2014 > PharMEDium Services, LLC 7/18/14 http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm406105.htm[7/23/2014 11:24:41 AM] A to Z Index Follow FDA En Español Home Inspections, Compliance, Enforcement, and Criminal Investigations Compliance Actions and Activities Warning Letters 2014 Inspections, Compliance, Enforcement, and Criminal Investigations PharMEDium Services, LLC 7/18/14 Department of Health and Human Services Public Health Service Food and Drug Administration Chicago District 550 West Jackson Blvd. 15th Floor Chicago, Illinois 60661 Telephone: 312-353-5863 July 18, 2014 WARNING LETTER CHI-10-14 VIA UPS NEXT DAY Mr. William R. Spalding Chief Executive Officer PharMEDium Services, LLC Two Conway Park 150 North Field Drive Suite 350 Lake Forest, IL 60045 Dear Mr. Spalding: Between February 19, 2013 and March 22, 2013, U.S. Food and Drug Administration (FDA) investigators conducted inspections of your facilities, PharMEDium Services, LLC, located at 913 N. Davis Ave., Cleveland, MS, 38732; 43 Distribution Blvd., Edison, NJ, 08817; 6100 Global Dr., Memphis, TN, 38141; and 12620 W. Airport Blvd. Ste. 130, Sugar Land, TX, 77478. The investigators observed serious deficiencies in your practices for producing sterile drug products at each of your facilities, which put patients at risk. For example, at some of your facilities, our investigators observed that operators did not properly sanitize their hands after touching non- sterile equipment and processed sterile drug products with exposed skin on their faces and wearing non-sterile masks. In addition, our investigators found that your firm failed to demonstrate through appropriate studies that your hoods are able to provide adequate protection of the ISO 5 areas in which sterile products are processed. Therefore, your products may be produced in an environment that poses a significant contamination risk. FDA issued Form FDA 483s at your facilities between February 22, 2013 and March 22, 2013. Based on these inspections, it appears that you are producing drugs that violate the Federal Food, Drug, and Cosmetic Act (FDCA). FDA acknowledges that PharMEDium registered all of its facilities with FDA as 503B outsourcing facilities on December 11, 2013. A. Compounded Drugs Under the FDCA At the time FDA inspected your facility, there were conflicting judicial decisions regarding the applicability of section 503A of the FDCA [21 U.S.C. § 353a], which exempts compounded drugs from several key statutory requirements if certain conditions are met.[1] Nevertheless, receipt of valid prescriptions for individually- identified patients prior to distribution of compounded drugs was relevant for both section 503A of the FDCA and the agency’s Compliance Policy Guide 460.200 (CPG) (2002), which was then in effect.[2] During the FDA inspections, the investigators observed that your firm does not receive valid prescriptions for individually- identified patients for the drug products you produce. Based on this factor alone, those drugs were not entitled to the statutory exemptions for compounded drugs described in section 503A of the FDCA and did not qualify for the agency’s exercise of enforcement discretion set forth in the CPG.[3] Since FDA inspected your facility, Congress enacted and the President signed into law the Compounding Quality Home Food Drugs Medical Devices Radiation-Emitting Products Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products Warning Letters 2014 Compliance Actions and Activities
Home Inspections, Compliance, Enforcement, and Criminal Investigations Compliance Actions and Activities Warning Letters2014
Inspections, Compliance, Enforcement, and Criminal Investigations
PharMEDium Services, LLC 7/18/14
Department of Health and Human ServicesPublic Health ServiceFood and Drug Administration
Chicago District550 West Jackson Blvd. 15th FloorChicago, Illinois 60661Telephone: 312-353-5863
July 18, 2014
WARNING LETTERCHI-10-14
VIA UPS NEXT DAY Mr. William R. SpaldingChief Executive OfficerPharMEDium Services, LLCTwo Conway Park150 North Field DriveSuite 350Lake Forest, IL 60045 Dear Mr. Spalding: Between February 19, 2013 and March 22, 2013, U.S. Food and Drug Administration (FDA) investigators conducted inspections of your facilities, PharMEDium Services, LLC, located at 913 N. Davis Ave., Cleveland, MS, 38732; 43 Distribution Blvd., Edison, NJ, 08817; 6100 Global Dr., Memphis, TN, 38141; and 12620 W. Airport Blvd. Ste. 130, Sugar Land, TX, 77478. The investigators observed serious deficiencies in your practices for producing sterile drug products at each of your facilities, which put patients at risk. For example, at some of your facilities, our investigators observed that operators did not properly sanitize their hands after touching non-sterile equipment and processed sterile drug products with exposed skin on their faces and wearing non-sterile masks. In addition, our investigators found that your firm failed to demonstrate through appropriate studies that your hoods are able to provide adequate protection of the ISO 5 areas in which sterile products are processed. Therefore, your products may be produced in an environment that poses a significant contamination risk. FDA issued Form FDA 483s at your facilities between February 22, 2013 and March 22, 2013. Based on these inspections, it appears that you are producing drugs that violate the Federal Food, Drug, and Cosmetic Act (FDCA). FDA acknowledges that PharMEDium registered all of its facilities with FDA as 503B outsourcing facilities on December 11, 2013.
A. Compounded Drugs Under the FDCA At the time FDA inspected your facility, there were conflicting judicial decisions regarding the applicability of section 503A of the FDCA [21 U.S.C. § 353a], which exempts compounded drugs from several key statutory requirements if certain conditions are met.[1] Nevertheless, receipt of valid prescriptions for individually-identified patients prior to distribution of compounded drugs was relevant for both section 503A of the FDCA and the agency’s Compliance Policy Guide 460.200 (CPG) (2002), which was then in effect.[2] During the FDA inspections, the investigators observed that your firm does not receive valid prescriptions for individually-identified patients for the drug products you produce. Based on this factor alone, those drugs were not entitled to the statutory exemptions for compounded drugs described in section 503A of the FDCA and did not qualify for the agency’s exercise of enforcement discretion set forth in the CPG.[3] Since FDA inspected your facility, Congress enacted and the President signed into law the Compounding Quality
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Act (CQA),[4] which amended FDCA section 503A by eliminating the advertising restrictions that had been the basis for conflicting judicial decisions. The CQA otherwise left section 503A intact, and so clarified that the remainder of section 503A, including the requirement of valid prescriptions for individually-identified patients, is applicable in every federal judicial circuit. The CQA adds a new section 503B to the FDCA [21 U.S.C. § 353b].[5] Under section 503B(b), a compounder can register as an outsourcing facility with FDA.[6] As noted previously, PharMEDium registered all of the facilities referenced in this letter with FDA as section 503B outsourcing facilities on December 11, 2013. Drug products compounded in a registered outsourcing facility can qualify for exemptions from the FDA approval requirements in section 505 of the FDCA [21 U.S.C. § 355(a)] and the requirement to label products with adequate directions for use under section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)] if the requirements in section 503B are met. In addition, prescriptions for individually-identified patients are not required for products produced under section 503B of the FDCA. To qualify for the exemptions under section 503B, the drug products must be compounded in a 503B outsourcing facility that meets all of the conditions set forth in section 503B of the FDCA, which include, but are not limited to, submitting adverse event reports, labeling compounded products with certain information, and compounding drug products by or under the direct supervision of a licensed pharmacist. In addition, outsourcing facilities must comply with other provisions of the FDCA, including the current good manufacturing practice (CGMP) requirements under section 501(a)(2)(B) [21 U.S.C. § 351(a)(2)(B)] and the prohibition on preparing, packing, or holding drugs under insanitary conditions found in section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)]. Generally, CGMP requirements for finished drug products are established in Title 21 of the Code of Federal Regulations (CFR) parts 210 and 211. As discussed further below, PharMEDium does not comply with certain CGMP requirements. It is also noteworthy that this is not the first Warning Letter that FDA has issued to PharMEDium for CGMP violations. FDA issued a Warning Letter on April 13, 2007 noting CGMP violations at two of your facilities.
B. Violations of FDCA
Because the drug products that you manufactured and distributed without valid prescriptions for individually-identified patients were not the subject of approved applications, they are unapproved new drugs in violation of section 505(a) of the FDCA. In addition, because these products were intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions could not be written for them so that a layman could use these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses, causing them to be misbranded under section 502(f)(1) of the FDCA. In addition, your sterile drug products are prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth or rendered injurious to health. As such, all sterile drug products you manufacture are adulterated within the meaning of section 501(a)(2)(A) of the FDCA. Furthermore, because you manufactured and distributed your drugs without valid prescriptions for individually-identified patients, the manufacture of those drugs was also subject to FDA’s CGMP regulations for Finished Pharmaceuticals, Title 21 CFR parts 210 and 211. FDA investigators observed significant CGMP violations at your facility, causing such drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. Because your facilities are now registered as section 503B outsourcing facilities, this letter focuses on the insanitary conditions and violations of CGMP requirements that continue to apply even though you registered your facilities as outsourcing facilities. Insanitary Conditions Observed During FDA’s Inspections Based on the February and March 2013 inspections of your facilities, FDA investigators noted that your sterile drug products were prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth, or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) [21 U.S.C. §351 (a)(2)(A)] of the FDCA. For example, at some of your facilities our investigators observed that:
1. Your firm’s operators did not properly sanitize their hands after touching non-sterile equipment and were observed processing sterile drug products with exposed skin on their faces and while wearing non-sterile masks. Furthermore, we observed operators at one facility re-using gowns throughout the day and during periods of production. 2. Your firm did not perform personnel monitoring of all operators at least daily during periods of production to examine the practices of personnel and assess contamination risk to product by poor practices. 3. Your firm did not demonstrate through appropriate studies that your hoods are able to provide adequate protection of the ISO 5 area in which sterile products are processed. For example, your airflow studies do not consider the full operational conditions of the room, including the fact that your firm has numerous hoods within the clean room and that a single hood is used to support multiple compounding processes that are occurring at the same time.
As noted above, outsourcing facilities, like any other compounder, may not prepare, pack, or hold drugs under insanitary conditions (section 501(a)(2)(A) of the FDCA). CGMP Violations Observed During FDA’s Inspections FDA investigators also noted CGMP violations at your facilities, causing the drug products for which you did not
obtain valid prescriptions for individually-identified patients to be adulterated under section 501(a)(2)(B) of the FDCA . Such violations observed at some of your facilities include, for example:
1. Your firm failed to adequately design the facility with adequate separation or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(b)). 2. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups during the course of certain procedures (21 CFR 211.42(c)). 3. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic processes (21 CFR 211.113(b)). 4. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)). 5. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)). 6. Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)). 7. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)). 8. Your firm did not have, for each batch of drug product purporting to be sterile and/or pyrogen-free, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product (21 CFR 211.167(a)). 9. Your firm did not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).
As noted above, outsourcing facilities must comply with current good manufacturing practice (CGMP) requirements under section 501(a)(2)(B) of the FDCA. On July 1, 2014, FDA issued a draft guidance, Current Good Manufacturing Practice — InterimGuidance for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act. Until final regulations are promulgated, this draft interim guidance describes FDA’s expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211. You should consult the interim guidance for FDA’s expectations regarding the particular provisions in 21 CFR Parts 210 and 211 cited above pending the development of the new regulations. Your attention is directed in particular to the provisions with regard to sterility testing and stability testing, and the establishment of beyond use dates. Corrective Actions In your responses submitted March 18, 2013, March 20, 2013, March 21, 2013, and April 12, 2013, you described certain corrective actions you took in response to the Form FDA 483 observations. You also indicated that you adhere to USP Chapter <797> “Pharmaceutical Compounding – Sterile Preparations” and comply with statutory GMPs. You also acknowledged that companies like yours need to more closely align with the CGMP requirements in 21 CFR 211. Since providing these responses, you registered your four facilities as outsourcing facilities, and are subject to CGMP requirements under the new law. In addition, you remain subject to section 501(a)(2)(A)) of the FDCA. Although several of your proposed corrective actions appear adequate, others are deficient. In your response to our observation of inadequate media fills, you indicated that you have made procedural changes to include an additional step that represents the continuous processes of pooling, subassembly, and finished container filling as well as packaging. You also stated that you performed a growth promotion study. These corrections will improve your knowledge of your process, but will not provide sufficient information to assess the risk in the clean room to product sterility assurance since your procedures still require media fills to be performed in an area physically segregated from production. In your response to our observation of inadequate air flow studies, you indicated that you will require documentation of various items such as the equipment, the equipment placement, presence of separator panels that allow for two operations to occur within the same hood, and location of personnel that are present during dynamic air flow studies. Because you have sterile compounding activities occurring simultaneously in up to (b)(4) hoods in some of your firm’s clean rooms, and at times use a single hood to support multiple compounding processes at the same time, your air flow studies should also account for these activities. In your response to our observation of inadequate gowning of operators during production, you indicated that sterile gowning is not a USP <797> requirement, but that you procedurally require operators to wear sterile gowns. Your response is inadequate because your procedure continues to allow operators to have exposed skin and use non-sterile facemasks, and you did not address training that may be required to ensure employees are properly gowned. Furthermore, the procedure still allows for gowning to be reused throughout the day which poses an unacceptable risk of contamination to products. In your response to our observation of poor aseptic practices, you committed to making procedural changes to prohibit operators from leaning into hoods and enhanced the procedure for component transfers into the
hood. This is inadequate to address the fundamental lack of proper aseptic behaviors that was observed and the disregard for written procedures. Your firm’s planned corrections do not meet the minimum requirements of 21 CFR parts 210 and 211, and there is no assurance that the drug products produced by your firm conform to the basic quality standards that ensure safety, identity, strength, quality, and purity. FDA strongly recommends that your management immediately undertake a comprehensive assessment of your operations corporate-wide, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess your aseptic processing operations and design. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation. Conclusion The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facilities. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations. 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. Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps you have taken to correct violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you do not believe that the products discussed above are in violation of the FDCA, include your reasoning and any supporting information for our consideration. If the corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time frame within which the corrections will be completed. Your written notification should be addressed to:
Carrie Ann Plucinski, Compliance OfficerFood and Drug Administration550 W. Jackson Blvd. Suite 1500Chicago, IL 60661
If you have questions regarding any issues in this letter, please contact Ms. Plucinski at 312-596-4224 or via email at [email protected]. Sincerely,/S/ Scott J. MacIntireDistrict Director cc: Dr. Yashwant Amin Director of Drug Compliance Illinois Department of Financial and Professional Regulation 9511 Harrison Street Des Plaines, IL 60017 Mississippi Board of Pharmacy 6360 I-55 North, Suite 400 Jackson, MS 39211 Anthony Rubinaccio, RPh, Executive Director New Jersey Board of Pharmacy P.O. Box 45013 Newark, NJ 07101 Tennessee Department of Health Health Related Boards Tennessee Board of Pharmacy 665 Mainstream Drive Nashville, TN 37243 Gay Dodson, RPh, Executive Director Texas State Board of Pharmacy William P. Hobby Building Tower 3, Suite 600 333 Guadalupe Street Austin, TX 78701
[1] Compare Western States Med. Ctr. v. Shalala, 238 F.3d 1090 (9th Cir. 2001) with Medical Ctr. Pharm. v. Mukasey, 536 F.3d 383 (5th Cir. 2008).
[2] The CPG set forth a non-exhaustive list of factors that FDA considered in determining whether to take enforcement action when the scope and nature of a pharmacy's activities raised concerns. This CPG has been withdrawn in light of new legislation. See below.[3] See 21 U.S.C. § 353a(a) (granting compounded drugs statutory exemptions if, among other things, “the drug product is compounded for an identified individual patient based on the . . . receipt of a valid prescription order or a notation, approved by the prescribing practitioner, on the prescription order that a compounded product is necessary for the identified patient . . . .”); CPG at 2 (“FDA recognizes that pharmacists traditionally have extemporaneously compounded and manipulated reasonable quantities of human drugs upon receipt of a valid prescription for an individually-identified patient from a licensed practitioner. This traditional activity is not the subject of this guidance.”).[4] Drug Quality and Security Act, Public Law 113-54, 127 Stat. 587 (Nov. 27, 2013).[5] See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).[6] See Draft Guidance for Industry, “Registration for Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” (December, 2013).
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Home Inspections, Compliance, Enforcement, and Criminal Investigations Compliance Actions and Activities Warning Letters2014
Inspections, Compliance, Enforcement, and Criminal Investigations
Oakdell Pharmacy, Inc 5/27/14
Department of Health and Human ServicesPublic Health ServiceFood and Drug Administration
Dallas District4040 North Central ExpresswayDallas, Texas 75204-3128
May 27, 2014 2014-DAL-WL-04
WARNING LETTER UPS OVERNIGHT
John R. Carson, President and CEOOakdell Pharmacy, Inc.7220 Louis Pasteur Drive, Suite 176San Antonio, TX 78229 Dear Mr. Carson: From February 25 to March 1, 2013, U.S. Food and Drug Administration (FDA) investigators conducted inspections of your facility known as Oakdell Pharmacy, Inc., located at 7220 Louis Pasteur Drive, Suite 176, San Antonio, TX 78229. FDA conducted a limited follow up inspection from January 6 to January 14, 2014, focusing on whether you were obtaining prescriptions for your compounded products and whether you were engaging in interstate distribution. During the inspections, the investigators noted that you were not receiving valid prescriptions for individually-identified patients for a portion of drug products you were producing. In addition, the investigators observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk. For example, our inspection found that your firm’s “ISO 5” workbenches are constructed from particleboard with a laminated surface. The laminated surface is porous and difficult to clean, and can harbor contamination. In addition, we observed a technician wearing a non-sterile laboratory coat, with exposed skin (forehead and neck), and resting his elbows on the bench top of the “ISO 5” workbench while performing aseptic processing of ophthalmic drops. These observations and others were noted on a Form FDA 483 issued on March 1, 2013. No 483 was issued at the end of the follow-up inspection in January 2014. Based on these inspections, it appears that you are producing drugs that violate the Federal Food, Drug, and Cosmetic Act (FDCA). A. Compounded Drugs Under the FDCA Section 503A of the FDCA exempts compounded drugs from several key statutory requirements if certain conditions are met, including receipt of valid prescriptions for individually-identified patients prior to distribution of compounded drugs.[1] During the FDA inspections, investigators observed that your firm does not receive valid prescriptions for individually-identified patients for a portion of the drug products you produce. Based on this factor alone, those drugs were not entitled to the statutory exemptions for compounded drugs described in section 503A of the FDCA.[2] Since FDA first inspected your facility, Congress enacted and the President signed into law the Compounding Quality Act (CQA) , which amended FDCA section 503A by eliminating the advertising restrictions that had been the basis for conflicting judicial decisions. The CQA otherwise left section 503A intact, and so clarified that the remainder of section 503A, including the requirement of valid prescriptions for individually-identified patients, is applicable in every federal judicial circuit. Accordingly, the drugs you compound without valid prescriptions for individually-identified patients are not entitled to the exemptions in section 503A.[4] In addition, we remind you that there are a number of other conditions that must be satisfied to qualify for the
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exemptions in section 503A of the FDCA.[5] B. Violations of the FDCA The drug products that you manufacture and distribute without valid prescriptions for individually-identified patients are misbranded drugs in violation of section 502(f)(1) [21 U.S.C. § 352(f)(1)] of the FDCA. In addition, your sterile drug products are prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth, or whereby they may have been rendered injurious to health. As such, all sterile products you manufacture are adulterated within the meaning of section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)] of the FDCA. Furthermore, because you manufacture and distribute drugs without valid prescriptions for individually-identified patients, the manufacture of those drugs is also subject to FDA’s Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211. FDA investigators observed significant CGMP violations at your facility, causing such drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. Misbranded Drug Products Because the drug products for which you have not obtained valid prescriptions for individually-identified patients are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written for them so that a layman can use these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses, causing them to be misbranded under section 502(f)(1) of the FDCA, and they are not exempt from the requirements of section 502(f)(1) of the FDCA (see, e.g., 21 CFR 201.115). It is a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being misbranded. Adulteration Charges Additionally, FDA investigators noted that your sterile drug products were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA. Examples of these conditions include that your firm’s “ISO 5” workbenches are constructed from particleboard with a laminated surface. The laminated surface is porous and difficult to clean, and can harbor contamination. In addition, we observed a technician wearing a non-sterile laboratory coat, with exposed skin (forehead and neck), and resting his elbows on the bench top of the “ISO 5” workbench while performing aseptic processing of ophthalmic drops. FDA investigators also noted CGMP violations at your facility, causing the drug products for which you have not obtained valid prescriptions for individually-identified patients to be adulterated under section 501(a)(2)(B) of the FDCA. The violations include, for example:
1. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug products from contamination [21 CFR 211.28(a)].
2. Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic
conditions [21 CFR 211.42(c)(10)(vi)].
3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas [21 CFR 211.42(c)(10)(iv)].
4. Your firm failed to establish and follow appropriate written procedures that are designed to prevent
microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes [21 CFR 211.113(b)].
5. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to
produce aseptic conditions [21 CFR 211.42(c)(10)(v)].
6. Your firm failed to ensure that its drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).
It is a prohibited act under section 301(k) of the FDCA to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being adulterated. C. Corrective Actions In your April 11, 2013 response the Form FDA 483, you reference your purported compliance with United States Pharmacopeia (USP)-National Formulary (NF) General Chapter <797> Pharmaceutical Compounding-- Sterile Preparations. As noted above, your firm has manufactured and distributed a portion of drugs without valid prescriptions for individually-identified patients, and the manufacture of such drugs is subject to FDA’s drug CGMP regulations (21 CFR Parts 210 and 211). In addition, your firm indicates plans to address our inspectional findings with corrective actions. Your firm's planned corrections do not meet the minimum requirements of 21 CFR Part 211, and there is no assurance that the drug product(s) produced by your firm without valid prescriptions for individually-identified patients conform to the basic quality standards that ensure safety, identity, strength, quality, and purity. FDA strongly recommends your management immediately undertake a comprehensive assessment of your operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess your aseptic processing operations. A third party consultant with relevant sterile drug
manufacturing expertise could be useful in conducting this comprehensive evaluation. You should fully implement corrections that meet the minimum requirements of 21 CFR Part 211 in order to provide assurance that the drug product(s) produced by your firm conform to the basic quality standards that ensure safety, identity, strength, quality, and purity. In addition, you should correct the violations of FDCA section 502(f)(1) noted above. D. Conclusion The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law and FDA regulations. 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. 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 violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you do not believe that the products discussed above are in violation of the FDCA, include your reasoning and any supporting information for our consideration. If the corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time frame within which the corrections will be implemented. Your notification should be addressed to:
Rose Ashley, Compliance OfficerFDA Dallas District OfficeU.S. Food and Drug Administration4040 North Central ExpresswaySuite 300Dallas, TX 75204-3158
If you have questions regarding any issues in this letter, please contact our office at 210-308-1407. Sincerely,/S/Reynaldo Rodriguez, Jr.Dallas District Director
[1] While there were conflicting judicial decisions regarding the applicability of section 503A at the time FDA first inspected your facility, your firm resided in the Fifth Circuit where section 503A of the FDCA applied. Compare Western States Med. Ctr. v. Shalala, 238 F.3d 1090 (9th Cir. 2001); with Medical Ctr. Pharm. v. Mukasey, 536 F.3d 383 (5th Cir. 2008). [2] See 21 U.S.C. § 353a(a) (granting compounded drugs statutory exemptions if, among other things, “the drug product is compounded for an identified individual patient based on the . . . receipt of a valid prescription order or a notation, approved by the prescribing practitioner, on the prescription order that a compounded product is necessary for the identified patient . . . .”).[3]Drug Quality and Security Act, Public Law 113-54, 127 Stat. 587 (Nov. 27, 2013).[4]The CQA contains a number of other provisions, including new exemptions and requirements for compounders seeking to operate as outsourcing facilities. A discussion of the CQA and the agency’s plans to implement the new law may be found at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/default.htm.[5] For example, section 503A also addresses anticipatory compounding, which includes compounding (not distribution) before receipt of a valid prescription order for an individual patient. We are not addressing anticipatory compounding here.
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Home Inspections, Compliance, Enforcement, and Criminal Investigations Compliance Actions and Activities Warning Letters2014
Inspections, Compliance, Enforcement, and Criminal Investigations
Home Intensive Care Pharmacy, Inc. 1/22/14
Department of Health and Human ServicesPublic Health ServiceFood and Drug Administration
Dallas District4040 North Central ExpresswaySuite 300Dallas, TX 75204-3158
January 22, 2014
Ref. 2014-DAL-WL-02
WARNING LETTER John R. Carson, President and CEOHome Intensive Care Pharmacy, LLC7220 Louis Pasteur Drive, Suite 168San Antonio, TX 78229 Dear Mr. Carson: From February 25 to March 1, 2013, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility known as Home Intensive Care Pharmacy, Inc., located at 7220 Louis Pasteur Drive, Suite 168, San Antonio, TX 78229. During the inspection, the investigators noted that you were not receiving valid prescriptions for individually-identified patients for a portion of drug products you were producing. In addition, the investigators observed significant deficiencies regarding the poor aseptic processing area design and unacceptable aseptic practices, which place sterile products at considerable risk of microbial contamination. For example, our inspection found that your firm’s “ISO 5” workbenches are constructed from particleboard with a laminated surface. The laminated surface is porous and difficult to clean, and can harbor contamination. In addition, we observed a technician wearing a non-sterile laboratory coat and resting his elbows on the bench top of the “ISO 5” workbench with exposed skin from his forearm while performing aseptic processing of an intrathecal medication. These observations and others were noted on a Form FDA 483 issued on March 1, 2013. Based on this inspection, it appears that you are producing drugs that violate the Federal Food, Drug, and Cosmetic Act (FDCA). A. Compounded Drugs Under the FDCA Section 503A of the FDCA exempts compounded drugs from several key statutory requirements if certain conditions are met, including receipt of valid prescriptions for individually-identified patients prior to distribution of compounded drugs.[1] During the FDA inspection, investigators observed that your firm does not receive valid prescriptions for individually-identified patients for a portion of the drug products you produce. Based on this factor alone, those drugs were not entitled to the statutory exemptions for compounded drugs described in section 503A of the FDCA.[2] Since FDA inspected your facility, Congress enacted and the President signed into law the Compounding Quality Act (CQA) , which amended FDCA section 503A by eliminating the advertising restrictions that had been the basis for conflicting judicial decisions. The CQA otherwise left section 503A intact, and so clarified that the remainder of section 503A, including the requirement of valid prescriptions for individually-identified patients, is applicable in every federal judicial circuit. Accordingly, the drugs you compound without valid prescriptions for individually-identified patients are not entitled to the exemptions in section 503A.[4] In addition, we remind you that there are a number of other conditions that must be satisfied to qualify for the exemptions in section 503A of the FDCA.[5]
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B. Violations of the FDCA The drug products that you manufacture and distribute without valid prescriptions for individually-identified patients are misbranded drugs in violation of section 502(f)(1) [21 U.S.C. § 352(f)(1)] of the FDCA. In addition, your sterile drug products are prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth, or whereby they may have been rendered injurious to health. As such, all sterile products you manufacture are adulterated within the meaning of section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)] of the FDCA. Furthermore, because you manufacture and distribute drugs without valid prescriptions for individually-identified patients, the manufacture of those drugs is also subject to FDA’s Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211. FDA investigators observed significant CGMP violations at your facility, causing such drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA [21 U.S.C. § 351(a)(2)(B)]. Misbranded Drug Products Because the drug products for which you have not obtained valid prescriptions for individually-identified patients are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written for them so that a layman can use these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses, causing them to be misbranded under section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)], and they are not exempt from the requirements of section 502(f)(1) of the FDCA (see, e.g., 21 C.F.R. § 201.115). It is a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being misbranded. Adulteration Charges Additionally, FDA investigators noted that your sterile drug products were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA [21 U.S.C. § 351(a)(2)(A)]. The conditions include that your firm’s “ISO 5” workbenches are constructed from particleboard with a laminated surface. The laminated surface is porous and difficult to clean, and can harbor contamination. In addition, we observed a technician wearing a non-sterile laboratory coat and resting his elbows on the bench top of the “ISO 5” workbench with exposed skin from his forearm while performing aseptic processing of an intrathecal medication. FDA investigators also noted CGMP violations at your facility, causing the drug products for which you have not obtained valid prescriptions for individually-identified patients to be adulterated under section 501(a)(2)(B) of the FDCA [21 U.S.C. § 351(a)(2)(B)]. The violations include, for example: CGMP violations
1. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug products from contamination [21 CFR 211.28(a)].
2. Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic
conditions [21 CFR 211.42(c)(10)(vi)].
3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas [21 CFR 211.42(c)(10)(iv)].
4. Your firm failed to establish and follow appropriate written procedures that are designed to prevent
microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes [21 CFR 211.113(b)].
5. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to
product aseptic conditions [21 CFR 211.42(c)(10)(v)]. It is a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being adulterated. C. Conclusion The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law and FDA regulations. 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. In your response to the Form FDA 483, your firm indicates plans to address our inspectional findings with corrective actions. Your firm's planned corrections do not meet the minimum requirements of 21 CFR part 211, and there is no assurance that the drug product(s) produced by your firm without valid prescriptions for individually-identified patients conform to the basic quality standards that ensure safety, identity, strength, quality, and purity. FDA strongly recommends that your management undertake a comprehensive assessment
of your manufacturing operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess the acceptability of your aseptic processing operations. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation. 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 violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If the corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time frame within which the corrections will be implemented. Your notification should be addressed to:
Rose Ashley, Compliance OfficerFDA Dallas District OfficeU.S. Food and Drug Administration4040 North Central ExpresswaySuite 300Dallas, TX 75204-3158
If you have questions regarding any issues in this letter, please contact Mrs. Ashley at 210-308-1407. Sincerely,/S/Reynaldo R. Rodriguez, Jr.Dallas District Director
[1] In your response to the 483, you stated that your firm’s produced drugs fell within the exercise of enforcement discretion set forth in Compliance Policy Guide 460.200 on Pharmacy Compounding (CPG) (2002). While there were conflicting judicial decisions regarding the applicability of section 503A at the time FDA inspected your facility, your firm resided in the Fifth Circuit where section 503A of the FDCA applied. Compare Western States Med. Ctr. v. Shalala, 238 F.3d 1090 (9th Cir. 2001); with Medical Ctr. Pharm. v. Mukasey, 536 F.3d 383 (5th Cir. 2008). Even if the CPG applied, your firm would not have qualified for the exercise of enforcement discretion set forth in the CPG because it did not receive valid prescriptions for individually-identified patients for a portion of the drug products it produces. We also note that the CPG has been withdrawn in light of new legislation. See below.[2] See 21 U.S.C. § 353a(a) (granting compounded drugs statutory exemptions if, among other things, “the drug product is compounded for an identified individual patient based on the . . . receipt of a valid prescription order or a notation, approved by the prescribing practitioner, on the prescription order that a compounded product is necessary for the identified patient . . . .”).[3]Drug Quality and Security Act, Public Law 113-54, 127 Stat. 587 (Nov. 27, 2013).[4]The CQA contains a number of other provisions, including new exemptions and requirements for compounders seeking to operate as outsourcing facilities. A discussion of the CQA and the agency’s plans to implement the new law may be found at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/default.htm.[5] For example, section 503A also addresses anticipatory compounding, which includes compounding (not distribution) before receipt of a valid prescription order for an individual patient. We are not addressing anticipatory compounding here.
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July 14, 2014 Raymond R. Carlson, OwnerRC Compounding Services, LLC3030 Center RoadPoland, OH 44514 Dear Mr. Carlson: Between February 5, 2013, to February 7, 2013, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, RC Compounding Services, LLC, located at 3030 Center Road, Poland, Ohio 44514. During the inspection, the investigator(s) identified serious deficiencies in your practices for producing sterile drug products which put patients at risk. For example, we observed that your firm performs aseptic processing in a room that has a wall mounted air conditioning unit and your firm does not have an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions. Further, because your firm uses gowns that are not sterile, your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug products from contamination. During the inspection, our investigators observed that you were repackaging Avastin for ophthalmic use under conditions not appropriate for ensuring the sterility of the product. An FDA Form 483 was issued to your firm on February 7, 2013. You failed to provide a response to the observations noted in the Form FDA-483. We acknowledge your written statement of February 6, 2013, that you wish to rescind your FDA registration as a repackager. FDA also acknowledges that RC Compounding registered its facility with FDA as a 503B outsourcing facility on February 12, 2014. A. Adulteration Charges Under section 501(a)(2)(A) of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 351(a)(2)(A)], a drug is adulterated if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth or rendered injurious to health. Numerous subvisible microorganisms and other contaminants are ubiquitous in an ordinary environment. A firm producing sterile products must take certain steps in order to ensure removal of contaminants through various controls that focus on safeguarding sterility by assuring the quality of the processing environment (e.g., surfaces, personnel, air) and the materials that go into a drug product. Otherwise, products that are intended or expected to be sterile may become contaminated during preparation and, when administered to a patient, may result in infections and/or pyrogenic responses that pose a life-threatening health risk to a patient. Failure to take these steps when producing drugs that are intended or expected to be sterile causes the drug to be prepared, packed, or held under insanitary conditions. FDA investigators observed that your drug products that were intended or expected to be sterile were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered
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injurious to health, causing these drug products to be adulterated under section 501(a)(2)(A) of the FDCA [21 U.S.C. § 351(a)(2)(A)]. During FDA’s inspection of your firm, the investigators observed poor aseptic practices on the part of your firm’s personnel. For example, the investigator observed that your firm performs aseptic processing in a room that has a wall mounted air conditioning unit and your firm does not have an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions. Further, because your firm uses gowns that are not sterile, your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug products from contamination. During the inspection, our investigators observed that you were repackaging Avastin for ophthalmic use under conditions not appropriate for ensuring the sterility of the product. The introduction or delivery for introduction into interstate commerce of your adulterated products, is a prohibited act under section 301(a) of the FDCA [21 U.S.C. § 331(a)]. It is also a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being adulterated. B. Corrective Action FDA strongly recommends that your management immediately undertake a comprehensive assessment of your manufacturing operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess your aseptic processing operations and design. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation. C. Conclusion The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facility. You are responsible for investigating and determining the causes of the insanitary conditions identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA regulations. 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. 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 violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you do not believe that the products discussed above are in violation of the FDCA, include your reasoning and any supporting information for our consideration. If the corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time frame within which the corrections will be implemented. Your written notification should be addressed to: Stephen J. Rabe, Compliance OfficerFDA Cincinnati District OfficeU.S. Food and Drug Administration6751 Steger DriveCincinnati, OH 45237-3097 If you have questions regarding any issues in this letter, please contact our office at 513-679-2700 ext. 2163. Sincerely,/S/Paul J. TeitellDistrict DirectorCincinnati District
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Home Inspections, Compliance, Enforcement, and Criminal Investigations Compliance Actions and Activities Warning Letters2014
Inspections, Compliance, Enforcement, and Criminal Investigations
Pharmacy Creations 6/23/14
Department of Health and Human ServicesPublic Health ServiceFood and Drug Administration
New Jersey District OfficeCentral RegionWaterview Corporate Center10 Waterview Blvd. 3rd FloorParsippany, New Jersey 07054Telephone: (973) 331-4900FAX: (973) 331-4969
WARNING LETTER June 23, 2014 VIA UNITED PARCEL SERVICE
14-NWJ-09 Scott Karolchyk, R.Ph., MS, Pharmacist-in-Charge and Co-ownerBernard Covalesky, R.Ph, Co-ownerPharmacy Creations540 Route 10 WestRandolph, NJ 07869 Dear Mr. Karolchyk and Mr. Covalesky: From August 5, 2013 to August 19, 2013, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, Pharmacy Creations, located at 540 Route 10 West, Randolph, NJ 07869. During the inspection, the investigators noted that you were not receiving valid prescriptions for individually identified patients for a portion of the drug products you were producing. It was also noted that your firm continues to make domperidone drug products, despite having received prior warnings regarding this practice in a Warning Letter issued on October 31, 2006, and in a meeting with FDA on June 11, 2008. Domperidone is not the subject of an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph, nor is it a component of an FDA-approved human drug product, nor does it appear on a list developed by the Secretary under section 503A(b)(1)(A)(i)(III) of the Federal Food Drug, and Cosmetic Act (FDCA) [21 U.S.C.§353a]. In addition, the investigators observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk. For example, your firm produces sterile injectable drug products in multiple-dose containers without a preservative added to the formulations. There is a significant risk that your formulation is unsuitable formultiple uses, and will present an increased risk of infection to patients. In addition, your firm produces lyophilized epinephrine (b)(4). Your firm has failed to demonstrate that the process does not place product at risk of microbial contamination and is capable of producing product of a consistent potency. These observations and others were noted on a Form FDA 483, issued on August 19, 2013. Based on this inspection, it appears that you are producing drugs that violate the Federal Food, Drug, and Cosmetic Act (FDCA). A. Compounded Drugs Under the FDCA At the time FDA inspected your facility, there were conflicting judicial decisions regarding the applicability of section 503A of the FDCA [21 U.S.C. § 353a], which exempts compounded drugs from several key statutory requirements if certain conditions are met.1 Nevertheless, receipt of valid prescriptions for individually-identified patients prior to distribution of compounded drugs was relevant for both section 503A of the FDCA and the agency's Compliance Policy Guide 460.200 on Pharmacy Compounding (CPG) (2002), which was then in
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effect.2 During the FDA inspection, investigators observed that your firm does not receive valid prescriptions for individually-identified patients for a portion of the drug products you produce. Based on this factor alone, those drugs were not entitled to the statutory exemptions for compounded drugs described in section 503A of the FDCA and did not qualify for the agency's exercise of enforcement discretion set forth in the CPG.3 In addition, under the CPG, when determining whether to initiate enforcement action, FDA considered whether a firm compounded finished drugs from bulk active ingredients that were not components of FDA-approved drugs without an FDA sanctioned investigational new drug application. Because domperidone was not a component of an FDA-approved human drug, your compounded drugs containing domperidone would not qualify for the exercise of enforcement discretion set forth in the CPG. Further, the exemptions provided by section 503A(a) did not apply to compounded drug products containing domperidone because domperidone was not the subject of an applicable USP or NF monograph, was not a component of an FDA-approved human drug under section 503A(b)(1)(A)(i) of the FDCA, and did not appear on a list developed by the Secretary under 503A(b)(1)(A)(i)(III). Since FDA inspected your facility, Congress enacted and the President signed into law the Compounding Quality Act (CQA)4, which amended FDCA section 503A by eliminating the advertising restrictions that had been the basis for conflicting judicial decisions. The CQA otherwise left section 503A intact, and so clarified that the remainder of section 503A is applicable in every federal judicial circuit, including the requirement for valid prescriptions for individually identified patients, and the requirement to only compound drug products using bulk drug substances if each bulk drug substance is the subject of an applicable USP or NF monograph, is a component of an FDA-approved human drug, or appears on a list developed by the Secretary under section 503A(b)(l)(A)(i)(III). Accordingly, the drugs you compound without valid prescriptions for individually-identified patients and any drug products you compound using domperidone, which is not the subject of an applicable USP or NF monograph, not a component of an FDA-approved human drug, and did not appear on a list developed by the Secretary under section 503A(b)(1)(A)(i)(III), are not entitled to the exemptions in section 503A.5 In addition, we remind you that there are a number of other conditions that must be satisfied to qualify for the exemptions in section 503A of the FDCA.6 B. Violations of the FDCA Because both the domperidone drug products and the drug products that you manufacture and distribute without valid prescriptions for individually-identified patients are not the subject of approved applications, they are unapproved new drugs and misbranded drugs in violation of sections 505(a) and 502(f)(1) [21 U.S.C. § 355(a) and 352(f)(1)] of the FDCA, respectively. In addition, the manufacture of those drug products is also subject to FDA's Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211. FDA investigators observed significant CGMP violations at your facility, causing such drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA [21 U.S.C. § 351(a)(2)(B)]. Unapproved New Drug Products You do not have any FDA-approved applications on file for the drug products for which you have not obtained valid prescriptions for individually-identified patients.7 Additionally, you produce domperidone drug products that are not the subject of an applicable USP or NF monograph, are not a component of an FDA-approved drug under section 503A(b)(1)(A)(i) of the FDCA, and do not appear on a list developed by the Secretary under 503A(b)(1)(A)(i)(III).7 Under sections 301(d) and 505(a) of the FDCA [21 U.S.C. §§ 331(d) and 355(a)], a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FDCA [21 U.S.C. § 355) is in effect for the drug. Your marketing of these products, or other applicable products without an approved application violates these provisions of the FDCA. Misbranded Drug Products Because the domperidone drug products and the drug products for which you have not obtained valid prescriptions for individually-identified patients are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written for them so that a layman can use these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses, causing them to be misbranded under section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)], and they are not exempt from the requirements of section 502(f)(1) of the FDCA [see, e.g., 21 CFR §201.115]. The introduction or delivery for introduction into interstate commerce of these products therefore violates sections 301(a) of the FDCA [21 U.S.C. §331(a)]. It is also a prohibited act under section 301(k) of the FDCA [21 U.S.C.§ 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being misbranded. Adulteration Charges FDA investigators also noted CGMP violations at your facility, causing the drug products for which you have not obtained valid prescriptions for individually-identified patients to be adulterated under section 501(a)(2)(B) of the FDCA [21 U.S.C. § 351(a)(2)(B)]. The violations include, for example:
1. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and also failed to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).
2. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)). 3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)). 4. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). 5. Your firm failed to clean and, where indicated by the nature of the drug, sterilize and process container closures to remove pyrogenic properties to assure they are suitable for their intended use (21 CFR 211.94(c)). 6. Your firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(2)) and your firm failed to subject each lot of a component that is liable to microbiological contamination that is objectionable in view of its intended use to microbiological tests before use (21 CFR 211.84(d)(6)). 7. Your firm did not conduct, for each batch of drug product purporting to be sterile and/or pyrogen-free, appropriate laboratory testing to determine whether each batch was sterile or pyrogen-free (21 CFR 211.167(a)). 8. Your firm did not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).
Items 4, 6, 7, and 8 are based on repeat observations from the warning letter dated October 31, 2006. Under section 301(a) of the FDCA [21 U.S.C. § 331(a)] the introduction or delivery for introduction into interstate commerce of any drug that is adulterated is a prohibited act. Further, it is a prohibited act under section 301(k) of the FDCA [21 U.S.C. §331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being adulterated. C. Corrective Actions In your response dated September 3, 2013, to the Form FDA-483, you reference your purported compliance with United States Pharmacopeia (USP)-National Formulary (NF) General Chapter <797> Pharmaceutical Compounding -- Sterile Preparations. However, as discussed above, your firm has manufactured and distributed drug products without valid prescriptions for individually identified patients, and the manufacture of such drugs is subject to FDA's drug CGMP regulations (21 CFR Parts 210 and 211). Furthermore, on August 26, 2013, you recalled two lots of products as a result of sterility failures. FDA strongly recommends that your management immediately undertake a comprehensive assessment of your operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assessyour aseptic processing operations and design. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conductingthis comprehensive evaluation. Your firm's planned corrections do not meet the minimum requirements of 21 CFR Part 211,and there is no assurance that such human drug product(s) produced by your firm conform to the basic quality standards that ensure safety, identity, strength, quality, and purity. In addition to the issues discussed above, you should note that CGMP requires the implementation of quality oversight and controls over the manufacture of drugs, including the safety of raw materials, materials used in drug manufacturing, and finished drug products. See FDCA, as amended by the Food and Drug Administration Safety and Innovation Act (Pub.L. 112-144, Title VII, section 711). We note that you have chosen to hire contract testing laboratories to perform some of the required testing of your finished drug products. FDA inspected these laboratories in 2012 and 2013 and observed deficiencies in their practices. If you choose to contract with a laboratory to perform some functions required by CGMP, it is essential that you select a qualified contractor and that you maintain sufficient oversight of the contractor's operations to ensure that it is fully CGMP compliant. Regardless of whether you rely on a contract facility, you are responsible for assuring that drugs you introduce into interstate commerce are neither adulterated nor misbranded. See 21 CFR 210.1(b), 21 CFR 200.10(b). In addition, you should also correct the violations of FDCA section 505(a) and 502(f)(1) noted above. D. Conclusion The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law and FDA regulations. 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. 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 violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you do not believe that the products
discussed above are in violation of the FDCA, include your reasoning and any supporting information for our consideration. If you cannot complete corrective action within15 working days, state the reason for the delay and the time frame within which you will complete the correction. Your written notification should be addressed to:
Erin McCaffery, Compliance OfficerFDA New Jersey District OfficeU.S. Food and Drug AdministrationWaterview Corporate Center10 Waterview Blvd, 3rd FloorParsippany, NJ 07054
If you have questions regarding any issues in this letter, please contact our office at 973-331-4993. Sincerely,/S/Diana Amador ToroDistrict Director ___________________________________________________ 1 Compare Western States Med. Ctr. v. Shalala, 238 F.3d 1090 (9th Cir. 2001) with Medical Ctr. Pharm. v. Mukasey, 536 F.3d 383 (5th Cir. 2008).2 The CPG set forth a non-exhaustive list of factors that FDA considered in determining whether to take enforcement action when the scope and nature of a pharmacy's activities raised concerns. This CPG has been withdrawn in light of new legislation. See below.3 See 21 U.S.C. § 353a(a) (granting compounded drugs statutoryexemptionsif, among other things,"the drug product is compounded for an identified individual patient based on the...receipt of a valid prescription order or a notation, approved by the prescribing practitioner, on the prescription order that a compounded product is necessary for the identified patient...."); CPG at 2 ("FDA recognizes that pharmacists traditionally have extemporaneously compounded and manipulated reasonable quantities of human drugs upon receipt of a valid prescription for an individually-identified patient from a licensed practitioner. This traditional activity is not the subject of this guidance.").4 Drug Quality and Security Act, Public Law 113-54, 127 Stat. 587 (Nov. 27, 2013).5 The CQA contains a number of other provisions, including new exemptions and requirements for compounders seeking to operate as outsourcing facilities. A discussion of the CQA and the agency's plans to implement the new law may be found at http://www.fda.gov/Drugs/GuidanceComplianceRegulatorylnformation/PharmacyCompounding/default.htm6 For example, section 503A also addresses anticipatory compounding, which includes compounding (not distribution) before receipt of a valid prescription order for an individual patient. We are not addressing anticipatory compounding here.7 The specific products made by your firm are drugs within the meaning of section 201(g) of the Act, [21 U.S.C. § 321(g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases. Further, they are "new drugs" within the meaning of section 201(p) of the FDCA [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses.
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Home Inspections, Compliance, Enforcement, and Criminal Investigations Compliance Actions and Activities Warning Letters2014
Inspections, Compliance, Enforcement, and Criminal Investigations
JCB Labs LLC 7/7/14
Department of Health and Human ServicesPublic Health ServiceFood and Drug Administration
Kansas City DistrictSouthwest Region8050 Marshall Drive, Suite 205Lenexa, Kansas 66214-1524 Telephone: (913) 495-5100
July 7, 2014
WARNING LETTER UNITED PARCEL SERVICESIGNATURE REQUIRED CMS # 410466 Brian D. WilliamsonPresident and CEOJCB Labs, LLC7335 West 33 Street NorthWichita, KS 67205 Dear Mr. Williamson: Between February 12, 2013, to February 27, 2013, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, JCB Labs, LLC, located at 7335 West 33 Street North, in Wichita, Kansas 67205. FDA inspected your firm after receiving reports of adverse events in patients who were administered Propoven (propofol) 1% that your facility repackaged from 100 mL vials into 10 mL syringes. During FDA’s inspection, investigators observed serious deficiencies in your practices for producing sterile drug products, which could lead to contamination of the products, putting patients at risk. For example, your SOP 3.030, “Cleaning and Maintenance of the Clean Room Facility,” which includes instructions for the cleaning of the ISO-5 areas, specifies the use of disinfectants that are non-sterile and does not specify the use of sterile cleaning pads and towels or sporicidal agents. In addition, we documented that your firm does not repackage or store propofol injectable infusion properly. Propofol is unstable in oxygen and must be preserved under an inert atmosphere. These observations and others were noted on a Form FDA 483 issued on February 27, 2013. We note that on January 21, 2014, JCB Labs registered its facility with FDA as a section 503B outsourcing facility. A. Adulteration Charges Under section 501(a)(2)(A) of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 351(a)(2)(A)], a drug is adulterated if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth or rendered injurious to health. Numerous sub-visible microorganisms and other contaminants are ubiquitous in an ordinary environment. A firm producing sterile drugs must take certain steps in order to ensure removal of contaminants through
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various controls that focus on safeguarding drug sterility by assuring the quality of the processing environment (e.g., surfaces, personnel, air). Otherwise, drugs that are intended or expected to be sterile may become contaminated during preparation and, when administered to a patient, may result in infections and/or pyrogenic responses that pose a life-threatening health risk to a patient. Failure to take these steps when producing drugs that are intended or expected to be to be sterile causes the drug to be prepared, packed, or held under insanitary conditions. FDA investigators noted that your drug products that were intended or expected to be sterile were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA [21 U.S.C. § 351(a)(2)(A)]. For example, your firm failed to use sterile disinfectants, sterile cleaning pads and towels, or a sporicidal agent to disinfect the clean room and the ISO-5 area. The introduction or delivery for introduction into interstate commerce of any adulterated drug is a prohibited act under section 301(a) of the FDCA [21 U.S.C. § 331(a)]. It is also a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being adulterated. B. Misbranding Charges During the inspection, FDA investigators found that your firm does not package propofol in tight containers under an atmosphere of inert gas, which is the standard for packaging and storage of propofol established in the monograph by the United States Pharmacopeia (USP). As noted on the Form FDA 483 issued to your firm, you deviated from your established process during the repackaging of propofol 1% by venting the source vial to the pharmacy atmosphere without adequately determining what effects this has on finished drug product quality attributes. Under section 502(g) of the FDCA [21 U.S.C § 352(g)], a drug is misbranded if it purports to be a drug the name of which is recognized in an official compendium, unless it is packaged and labeled as prescribed therein. The propofol 1% repackaged by your firm is not packaged and stored as prescribed in the USP, causing it to be misbranded under the FDCA. The introduction or delivery for introduction into interstate commerce of any misbranded drug is a prohibited act under section 301(a) of the FDCA [21 U.S.C § 331(a)]. It is also a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being misbranded. C. Corrective Actions In your response to the Form FDA 483, you referenced your purported compliance with United States Pharmacopeia (USP)-National Formulary (NF) General Chapter <797> Pharmaceutical Compounding-- Sterile Preparations. As noted above, FDA investigators noted that your sterile drug products were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health. FDA strongly recommends that your management immediately undertake a comprehensive assessment of your operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess your aseptic processing operations and design. Although not a requirement, you may wish to consider engaging a third-party consultant with relevant sterile drug manufacturing expertise in conducting this comprehensive evaluation. In addition, you should package and label your propofol, and any other drug recognized in an official compendium, in the manner prescribed therein. D. Conclusion The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law and FDA regulations. 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. 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 violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you do not believe that the products discussed above are in violation of the FDCA, include your reasoning and any supporting information for our consideration. If you cannot complete corrective action within 15 working days, state the reason for the delay and the time within which you will complete the correction. Your written notification should be addressed to:
Danial S. Hutchison, Compliance OfficerFDA Kansas City District OfficeU.S. Food and Drug Administration8050 Marshall Drive Suite 205Lenexa, KS 66214(913) [email protected].
If you have questions regarding any issues in this letter, please contact our office at 913-495-5100. Sincerely,/S/ Cheryl A. BighamDistrict Director
Accessibility Contact FDA Careers FDA Basics FOIA No Fear Act Site Map Transparency Website Policies
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Page Last Updated: 07/14/2014 Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.
