The Food and Drug Administration (FDA) is drafting a new regulation that enables a pharmaceutical company to register an outsourcing facility with the FDA. This regulation, called 503B, is part of the Drug Quality and Security Act. It is also issuing an associated guidance that further clarifies its position on outsourcing facilities and current Good Manufacturing Practices.
The new regulation is intended to provide more detailed specifications regarding the design of a facility, monitoring of personnel and environmental issues, equipment used in the manufacturing of a drug, controlling of the process of manufacturing and producing a drug, quality testing of a drug before it is released, laboratory controls, and other areas of potential concern.
Some specific criteria regarding the design of outsourcing facilities include:
- Processing and controlled areas should be clean and free of mold, mildew, insects, dirt, and other debris that could contaminate the drug.
- The area should not use damaged or dirty HEPA filters.
- Sterile drugs should be produced in an area that has an air quality of at least ISO 5.
- The area should have a cascading air quality so that the requirements of ISO 5 are met.
- The area should be designed so that contaminants cannot enter from adjoining areas.
- Areas adjacent to the area with the ISO 5 designation should have a designation of at least ISO 7.
- Areas surrounding those that use isolators should have a designation of at least ISO
Tests and studies should be conducted to ensure that the area meets ISO 5 standards. These tests include airflow studies under dynamic conditions. The area should be retested at least every six months. The testing should include tests of the HEPA filter, the number of particles in the air, and the velocity of the air in the room. Any issues found during the tests should be corrected. If a portable ISO 5 unit is moved, the unit needs to be recertified before it is used again.
The regulation will establish control systems in facilities that are outsourced. For instance, large equipment should not obstruct the ventilation ducts, and instruments should be built in to detect any variations in the quality of the air. The room should be monitored while the drug is being produced. If any errors are found, production of the drug should stop until the problem is corrected. Any instances in which positive pressure in a clean room is lost should also be documented.
Cleaning and prevention of cross contamination is an important control system defined under the regulation. Manufacturers should have measures to prevent cross-contamination of drugs in powder form. Cleaning procedures for equipment on which all drugs are manufactured should be well defined. However, for drugs manufactured in multiple-use facilities and on multiple-use equipment, the manufacturers should have specific cleaning procedures to prevent cross-contamination. The suitability and efficacy of the cleaning agents should also be monitored.
Environmental controls will also be established for outsourced facilities through this regulation. According to the regulation, adequate measures should be in place to monitor the environment where the drug is manufactured for microbial contamination. A system should be in place to monitor the state of the environment and the extent to which it is being controlled. This should cover all shifts during which the drug is being manufactured, provide daily monitoring for rooms with an ISO 5 status, provide an alert system and appropriate responses if a mishap occurs, and describe how samples are going to be collected and tested. The methods that are used should be supported by evaluations of the sampling methods.
This regulation will also establish measures for monitoring of personnel working in outsourced facilities. Personnel should be appropriately trained before they handle the product. They can be considered appropriately trained if they successfully perform at least three simulations. Measures that monitor the gloves and gowns of employees working in the facilities should be implemented. If the practices go beyond accepted parameters, measures that call for investigation of the results and how they impact safety and the sterility of the product should be in place. Mechanisms for corrective actions should also be implemented.
According to the regulation, control measures for equipment and containers should also be in place for outsourcing facilities. For instance any equipment or containers should be evaluated to determine whether they are appropriate for their intended use. Equipment and containers that have not been sterilized beforehand must be sterilized before they are used. The sterilization processes should be validated to determine that they are consistent and reliable. The equipment should be examined to determine that it is in fact the correct product and that it conforms to the appropriate guidelines and specification before it is used. Containers must also be checked to ensure that the labeling conforms to the requirements. If a package is shipped, the recipients must verify its integrity before using its contents. The contents should also be tested and retested as applicable.
The regulation also specifies that written procedures to control the process must be developed and followed to ensure the purity and integrity of the product. Batch records should contain documentation of the process. The projected batch records should be checked against the actual batch records to determine whether there are any problems with the production of the drug. The final product should also be tested to make sure it meets the appropriate specifications. The product should not be released if it does not meet these specifications. The procedures for testing the final product should also be documented.
However, the FDA has said that there are some exceptions to this regulation. For instance, FDA will not act against a manufacturer if the product is a final and approved drug. They will also not take action if the package was received from a manufacturer already registered and listed with the FDA and the packaging has not been altered. Similarly, if the package’s integrity was verified when it was received and before it was used and if the manufacturer has examined the label and verified the integrity for each lot, the FDA will not act against the manufacturer.
The FDA is also requesting that the manufacturers provide input on alternative approaches regarding outsourcing. As such, manufacturers will have an opportunity discuss the process with the FDA. This collaboration will enable the FDA to provide the most effective regulations regarding outsourcing.