Sterile Drug Products CGMP Guidelines

The purpose of this appendix is to supplement the guidance provided in this document with information on products regulated by CBER or CDER that are subject to aseptic processing at points early in the manufacturing process, or that require aseptic processing through the entire manufacturing process because it is impossible to sterile filter the final drug product. The scope of this appendix includes aseptic processing activities that take place prior to the filling and sealing of the finished drug product. Special considerations include those for:

A. Aseptic processing from early manufacturing steps

Some products undergo aseptic processing at some or all manufacturing steps preceding the final product closing step. With other products, there is a point in the process after which they can no longer be rendered sterile by filtration. In such cases, the product would be handled aseptically at all steps subsequent to sterile filtration. In other instances, the final drug product cannot be sterile-filtered and, therefore, each component in the formulation would be rendered sterile and mixed aseptically. For example, products containing aluminum adjuvant are formulated aseptically because once they are alum adsorbed, they cannot be sterile-filtered.

When a product is processed aseptically from the early stages, the product and all components or other additions are rendered sterile prior to entering the manufacturing process. It is critical that all transfers, transports, and storage stages be carefully controlled at each step of the process to maintain sterility of the product. In some cases, bulk drug substances or products should be tested for sterility.

Procedures (e.g., aseptic connection) that expose a product or product contact surfaces should be performed under unidirectional airflow in a Class 100 (ISO 5) environment. The environment of the room surrounding the Class 100 (ISO 5) environment should be Class 10,000 (ISO 7) or better. Microbiological and airborne particle monitoring should be performed during operations. Microbial surface monitoring should be performed at the end of operations, but prior to cleaning. Personnel monitoring should be performed in association with operations.

Process simulation studies covering the steps preceding filling and sealing should be designed to incorporate all conditions, product manipulations, and interventions that could impact on the sterility of the product. The process simulation, from the early process steps, should demonstrate that process controls are adequate to protect the product during manufacturing. These studies should incorporate all product manipulations, additions, and procedures involving exposure of product contact surfaces to the environment. The studies should include worst-case conditions such as maximum duration of open operations and maximum number of participating operators. However, the process simulations do not need to mimic total manufacturing time if the manipulations that occur during manufacturing are adequately represented.

It is also important that process simulations incorporate storage of sterile bulk drug substances or product and transport to other manufacturing areas. For instance, there should be assurance of bulk vessel integrity for specified holding times. The transport of sterile bulk tanks or other containers should be simulated as part of the media fill. Please refer to Section IX.A for more guidance on media simulation studies. Process simulation studies for the formulation stage should be performed at least twice per year.

B. Aseptic processing of cellular therapy products and cell-derived pharmaceutical products

Cellular therapy and some cell-derived products (e.g., lysates, semi-purified extracts) represent a subset of the products that cannot be filter-sterilized and therefore undergo aseptic manipulations throughout the manufacturing process. Where possible, closed systems should be used during manufacturing. Cellular therapy products often have short processing times at each manufacturing stage, particularly between the harvest, formulation of the final product, and product release. These products are frequently released from the manufacturing facility and administered to patients before final product sterility testing results are available. In situations where results of final sterility testing are not available before the product is administered, additional controls and testing should be considered. For example, additional sterility tests can be performed at intermediate stages of manufacture, such as after the last manipulation of the product prior to harvest. Other tests that may indicate microbial contamination, such as microscopic examination, Gram stain (or other bacterial and fungal stain), and endotoxin testing should be performed and meet acceptance criteria prior to product release. Also see Pharma Process Validation

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This Guidance is published by US FDA on September 2004

We also recommend our readers to visit US FDA’S website for undated guidances on sterile drug products