GMP API Development Process at TBD
At TBDPharmatech, we specialize in the development and manufacturing of Active Pharmaceutical Ingredients, commonly known as APIs, designed for use in medicine. APIs serve as the biologically active compounds within medications. Our emphasis is on the meticulous development and manufacturing of these vital compounds, as they serve as the driving force behind the intended outcomes in medicinal formulations.
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The development process initiates with route scouting or technology transfer, advancing through successive stages of process development, culminating in the establishment of production-ready technology for Good Manufacturing Practice (GMP)-compliant batches of the required size. Following the successful development of a compliant Active Pharmaceutical Ingredient (API), regulatory approvals are sought by submitting the appropriate ASMF/DMF documentations to relevant agencies. Upon achieving market readiness, the API progresses to commercial production.
The production of API is done in compliance with current Good Manufacturing Practices (GMP). Adhering to GMP standards guarantees that the API manufacturing process aligns with industry best practices, reinforcing the commitment to delivering high-quality, safe, and effective APIs.
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We categorize our development process into 8 steps:
- Route Scouting:
- Route scouting serves the crucial purpose of identifying the most efficient and cost-effective synthesis pathways for a specific compound. This involves the evaluation of multiple chemical routes to determine the optimal synthesis, also establishing the initial set of analytical methods needed for starting materials, reagents, and products in subsequent development phases.Whether dealing with innovative molecules demanding novel synthesis methods or older generics, route scouting is indispensable in establishing the foundation for a resilient and cost-effective manufacturing process. It plays a pivotal role in ensuring the production of high-quality APIs.
- Process Optimization & Scale-Up:
- After identifying a viable synthesis route, the subsequent step involves optimizing the manufacturing process for efficiency, yield, and quality. This encompasses the determination of optimal reaction conditions, refinement of purification techniques, and addressing any challenges associated with scalability. The process is then scaled up, transitioning from laboratory-scale to industrial-scale production.
- Key process parameters, including temperature, pressure, and reaction times, are refined to maximize both yield and quality. Analytical support plays a crucial role in ensuring reliability and consistency as the process volumes are scaled up. These stages are indispensable for validating and refining the process technology before progressing to larger batch sizes.
- Typically, the preliminary process development culminates with the creation of a representative technical batch, intended to align with the required technical specifications.
- Analytical Development:
- Analytical methods are crucial for monitoring and ensuring the quality of APIs during manufacturing. These methods, including chromatography and spectroscopy, are used to characterize and quantify the API. Analytical development packages validate testing methods for starting materials, intermediates, and the final API product. The goal is to maintain the quality and safety of all compounds in the manufacturing process.
- For process reagents and intermediates, standard activities include developing and validating analytical methods, synthesizing and characterizing impurities, qualifying reference materials, and controlling potentially genotoxic impurities.
- Final API development involves extensive tests such as assay validation, testing for related substances, verifying residual solvents, analyzing water content, conducting forced degradation studies, performing microbiological tests, assessing endotoxins, determining the limit of detection (LoD), utilizing powder X-ray diffraction (PXRD), evaluating photostability, assessing mutagenic impurities, measuring particle size distribution (PSD), applying chiral high-performance liquid chromatography (HPLC), gauging optical rotation, analyzing specific impurities, establishing melting points, and testing counter-ions. These activities are crucial for quality assurance in API manufacturing.
- GMP Documentation:
- GMP documentation is crucial for maintaining the quality and consistency of APIs. This involves comprehensive documentation of manufacturing processes, quality control procedures, and standard operating procedures (SOPs). Adhering to GMP guidelines ensures that the API is produced in a controlled and regulated environment.
- Proof of compliance with GMP regulations requires a comprehensive set of documents and records, including development reports, batch master records, technology flowcharts, drafts of SOPs, process validation plans, cleaning protocols, and risk assessments. These records ensure process traceability, guide manufacturing operations, document technical details, assist in quality control, and fulfill regulatory mandates. Such documentation is essential for ensuring operational consistency, maintaining product integrity, and meeting regulatory standards.
- GMP Process Validation:
- GMP process validation is a crucial step in confirming that the manufacturing process consistently produces APIs of the desired quality. It involves a series of documented studies and tests to demonstrate that the process can consistently meet specified standards. This validation is essential for regulatory compliance and ensuring the reliability of the manufacturing process, aligning with GMP standards. For generic APIs, we typically produce three validation batches, while early-phase clinical material often requires only a single batch.
- Key tasks within this process include supplier qualification, GMP-compliant release of raw and starting materials, intermediate product testing, equipment qualification, compiling process validation reports, finalizing standard operating procedures (SOPs), conducting product release analytics, assessing elemental impurities, performing cleaning validation, and handling sample packaging and transportation. This validation process is pivotal for ensuring the manufacturing of APIs that are reliable, consistent, and compliant with regulatory requirements.
- Regulatory Documentation:
- Regulatory documentation is prepared to demonstrate compliance with local and international regulatory requirements, EU having Active Substance Master File (ASMF) and US having Drug Master File (DMF). These documentation packages include submission of data and information to regulatory authorities for approval. The documentation provides details about the manufacturing process, quality control measures, and safety assessments to ensure that the API is suitable for use in pharmaceutical products and is essential for assessing the quality and safety of manufactured APIs
GMP documentation is essential for maintaining API quality and consistency, encompassing detailed records of manufacturing processes, quality controls, and SOPs.
- Stability Studies:
- Stability studies assess the API’s performance and characteristics over time under various storage conditions. By exposing the Active Pharmaceutical Ingredient (API) to different conditions—like changes in temperature, humidity, and light—we can determine out how long it stays reliable and what might cause it to degrade. This information is key for deciding how to store it, determining expiration dates, and giving clear guidelines on handling. This helps determine the product’s shelf life and storage recommendations. Stability data is crucial for establishing appropriate storage and transportation conditions to maintain the API’s quality until it reaches the end user and that it keeps it’s quality, effectiveness and safety intact throughout its shelf life
- Commercial Manufacturing:
- The final stage involves the large-scale commercial production of the API following all established processes and quality standards. Continuous monitoring and quality control measures are maintained throughout commercial manufacturing to ensure the consistency and reliability of the produced API.
- At TBD, manufacturing projects stem from in-house API development or customer-led tech transfer. TBD is equipped to produce market-approved generics, cGMP innovative molecules for early-phase clinical trials, or custom small-molecules like excipients, intermediates, or impurities. Product specifications are tailored to align with industry requirements such as GMP compliance and other client preferences
In conclusion, the journey of Active Pharmaceutical Ingredient (API) development at TBD Pharmatech is marked by meticulous processes, from initial route scouting to large-scale commercial production. The commitment to Good Manufacturing Practices (GMP), rigorous analytical development, regulatory compliance, and stability studies ensures the production of high-quality, reliable APIs. With a focus on innovation and versatility, TBDPharmatech caters to a spectrum of manufacturing needs, from market-approved generics to custom small-molecules. The ongoing construction of a new production facility in Tartu, Estonia, reflects the company’s dedication to expanding capacity and staying at the forefront of pharmaceutical manufacturing.