WARNING LETTER
Professional Compounding Centers of America dba PCCA
MARCS-CMS 597638 —
January 27, 2021
Delivery Method:
VIA Electronic Mail
Product:
Drugs
Recipient:
Recipient Name
Mr. Fabian V. Zaccardo
Recipient Title
Chief Operating Officer
Professional Compounding Centers of America dba PCCA
9901 South Wilcrest Drive
Houston
,
TX
77099-5132
United States
Issuing Office:
Center for Drug Evaluation and Research | CDER
United States
Warning Letter 320-21-15
January 27, 2021
AMENDED
(This letter replaces Warning Letter No. 320-21-15 dated January 7, 2021)
Dear Mr. Zaccardo:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Professional Compounding Centers of America, Inc. (PCCA), FEI 1629694, at 9901 South Wilcrest Drive, Houston, Texas from October 22 to 29, 2019.
This warning letter summarizes significant violations, including deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API). CGMP violations identified at your suppliers caused drugs manufactured by these firms to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Your receipt in interstate commerce of adulterated drugs and the delivery or proffered delivery thereof, is a violation of section 301(c) of the FD&C Act, 21 U.S.C. 331(c).
Additionally, your glycerin United States Pharmacopeia (USP) product is adulterated under section 501(b) of the FD&C Act, 21 U.S.C. 351(b), for failure to conform to compendial standards for identity, strength, quality, or purity. Your glycerin USP product is also misbranded under section 502(e)(3)(B) and (g) of the FD&C Act because it fails to meet the applicable USP standard of identity. Furthermore, because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your glycerin API is adulterated within the meaning of section 501(a)(2)(B) of FD&C Act, 21 U.S.C. 351(a)(2)(B).
Finally, your drug products tramadol HCl, fentanyl citrate, buprenorphine HCl and morphine sulfate are misbranded under section 502(a) of the FD&C Act.
We reviewed your November 19, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigator observed specific violations and deviations including, but not limited to, the following.
Receipt of Adulterated Drugs
Your receipt in interstate commerce of adulterated drugs (i.e., those listed on an import alert) and the delivery or proffered delivery thereof, is a violation of section 301(c) of the FD&C Act, 21 U.S.C. 331(c).
Our inspection and review of import data revealed your firm received
(b)(4)
from
(b)(4)
, FEI
(b)(4)
, on July 30, 2018. An inspection of
(b)(4)
in
(b)(4)
revealed significant CGMP deviations including sourcing drugs from a firm that refused an FDA inspection, destruction of batch records in a
(b)(4)
, and
(b)(4)
on product contact surfaces. As a result of these and other deviations, all drugs manufactured by
(b)(4)
, were listed on Import Alert 66-40 (IA 66-40) on
(b)(4)
, and the firm was issued a warning letter on
(b)(4)
.
1
All drugs from
(b)(4)
. remain listed on IA 66-40 at this time.
Other Drug Suppliers in Your Supply Chain with a History of Non-Compliance
We note that an inspection of records at your facility and a review of FDA import data demonstrated that FDA has, in the past, taken regulatory action against at least 23 of your other API suppliers for the manufacture of adulterated drugs under section 501 of the FD&C Act by either listing their drugs on import alert and/or issuing them warning letters. Drugs from multiple API suppliers used by PCCA were listed on an import alert, including IA 66-40 for the supplier’s failure to conform to CGMP within the meaning of section 501(a)(2)(B) and Import Alert 99-32 (IA 99-32) for the supplier’s conduct in delaying, denying, or limiting FDA inspections of foreign facilities or providing reasonable access to FDA's inspectional personnel. To understand whether PCCA has received or introduced additional adulterated drugs in interstate commerce, we are therefore requesting information regarding timing of receipt and distribution of drugs from the 23 facilities listed below.
PCCA suppliers with drugs listed on Import Alert 66-40 for suppliers’ failure to comply with CGMP
1.
(b)(4)
, FEI
(b)(4)
, was issued a warning letter on
(b)(4)
, and all drugs from
(b)(4)
were listed on IA 66-40 on
(b)(4)
, for among other things, the firm’s failure to have procedures for change control, out-of-specification investigations, process deviation investigations, laboratory incidents and failure to validate the manufacturing process. FDA determined that this facility had adequately addressed the deviations and after
(b)(4)
the firm’s drugs were removed from IA 66-40. A Warning Letter Close Out (WLCO) letter was issued on
(b)(4)
.
2. Drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 66-40 on
(b)(4)
,
2
and the firm was issued a warning letter on
(b)(4)
, for among other things,
(b)(4)
. FDA determined the firm had adequately addressed the deviations on
(b)(4)
.
3
The firm’s drug products were removed from IA 66-40 on
(b)(4)
and a WLCO letter was issued on
(b)(4)
.
3. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 66-40 on
(b)(4)
, and the firm was issued a warning letter on
(b)(4)
, for among other things, manipulating analytical data, including deleting chromatograms and retesting samples into compliance. All drugs from
(b)(4)
remain listed on IA 66-40 at this time.
4. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 66-40 on
(b)(4)
, and the firm was issued a warning letter on
(b)(4)
, for among other things, inadequate impurity testing, and lack of audit trails to support CGMP activities. FDA determined that the firm had adequately addressed the deviations on
(b)(4)
. A WLCO letter was issued on
(b)(4)
and the firm’s drug products were removed from IA 66-40 on
(b)(4)
.
5. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 66-40 on
(b)(4)
, and the firm was issued a warning letter on
(b)(4)
, for among other things,
(b)(4)
. All drugs from
(b)(4)
remain listed on IA 66-40 at this time.
6. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 66-40 on
(b)(4)
, and the firm was issued a warning letter on
(b)(4)
, for among other things,
(b)(4)
. All drugs from
(b)(4)
remain listed on IA 66-40 at this time.
7. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 66-40 on
(b)(4)
, and the firm was issued a warning letter on
(b)(4)
, for among other things, a failure to ensure that quality-related complaints are investigated and resolved. All drugs from
(b)(4)
remain listed on IA 66-40 at this time.
8. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 66-40 on
(b)(4)
. All drugs from
(b)(4)
remain listed on IA 66-40 at this time.
For manufacturers whose drugs are listed on IA 66-40 for failure to conform to CGMP within the meaning of section 501(a)(2)(B), FDA has evidence that the drugs listed in the import alert appear to be adulterated. You are responsible for ensuring that the drugs you distribute are manufactured in compliance with all relevant CGMP requirements for drugs. Up to date information regarding import alerts can be found at the following FDA website:
https://www.accessdata.fda.gov/cms_ia/ialist.html
PCCA suppliers with drugs listed on Import Alert 99-32 for Delaying, Denying, Limiting, or Refusing an FDA Drug Inspection
9. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 99-32 on
(b)(4)
, due to the firm’s denying FDA’s attempt to schedule a pre-announced inspection. All drugs from
(b)(4)
remain listed on IA 99-32 at this time.
10. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 99-32 on
(b)(4)
, due to the firm’s denying FDA’s attempt to schedule a pre-announced inspection. All drugs from
(b)(4)
remain listed on IA 99-32 at this time.
11. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 99-32 on
(b)(4)
, due to the firm’s denying FDA’s attempt to schedule a pre-announced inspection. All drugs from
(b)(4)
remain listed on IA 99-32 at this time.
12. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 99-32 on
(b)(4)
, due to the firm’s delaying and ultimately denying an inspection. All drugs from
(b)(4)
remain listed on IA 99-32 at this time.
13. All drugs from
(b)(4)
, FEI:
(b)(4)
, were listed on IA 99-32 on
(b)(4)
, due to the firm’s refusing to accept proposed inspection dates. All drugs from
(b)(4)
remain listed on IA 99-32 at this time.
14. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 99-32 on
(b)(4)
, due to the firm’s denying FDA’s attempt to schedule a pre-announced inspection. All drugs from
(b)(4)
remain listed on IA 99-32 at this time.
15. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 99-32 on
(b)(4)
, due to the firm’s denying FDA’s attempt to schedule a pre-announced inspection. All drugs from
(b)(4)
remain listed on IA 99-32 at this time.
16. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 99-32 on
(b)(4)
, due to the firm’s denying FDA’s attempt to schedule a pre-announced inspection. All drugs from
(b)(4)
remain listed on IA 99-32 at this time.
17. All drugs from
(b)(4)
, FEI
(b)(4)
, were listed on IA 99-32 on
(b)(4)
, due to the firm’s delaying and ultimately denying an inspection. All drugs from
(b)(4)
remain listed on IA 99-32 at this time.
PCCA suppliers that received warning letters not otherwise listed above
18.
(b)(4)
, FEI
(b)(4)
, was issued a warning letter on
(b)(4)
, for among other things,
(b)(4)
.
19.
(b)(4)
, FEI
(b)(4)
, was issued a warning letter on
(b)(4)
, for among other things,
(b)(4)
. Furthermore, buildings used in the production of API were observed to contain
(b)(4)
, and
(b)(4)
material on the floors. On
(b)(4)
, FDA determined that the firm had adequately addressed the deviations contained in that warning letter, and a WLCO letter was issued.
20.
(b)(4)
, FEI
(b)(4)
, was issued a warning letter on
(b)(4)
, for among other things, failure to ensure cleaning practices were adequate to prevent contamination on shared equipment used for API manufacture.
21.
(b)(4)
, FEI
(b)(4)
, was issued a warning letter on
(b)(4)
, for among other things, inadequate investigation of failing test results, and failure to maintain complete data for API tested and distributed to the United States. This warning letter also noted that similar CGMP deficiencies were cited in earlier inspections of the firm, and that the recurring deviations demonstrate that the facility’s oversight and control over the manufacture of drugs is inadequate.
22.
(b)(4)
, FEI
(b)(4)
, was issued a warning letter on
(b)(4)
, for among other things,
(b)(4)
.
23.
(b)(4)
, FEI
(b)(4)
, was issued a warning letter on
(b)(4)
, for among other things,
(b)(4)
.
In response to this letter, provide the lot numbers and dates of distribution for all drugs received from each facility listed above. Include the identity of PCCA’s customers who received drugs from the facilities listed above, and whether you distributed the drugs from a listed facility during the time period after the aforementioned warning letters and/or import alerts were issued and before a close-out letter was issued and/or the firm’s drugs were removed from the import alert. For lots of drug product API received and distributed by PCCA during the relevant time frame, include whether you have notified your customers that they received adulterated drugs from PCCA. If you have not notified any customer who received adulterated drug API from PCCA, notify them, and provide a copy of that notification in your response.
Considering that FDA has found a pattern of drug manufacturers with serious CGMP or other adulteration violations in your supply chain, in response to this letter, also provide a detailed plan to ensure you do not receive or deliver adulterated drugs in interstate commerce, in violation of section 301(c) of the FD&C Act, 21 U.S.C. 331(c). Items in your plan should include a full evaluation of your supplier program, including a plan to audit your suppliers. Furthermore, you should also include a full reconciliation of any drugs from the manufacturers listed above, as well as for all firms or drugs currently on FDA import alerts, to determine if you have any remaining drugs in your possession. Up to date information regarding import alerts can be found at the following FDA website:
https://www.accessdata.fda.gov/cms_ia/ialist.html
Adulteration and Misbranding of Glycerin API
You repackage glycerin USP and distribute this drug to your customers which include pharmacy compounders. Repackaged glycerin intended as an excipient or other component of a drug product is a drug as defined by section 201(g)(1) the FD&C Act, 21 U.S.C. 321(g)(1). Glycerin is also a drug the name of which is recognized in an official compendium (the USP).
4
A drug with a name recognized in USP–NF must comply with compendial identity standards or be deemed adulterated, misbranded, or both. Sections 501(b) and 502(e)(3)(B) and (g) of the FD&C Act, 21 U.S.C. 351(b), 352(e)(3)(B); see also 21 CFR 299.5(a) and (b). In such cases, the identity is determined by the official tests, procedures and acceptance criteria in the applicable USP-NF monograph. USP-NF General Notices 2.30. Furthermore, in accordance with section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B), a drug is adulterated “if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.”
FDA compared the testing required in the identification section of the USP monograph for glycerin with PCCA analytical test results, which reference the USP method, and determined the testing for identity of glycerin conducted by PCCA was incomplete and therefore was not adequate to assure that your glycerin conformed to the compendial standards of identity.
(b)(4)
. While your
(b)(4)
test using
(b)(4)
can identify glycerin, it is not an adequate test for detecting DEG and EG in glycerin at USP specified limits. Therefore, you failed to conduct adequate identity testing for glycerin USP and your glycerin drug product is adulterated and misbranded within the meaning of sections 501(b), 501(a)(2)(B), and 502(e)(3)(b) and (g) of the FD&C Act, 21 U.S.C. 351(b), 351(a)(2)(B), and 352(e)(3)(B) and (g), in that you do not have test data to demonstrate its identity meets the standards set forth in an official compendium (the USP) recognized in the FD&C Act. See also 21 CFR 299.5(a) and (b).
5
Your response stated that your firm has complied with the regulatory requirement because your firm performed identity testing on each lot prior to release. You further stated that each lot had been previously tested by the manufacturer prior to receipt by your firm. You note that during the initial supplier qualification, you tested the purchased glycerin using a third-party laboratory. You also stated in your response that with your efforts to “know (its) supply chain for glycerin, PCCA is confident that its supply of glycerin is free from DEG contamination.” Moving forward, you committed to requalify your supplier on an
(b)(4)
basis. You further stated that you believe that you do not need to test your incoming glycerin for the presence of DEG and EG impurities as it is “superfluous, and simply not required.”
Your response is inadequate because the test you perform for identity on the bulk glycerin that you repackage cannot determine if a batch of glycerin is adulterated with DEG and EG contaminants and does not conform to the identification section of the applicable USP monograph. You cannot ensure the quality and security of the supply chain with regard to DEG and EG adulteration given your current practice because you do not independently verify that the API manufacturer’s reports are reliable through adequate identity testing consistent with the applicable USP monograph upon receipt. Reliability of a supplier is generally established by the receiving entity’s own testing which, when compared to the supplier’s data, shows agreement within the specified limits over a period of time. Periodic monitoring is also generally necessary in order to assure the continued reliability of a supplier’s test results. Relying solely on the manufacturer’s COA is not adequate to comply with applicable requirements as described above. Although, in your response to FDA’s 483, PCCA does commit to re-qualifying its supplier of glycerin on an
(b)(4)
basis, it is unclear whether PCCA will verify the API supplier’s COA as part of that
(b)(4)
qualification process using an adequate identity test that meets applicable standards.
FDA has received reports about fatal DEG poisoning of consumers who ingested medicinal syrups, such as cough syrup or acetaminophen syrup, that were manufactured with DEG-contaminated glycerin. Historical DEG-related poisonings and fatalities stemmed from multiple violative practices in the glycerin supply chain, including manufacturers not conducting full and adequate identity testing; manufacturers relying on COAs; and COAs, such as those you provide with your glycerin and other drugs, not providing the name of the true manufacturer and thus masking the chain of custody of an adulterated product.
In response to this letter, provide the following:
• An update regarding implementation of DEG and EG testing for all lots of glycerin.
• A detailed risk assessment for drug products distributed by your firm that contain glycerin and are within expiry in the U.S. market.
• Test reserve samples of all lots of glycerin for DEG and EG with the test method and provide test results.
Misbranding Due to False or Misleading Labeling of Drug Products
Under section 502(a) of the FD&C Act, a drug is misbranded if its label is “false or misleading in any particular.” Further, 21 CFR 201.1(h)(2) specifies that “The appearance on a drug product label of a person's name without qualification is a representation that the named person is the sole manufacturer of the product. That representation is false and misleading, and the drug product is misbranded under section 502(a) of the [FD&C] act, if the person is not the manufacturer of the product in accordance with this section.”
The labels your firm affixed to the following repackaged/relabeled API identify PCCA, but do not designate your firm’s role:
• tramadol HCl (lot # C191954);
• fentanyl citrate (lot # C189348);
• buprenorphine HCl (lot # C191213); and,
• morphine sulfate (lot # C192769).
Evidence collected during the inspection of your facility establishes that other firms were involved in the manufacturing of these API. Because these API labels bear only the PCCA name without further qualifications, the labels falsely represent that PCCA is the sole drug manufacturer. Therefore, these repackaged/relabeled API are misbranded under section 502(a) of the FD&C Act because the labels are false and misleading.
Regulatory Meeting
Upon submission of your response to this letter, email CDR John W. Diehl, Director, Compliance Branch, FDA/ORA/OPQO Division II, at John.Diehl@fda.hhs.gov to schedule a meeting to discuss the adequacy of the corrective actions you proposed to prevent the continued introduction of adulterated and misbranded goods into interstate commerce. Topics of the regulatory meeting will also include supply chain controls and compliance with CGMP.
Conclusion
The deviations and violations cited in this letter are not intended to be an all-inclusive list of deviations and violations that exist at your facility. You are responsible for investigating and determining the causes of any deviations and violations and for preventing their recurrence or the occurrence of other violations and deviations.
If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
Professional Compounding Centers of America, Inc., Houston FEI: 1629694 Page 9
Failure to promptly address these deviations and violations may result in legal action without further notice including, without limitation, seizure and injunction. Other Federal agencies may take your compliance history into account when awarding contracts.
Failure to address violations of FD&C Act sections may be cause for FDA to withhold issuance of Export Certificates and may be cause for FDA to withhold approval of new applications or supplements listing your firm as a drug manufacturer. We may re-inspect to verify that you have completed your corrective actions.
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to address any deviations and violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot completely address deviations and violations within 15 working days, state your reasons for delay and your schedule for completion.
Please identify your response with FEI 1629694 and Case # 597638. Send your electronic reply to Monica R. Maxwell, Program Division Director, FDA/ORA/OPQO Division II at ORAPharm2_Responses@fda.hhs.gov.
If you have any questions concerning the letter, please direct those to CDR Diehl at
(214) 253-5288
or john.diehl@fda.hhs.gov.
Sincerely,
/S/
Alonza Cruse
Director
Office of Pharmaceutical Quality Operations
Office of Medical Products and Tobacco Operations
Office of Regulatory Affairs
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
___________________________
1
Products from
(b)(4)
, FEI
(b)(4)
, have also been placed on IA 66-40 because that facility ships products manufactured at FEI
(b)(4)
.
2
Certain drugs were carved out due to shortage concerns.
3
Throughout this letter, where applicable, we have provided the date of the memorandum documenting FDA’s internal determination that a firm’s deviations were adequately addressed prior to the final removal of the firm’s products from import alert.
4
USP Glycerin monograph, Document ID: GUID-6A5A5AD2-0762-4830-8E99-D593E5400FF0_4_en-US
5
See the identity test for glycerin included in the USP Monograph for glycerin, supra note 1
Content current as of:
01/27/2021
Regulated Product(s)
Drugs