Stat Rx USA 10/9/12
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Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
Atlanta District Office
60 Eighth Street N.E.
Atlanta, GA 30309
October 9, 2012
VIA UNITED PARCEL SERVICE
Gary A. Corless
President and Chief Executive Officer
PSS World Medical Inc.
4345 Southpoint Boulevard
Jacksonville, FL 32216
Dear Mr. Corless:
During our February 7-15, 2012 inspection of your pharmaceutical manufacturing facility, Stat Rx USA, LLC, located at 2481 Hilton Drive, Unit 5, Gainesville, GA 30501, an investigator from the U.S. Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, 21 C.F.R. Parts 210 and 211. These violations cause your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and, Cosmetic Act (the Act), 21 U.S.C. § 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We have conducted a detailed review of your firm’s response and note that it lacks sufficient corrective actions.
Our investigator observed specific violations during the inspection, including, but not limited to, the following:
1. Your firm failed to ensure that returned drugs meet appropriate standards of safety, identity, strength, quality and purity prior to redistributing. 21 C.F.R. § 211.204
For example, your firm has not established adequate written procedures for the handling of returned drugs. Draft SOP SRX-SOP-233 lacked sufficient details on what steps would be performed to fully evaluate the quality and integrity of a returned drug to justify any proposal to return it to stock for resale. The procedure also lacked information on how products will be evaluated for risks that your products may have been exposed to while the drugs were out of your control, such as exposure to adverse conditions (e.g., temperature abuse or excursions, exposure to moisture or light, oxidation, etc.), mishandling, or tampering.
In your response, your firm states that when implemented, the SOP will improve upon your current process of incoming inspection of all returned products; however, this procedure was not provided. Please ensure that the procedures include specific steps for the evaluation of quality defects that may have occurred while the drugs were out of your control. This includes evaluation of whether the drug product quality or integrity may have been compromised in any way. Examples include determining whether drug products have been stored outside of the labeled requirements, quality characteristics have been adversely impacted, or if there is evidence of tampering. The SOP should also include provisions for documenting the assessment of any quality or integrity impact, and a record documenting the disposition decision (including a justification for a return to stock decision).
2. Your firm does not have a written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates. 21 C.F.R. § 211.166(a)
For example, the work order for (b)(4) Lot #06FE1288 did not include instructions on whether or not to include a desiccant in the repackaged product despite the fact that the original container-closure system for these products includes the use of desiccants. It is FDA’s expectation that drug products are repackaged into equivalent container-closure systems that are at least as protective (including desiccants) as the manufacturer’s original container-closure system from which the drugs are being repackaged. Your firm does not have test data or scientific evaluation demonstrating that the repackaged product will be stable during the assigned expiration dates (original manufacturer’s dating minus three months).
In your response, your firm states that “Stat Rx has always been able to show that all repackaged ‘unit of use’ medication is repackaged in FDA compliant packaging, whether this is referring to the drug product containers (HDPE bottles) or drug product closures ((b)(4) rating caps and lining material) we match or exceed all industry standards…”. Although you provided some marketing materials and specifications from the manufacturers of the HDPE bottles you utilize, your response was inadequate because you did not present test data or a scientific evaluation to specifically support how the repackaged (b)(4) product would be stable under the conditions in which you repackage the product (i.e., excluding the desiccant used in the original manufacturer’s packaging) for the assigned expiration dates.
Additionally, in your response, you stated that Stat Rx would like further clarification from the Agency “because Stat Rx also feels that its relationship to the physician/pharmacist can be described as a pharmaceutical tech., repackaging ‘unit of use’ medication for the physician/pharmacist to be then prescribed directly to the patient.” As indicated above, your firm’s routine business operations of processing and repacking approved drugs for resale by other entities are considered drug manufacturing operations and your firm is subject to CGMP regulations that govern the manufacturing operations in which your firm is engaged. Such regulations include the requirement, among others, for a written testing program to determine appropriate storage conditions and expiration dates.
3. Your firm has failed to retain an appropriately identified reserve sample that is representative of each lot or batch of drug product. 21 C.F.R. § 211.170(b)
For example, you do not have any reserve samples of the drug products you repackaged.
In your response, your firm states that you are exempt from this requirement as it does not apply to drug repackagers. Your response is inadequate because repackagers are not exempt from the CGMP requirements to retain reserve samples of each lot or batch of drug product repackaged. Your firm must retain a reserve sample of the repackaged drug product from each shipment of each lot of drug product received by your firm. Additional reserve samples are required for each separate repackaging operation, if the bulk drug product is not completely repackaged in one operation.
The reserve samples must be of a sufficient quantity to conduct any required testing pursuant to investigations, and to perform the minimum yearly visual examination for evidence of any drug product deterioration. However, considering the limited testing of retains that is normally needed in association with repackaging operations, the size of the samples to be retained would usually be smaller than the size of samples retained by the original drug product manufacturer.
Reserve samples must be stored in the same immediate container-closure system in which the drug product is marketed or in one that has essentially the same characteristics. Since the CGMP regulations do permit the use of an immediate container-closure system having essentially the same characteristics, one size container may represent several sizes from the same lot or batch.
Reserve samples must be examined visually at least once a year for evidence of deterioration unless visual examination would affect the integrity of the reserve sample. The results of the examination, or justification for not conducting an examination of reserve samples, must be recorded and retained.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Other federal agencies may take this warning letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed..
In addition to the violations cited above, we are concerned about your firm’s history of repackaging beta-lactam drug products and non-beta-lactam drugs in the same facility without adequate separation of operations or containment controls (e.g., adequate facility design, differential air pressures, and a monitoring program). We acknowledge your commitment to cease all beta-lactam repackaging operations and outsource them to a contracted repackager. Please provide documentation to the Agency confirming that your firm ceased beta-lactam repackaging. Moreover, we are concerned about the potential for cross-contamination of products that your firm repackaged and distributed prior to your agreement to cease beta-lactam repackaging operations at the end of February 2012. In particular, although you have a designated “Antibiotic Room” within your production/fill area, your procedures and facilities were insufficient to prevent cross-contamination of non-beta-lactam products by beta-lactams such as penicillin, amoxicillin, and cephalosporin. We are also similarly concerned about the potential hazard presented by any operations that may have permitted cephalosporins to be repacked in the same facility as pencillins. You have not demonstrated how you plan to decontaminate your facility or the actions you will take to address any distributed products in expiry that may have been impacted by the above cross contamination risks.
During the inspection you stated that you would move the cephalosporin repackaging operations to (b)(4), a firm that currently repackages penicillin and amoxicillin under contract for Stat Rx. It is critical that your firm ensure that the contracted site performs beta-lactam repackaging operations in facilities that are segregated from facilities in which non-beta-lactam repacking is performed. Because of the health risks associated with cross-reactivity (cross-sensitivity) of beta-lactams, you should also ensure that the contracted facility (b)(4) has established these stringent controls to assure appropriate facility design provisions for separation.
Additionally, we note that your response claimed that your firm is operating as a “repackager (like a pharmacy) of ‘Unit of Use’ medications that we provide directly to the physician (acting as the pharmacist).” Your firm’s routine business operations (i.e., processing and repacking approved drugs for resale by other entities) exceed the traditional practice of pharmacy. Accordingly, your firm is a drug manufacturer subject to CGMP regulations that govern the manufacturing operations in which your firm is engaged.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, if you no longer manufacture or distribute any particular products, provide the date(s) and reason(s) you ceased production.
Please send your reply to the following address: Marie Mathews, Compliance Officer, Atlanta District Office, 60 Eighth Street N.E., Atlanta, GA 30309.
John R. Gridley, Director
Robert T. Ridge
Stat Rx USA, LLC
2481 Hilton Drive Unit 5
Gainesville, GA 30501