Robin Smith Hoke
- Leiter's Compounding
17 Great Oaks Blvd.
San Jose, CA 95119-1359
- Issuing Office:
- San Francisco District Office
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
San Francisco District
1431 Harbor Bay Parkway
Alameda, CA 94502
VIA UNITED PARCEL SERVICE
February 29, 2016
Dr. Charles W. Leiter, CEO
17 Great Oaks Blvd.
San Jose, CA 95119-1359
Dear Dr. Leiter:
You registered with the U.S. Food and Drug Administration (FDA) as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353b] on January 31, 2014, and re-registered on January 26, 2015. From September 15, 2014, to October 7, 2014, FDA investigators inspected your facility, Leiter’s Compounding, located at 17 Great Oaks Blvd., San Jose, California, 95119-1359. The investigators observed that you failed to meet the conditions under section 503B of the FDCA necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain requirements under the FDCA. FDA issued a Form FDA 483 to your facility on October 7, 2014 and a revised Form FDA 483 to your facility on October 8, 2014. FDA acknowledges receipt of your facility’s response, dated October 20, 2014. Based on this inspection, it appears your facility is producing drugs that violate the FDCA.
FDA acknowledges that you had another facility located at 1700 Park Avenue, San Jose, CA 95119-1359. According to your April 21, 2015, response to the April 14, 2015, FDA Warning Letter documenting apparent violations at the 1700 Park Avenue facility, that facility is no longer in operation .
A. Compounded Drugs under the FDCA
The Drug Quality and Security Act (DQSA) was enacted on November 27, 2013. Title I of the DQSA, the Compounding Quality Act (CQA), added a new section 503B to the FDCA. Under section 503B(b), a compounder can register as an outsourcing facility with FDA. Drug products compounded by or under the direct supervision of a licensed pharmacist in an outsourcing facility can qualify for exemptions from the drug approval requirements in section 505 of the FDCA [21 U.S.C. § 355(a)], the requirement in section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)] that labeling bear adequate directions for use and the Drug Supply Chain Security Act requirements in section 582 of the FDCA [21 U.S.C. § 360eee-1] if the conditions in section 503B of the FDCA are met.
An outsourcing facility, which is defined in section 503B(d)(4) of the FDCA [21 U.S.C. § 353b(d)(4)], is a facility at one geographic location or address that — (i) is engaged in the compounding of sterile drugs; (ii) has elected to register as an outsourcing facility; and (iii) complies with all of the requirements of this section. Outsourcing facilities must comply with other provisions of the FDCA, including section 501(a)(2)(B) [21 U.S.C. § 351(a)(2)(B)], regarding current good manufacturing practice (CGMP), and section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)], regarding insanitary conditions. Generally, CGMP requirements for the preparation of drug products are established in Title 21 of the Code of Federal Regulations (CFR) parts 210 and 211.
B. Violations of the FDCA
The FDA investigators observed significant CGMP violations at your facility, causing your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA.
In addition, the FDA investigators observed that your facility failed to meet the conditions of section 503B. For example, during the inspection, FDA investigators noted:
1. None of the drug products compounded at your facility include the statement “This is a compounded drug,” and the date that the drug was compounded on the label; some of the drug products compounded at your facility do not contain the quantity or volume on the label; and some of the labels for drug products do not contain the statement “Office Use Only” as required by Section 503B(a)(10) of the FDCA [21 U.S.C. §353b(a)(10)]].
2. Your facility failed to submit a report to FDA upon initial registration and again in June 2014, identifying the drug products that you compounded during the previous 6-month period [section 503B(b)(2) of the FDCA [21 U.S.C. §353b(b)(2)]].
Because your compounded drug products have not met all of the conditions in section 503B, they are not eligible for the exemptions under section 503B from the FDA approval requirements in section 505, the requirement under section 502(f)(1) that labeling bear adequate directions for use, and the Drug Supply Chain Security Act requirements described in section 582 of the FDCA.
Specific violations are described below.
Adulterated Drug Products
FDA investigators noted CGMP violations at your facility, causing your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations include, for example:
1. 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)).
2. 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)).
3. Your firm does 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)).
4. Your firm failed to establish time limits for the completion of each phase of production to assure the quality of the drug product (21 CFR 211.111).
5. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. FDA has issued a draft guidance, Current Good Manufacturing Practice — Interim Guidance for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act. This draft guidance, when finalized, will describe FDA’s expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211 until more specific CGMP regulations for outsourcing facilities are promulgated.
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 and results in the drug being adulterated.
Unapproved New Drug Products
You do not have any FDA-approved applications on file for your drug products.
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 or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FDCA is in effect for the drug.
Misbranded Drug Products
You compound drug products that are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, adequate directions for use cannot be written 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). The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the FDCA. 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 and results in the drug being misbranded.
Failure to Report Drugs
As noted above, your facility failed to submit a report to FDA upon initial registration as an outsourcing facility in January 2014, and again in June 2014, identifying the drug products that you compounded during the previous 6-month period. (Section 503B(b)(2) of the FDCA [21 U.S.C. § 353b(b)(2)]). The failure to report drugs by an entity that is registered with FDA in accordance with section 503B(b) is a prohibited act under section 301(ccc)(3) of the FDCA [21 U.S.C. § 331(ccc)(3)].
C. Corrective Actions
In your October 20, 2014, response to the revised Form FDA 483 issued on October 8, 2014, you describe certain corrective actions taken or expected to be implemented in response to the Form FDA 483 observations.
Although several of your proposed corrective actions appear to adequately address the conditions observed at your facility, others are deficient. For example, we acknowledge your statement that your facility commits to implement corrective actions to address the observed 503B label deficiencies. However, you did not commit to including the date on which a product was compounded on the label. Furthermore, we cannot fully evaluate the adequacy of some other corrective actions described in your response because you did not provide any documentation to demonstrate that you have successfully implemented the corrective actions, such as revised standard operating procedures and validation studies or reports.
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. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation. You should fully implement necessary corrections in order to ensure 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 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 section 501 of the 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 a contract testing laboratory to perform some of the required testing of your finished drug products. Your written response to FDA’s observation regarding lack of responsibility to approve and reject all procedures or specifications affecting the identity, strength, quality, and purity of drug products included data from your third party laboratory, (b)(4). However, according to documentation collected during the inspection, the laboratory test methods employed by the third party laboratory do not conform to USP<71> and the suitability test reports are not comprehensive as they are missing data regarding, for example, the volume of product taken from each container and growth promotion results for organisms in media. 71>
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).]
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, including 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. FDA intends to re-inspect your facility to verify corrective actions have been completed.
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.
Please address your reply to:
Lawton W. Lum
Director, Compliance Branch
U.S. Food and Drug Administration
San Francisco District
1431 Harbor Bay Parkway
Alameda, CA 94502
Please reference CMS #477540 in your response.
If you have questions regarding the contents of this letter, please contact William V. Millar, Compliance Officer at 510-337-6896 or email at firstname.lastname@example.org
Kathleen M. Lewis, J.D.
San Francisco District Director
 See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).  See, e.g., section 503B(a)(11) of the FDCA [21 U.S.C. § 353b(a)(11)].  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 and/or because they are intended to affect the structure or any function of the body. 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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