Pyrogens quality requirements

Sterility, freedom from pyrogens, and acceptably low level of extraneous particulate matter are critical quality attributes of all injectable products. Additional critical quality attributes depend on the clinical use of the product. For example, for IV, IM, and SC routes, isotonicity and physiological pH (7.4) are always desirable in order to minimize potential irritation upon injection. Other factors may preclude this, however. If the required dose of drug must be administered in a small volume, it may not be feasible to formulate an isotonic solution. Likewise, solubility or stability considerations may preclude formulation at physiological pH. This explains why formulation pH for injectable drugs varies from about pH 2 to about pH 11. 

To fulhll the monograph requirements with respect to the maximum allowed pyrogen content of about 0.25 endotoxin units per ml, the water used for distillation must be of very high microbial quality. 

For parenteral use, the antibiotic is packed in sterile vials as a freeze-dried power (reconstituted before use) or suspension. For oral use it is prepared in any of the standard presentations, such as film-coated tablets. Searching tests are carried out on a significant number of random samples of the finished product to ensure that it satisfies the stringent quality control requirements for potency, purity, freedom from pyrogens and sterility. 

Whereas readers are referred to these specific documents for details available on the Web site http //www.fda.gov/cder/fdama, some of the specifics are briefly mentioned here. The essence of this guidance emphasizes the importance of the overall quality assurance in manufacturing a PET radiopharmaceutical. All equipment and measurements used in the manufacture must be validated. The areas and hoods in which PET radiopharmaceuticals are manufactured must be run in a sterile condition. The personnel responsible for the manufacture must be well trained in the methodology, and an appropriate number of personnel are required in a production laboratory. Each step of the production must be verified and records must be maintained. The sterility and pyrogen testing of the finished product must be performed by appropriate methods. If a PET radiopharmaceutical is to be commercially distributed, appropriate containers and techniques must be adopted for safe shipments. 

It is undesirable to use in production any agent known to provoke sensitivity reactions in certain individuals, such as penicillin or other 8-lactam antibiotics. Many of the general requirements for the quality control of biological products, such as tests for potency, abnormal toxicity, pyrogenicity, stability and sterility, also apply to products made by rDNA techniques. 

The manufacture of sterile products is subject to special requirements in order to minimise risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance bears a particularly great importance, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test. 

The fabrication and packaging/labelling of sterile products requires special care and attention to detail because of the increased hazard to health should a product be non-sterile or otherwise contaminated. As the various processes used in the production of sterile drugs are susceptible to particulate, pyrogenic and microbiological contamination, the skill, training and altitudes of personnel involved are critical. Quality Assurance bears a particularly great importance this production must strictly follow carefully established and validated methods of preparation and procedures. 

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