Comment from Cantrell Drug Company

The use of bulk API to manufacture sterile products is a well-established practice for traditional manufacturing establishments operating under cGMP regulations. These products are manufactured using facilities, equipment, and procedures that ensure the sterility of the final product. The safe use of bulk API to compound sterile products has been demonstrated by Cantrell Drug Company using the same type of facilities and procedures used by traditional manufacturers. The equipment used by Cantrell Drug Company differs only in scale while providing a closed system for aseptic manipulations and sterile filtration. The bulk API is sourced only from FDA-registered manufacturers and thoroughly tested to meet predetermined specifications. Testing intermediate solutions and the final product for potency, endotoxin, and sterility ensures that the final product is safe for its intended use. Cantrell Drug Company strongly believes that use of bulk API must be extended to 503B outsourcing facilities. Cantrell Drug Company also strongly believes that this practice constitutes a safer approach for compounding sterile products. Only a few carefully controlled aseptic manipulations are required when starting with a bulk API. One should consider the alternate approach of beginning with commercially available product. There are 100 aseptic manipulations required to withdraw sufficient solution from the 10 mL vials of a commercial product to compound one liter of sterile solution. When necessary, dilution to the concentration of the final product requires additional aseptic manipulations. Moreover, when a commercial product is only available in single-dose vials or ampoules, the aseptic manipulations and associated risk multiply. Placing a large number of vials into the ISO 5 area and the repeated manipulations greatly increase the bioburden potential for introduction of microbes and particulates into the sterile solution. The possibility of technician fatigue also is a factor to be considered with many numerous manipulations in an aseptic environment. Also, it should be noted that the strengths of intrathecal products are higher than those available from commercial products necessitating use of a bulk API. Additionally, given the inconsistencies in supply of many generic injections, it becomes important for small batch production and a small business 503B outsourcer, to have reliable supplies of API. Arguably, generic injection supplies are not reliable. Consider a scenario where a small 503B company has invested in the development of cGMP compliant processes for a commercially available generic injection to be used as the API in a compounded preparation. If the supply chain is interrupted, the small 503B outsourcer will be forced to make critical adjustments in GMP processes to accommodate a bulk API. These adjustments would be overly burdensome from a time and resource standpoint. It would create a high-risk change in processes for a resource-limited small business. In addition, it is not possible to make such process changes in the short time frame demanded by the market. Consideration should be given to the quick response required of compounding operations to meet immediate needs of hospitals and physicians in order to treat patients effectively. To meet cGMP requirements for a new supplier of bulk API, and additionally, the cGMP requirements for the changes in processes and training, would be very time and resource consuming. If the purpose of limiting the use of bulk APIs for 503B companies is to protect the interest of generic pharmaceutical companies market, we point to the fact that 503B companies are prohibited from making copies of commercially available products. Should patients need a different strength, administration volume, container, or combination therapy, then bulk APIs should not be prohibited. For 503B companies to effectively fill the gap of pharmaceuticals needed to treat patients effectively, bulk APIs are a necessity. One final consideration is drug shortage of commercially available product which is a major concern to hospitals and health care practitioners. Cantrell Drug Company has already accumulated stability data for many drug preparations it has compounded using bulk API. As a result Cantrell Drug Company can respond quickly to drug shortage situations to provide a safe and stable drug product to the health care community in the desired strength and package configuration established on the basis of clinical need.