish risk control steps.
The ultimate goal of formulation development is to transfer the developed product prescriptions and processes to the production department for production. This handover process between the formulation development department and the formulation product production department is called technology transfer. Generally, the technology transfer first needs to draft a technology transfer plan, which should be drafted by the preparation R&D department according to the company’s template, then reviewed by the production department, and signed by both parties. If the production process is more complicated, a certain batch quantity can be pre-produced by the R&D department and then transferred to the production department. Technology transfer generally produces three batches: the first batch is produced by R&D personnel, called the demonstration batch; the second batch is jointly produced by both parties, called the handover batch; the third batch is produced by the production department, called the acceptance batch.