Active pharmaceutical ingredients govern the desired biological activity of every drug, and there are thousands of approved drug products on the market.
Each of these drugs contains at least one unique API. Hence, the realm of API manufacturing is extremely diverse.
API Manufacturing
The broad scope of API manufacturing is evident in the many key areas involved:
- Buildings and facilities, with requirements for design, sanitation, and maintenance
- Process equipment and its construction, cleaning, and validation
- Controls over raw materials
- Packaging and labelling
- Process validation
- Stability testing
This list is by no means exhaustive. But it does exemplify that API processing and holding are highly involved undertakings. They need robust quality systems and strict adherence to good manufacturing practices. Fortunately, regulators like the American Food and Drug Administration (FDA) and the European Medicines Agency (EMA) provide frameworks for controls and procedures to ensure APIs consistently meet their required quality attributes.
The FDA’s guidance factors into APIs derived from any source, from chemical manufacturing to herbal extraction. Yet, their guidance generally applies from the point at which the API is introduced into a starter material or process. That said, there are pre-processing considerations to bear in mind.
Pre-Processing Considerations
Rigorous pre-processing checks are essential to ensuring safety and regulatory compliance. These include a range of risk assessments. Identifying potential API toxicity or reactivity, for example. Manufacturers may also need to assess combustible dust hazards and install the proper controls. Though we’re focusing on FDA guidance in this article, it’s important to highlight that API manufacturing covers several regulations, including DSEAR and OSHA. All regulators expect manufacturers to establish risk mitigation strategies for identified hazards.
Containing potentially toxic or highly potent APIs (HPAPIs), for example, is essential for safety compliance. Facilities must validate cleaning procedures robustly to prevent cross-contamination and adhere to Good Manufacturing Practices (cGMP) that maintain the integrity and safety of pharmaceutical products.
Risk Assessment: Conduct thorough risk assessments to identify potential hazards associated with the API, such as toxicity, reactivity, and the potential for dust explosion. Based on these assessments, appropriate controls to mitigate identified risks should be implemented.
Containment Strategies: To protect operators from highly potent or hazardous APIs, containment strategies such as isolators and gloveboxes should be implemented. These systems ensure that exposure to dangerous substances is minimised.
Cleaning Validation: Establish and validate cleaning procedures to eliminate the risk of cross-contamination between different production batches. This includes developing specific cleaning protocols for all equipment used in the process.
Solid-Liquid Separation
Solid-liquid separation processes are critical in isolating and purifying APIs from chemical synthesis mixtures. These mixtures must be filtered and dried to separate and refine the product. There are myriad approaches to separation, but all equipment and methodologies must meet stringent regulatory guidelines to ensure they do not compromise the API’s quality. Process validation is critical in this regard. The FDA expects workflows to produce an API that meets all quality specifications consistently. Many workflows treat solid-liquid separation as a discrete stage prior to further processing (i.e. drying or final purification), but some equipment solutions combine multiple steps into a single station without compromising safety, efficacy, or regulatory standards
Containment and Handling
API handling requires strict containment measures to prevent contamination and ensure worker safety. Advanced engineering controls and personal protective equipment are regulated to limit exposure to potent pharmaceutical compounds. Transfer systems and containment strategies must be designed to meet occupational safety standards and ensure the integrity of the API during handling and transfer. The FDA guidelines emphasize the importance of cleaning validation and containment in maintaining the quality and compliance of the manufacturing environment.
Contained Transfer Systems: Techniques such as split butterfly valves and rapid transfer ports minimise operator exposure during material transfers.
Respiratory Protection and Engineering Controls: Appropriate respiratory protection and engineering controls must be implemented based on the API’s occupational exposure limit (OEL).
Cleaning Validation: Similar to pre-processing, validate cleaning procedures for all equipment and facilities to maintain a contamination-free environment. This requirement is particularly important in multi-product facilities with contract manufacturing organisation (CMO) profiles.
Storage and Packaging
Proper storage and packaging are critical to maintaining API stability and quality. Regulatory guidelines stipulate that APIs should be stored under conditions that protect them from chemical degradation and physical damage. The storage areas must be designed to maintain specific environmental conditions, such as temperature and humidity, which are determined based on the stability data of the APIs. Packaging materials must prevent exposure to light, moisture, and contamination and be rigorously tested to ensure compliance with FDA standards. Inventory control systems must be implemented to manage stock effectively and prevent mix-ups.
Interested in Learning More?
This guide is far from comprehensive, given the expansive nature of API manufacturing. However, it does serve as an overview of some key universal points driving safety, quality, and compliance. At Powder Systems Limited (PSL), we are committed to providing solutions that meet these essential requirements throughout the pharmaceutical development and manufacturing lifecycle. Our Agitated Nutsche Filter Dryers (ANFD) are designed with the latest technology to offer integrated filtration, washing, drying, and containment in a single, GMP-compliant system. These systems are scalable and versatile, accommodating various production sizes and requirements while maintaining stringent quality standards.
Contact us today for more information on how our equipment can be tailored to meet your specific needs.
