Inspections, Compliance, Enforcement, and Criminal Investigations
Physicians Total Care, Inc. 1/10/13
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
4040 North Central Expressway
Dallas, Texas 75204-3128
January 10, 2013
UPS OVERNIGHT MAIL
David L. Wilson, President
Warren G. Moseley, President
Barry A. Posner, President and Secretary
Kenneth H. Graeller, Executive Vice President
Physicians Total Care, Inc.
12515 E. 55th St., Ste 100
Tulsa, OK 74146
Dear Messrs. Wison, Moseley, Posner, and Graeller:
During our January 24 to February 24, 2012 inspection of your pharmaceutical manufacturing facility, Physicians Total Care, Inc. located at 12515 E. 55th St., Ste 100, Tulsa, Oklahoma, investigator(s) from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug product(s) to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with CGMP. In addition, your firm also repackages and distributes unapproved new drugs in violation of sections 301(d) and 505(a) of the Act, 21 U.S.C. §§ 331(d) and 355(a). Furthermore, by introducing misbranded drugs into interstate commerce, you are in violation of section 301(a) of the Act, 21 U.S.C. § 331(a).
We have conducted a detailed review of your firm's response, dated March 14, 2012, and note that it lacks sufficient corrective actions.
Our investigator(s) observed specific violations during the inspection, including, but not limited to, the following:
1. Your firm failed to test non-penicillin drug products for the presence of penicillin when a reasonable possibility existed that the non-penicillin drug product had been exposed to cross-contamination with penicillin (21 CFR 211.176).
For example, the door of the penicillin packaging room opens to the main packaging area where your firm packages other products including nonpenicillin beta lactams, antidepressants, nonsteroidal anti-inflammatory drugs (NSAID), calcium channel blockers, ACE inhibitors, and opioids. Penicillin packaging must be performed in facilities separate from those used for other drug products for human use to prevent cross contamination. Your firm did not separate these operations, therefore other products manufactured in the affected area need to be tested for the presence of penicillin.
In your response, you stated that your firm ceased packaging penicillin products and that you plan to (b)(4) this operation. Your response is inadequate because you did no~her products manufactured at your facility that are within their expiration date for the presence of penicillin.
2. Your firm failed 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)). Your firm failed to perform operations related to the manufacture, processing, and packing of penicillin in facilities separate from those used for other drug products for human use (21 CFR 211.42(d)). For example:
a. Your firm documented in the Batch Production and Control Record (BPCR) that on September 13, 2011, lot (b)(4) of Amoxicillin (antibiotic) capsules was packaged on the Repack Area (b)(4) table, located in the main packaging area. Lot (b)(4) of Amlodipine/Benazepril (calcium channel blocker/ACE inhibitor) capsules were also packaged on the Repack Area (b)(4) table on September 13, 2011.
b. Your firm packages cephalosporin (non-penicillin beta lactams) drug products in the main packaging area using the same equipment and in adjacent workstations without physical separation.
The main area shares one air handling unit and is used to package all types of drug products. In your response, you stated that your firm ceased packaging penicillin and cephalosporin products and that you plan to (b)(4) these operations. Your response is inadequate because you failed to provide timeframes for the (b)(4) of beta lactams. In addition, you failed to commit to cease operations until you conduct proper decontamination of the facility and comprehensive environmental testing to ensure no beta lactam residues remain in the facility.
Further, you have not conducted an evaluation of all the products packaged in your facility and within their expiration date to ensure they are not impacted. Please send a thorough assessment and decontamination plan with your response.
3. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21CFR 211.67(b)). For example:
a. Your cleaning procedures do not define the (b)(4) grade that personnel will use to clean the counting trays and spatulas in the main packaging area. Your firm's Production Manager stated that he thought your firm was using (b)(4) but the only bottle he could find during the inspection was (b)(4) The spray bottles used during cleaning were not marked to show content or the date the product was placed in the bottle.
b. Your cleaning procedures do not describe the frequency and method of cleaning of other production areas including the tables in the areas where you store the counting trays, spatulas, and pliers used for packaging operations. In addition, the procedure does not include directions for cleaning of the pliers used to pull or place cotton in bottles of packaged drug product.
In your response, you stated that your firm modified the cleaning procedures to clearly describe: (a) the use of (b)(4) for cleaning work surface areas, counting trays, spatulas, and pliers after completing the packaging of a batch; and (b) the clearance of packaging areas of all materials used in a prior batch. You also stated that you re-trained employees on February 27, 2012. Your response is inadequate because you did not include a scientifically sound justification for the use of (b)(4) for cleaning the packaging areas. Please note that you must not resume drug packaging operations until you perform adequate decontamination of your facility. Please provide a comprehensive explanation in your response.
4. 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).
For example, your firm did not have any written documentation of any investigation that was conducted due to the packaging (labeling) error of two lots of Morphine Sulfate packaged on October 13, 2010, and later recalled on November 10, 2010. Due to the lack of any investigation, your firm took no corrective or preventive actions.
In your response, you stated that you re-trained all employees on the complaint handling procedure on February 27, 2012. You also stated that you revised the complaint handling procedure to include a requirement to investigate and document packaging errors, and to document and maintain documentation of all corrective actions you take. Your response is inadequate because you have not investigated the Morphine Sulfate packaging error. Please provide a copy of this investigation including the implemented corrective and preventive actions.
5. Your firm failed to follow written procedure for the preparation of master production and control records designed to assure uniformity from batch to batch (21 CFR 211.186(a)).
For example, employees made handwritten changes to pre-printed information on Batch Production Control Records (BPCR) in order to describe drugs being packaged. However, your quality unit did not review or approve the corrections, nor did your firm revise the Master Production Control Record (MPCR). These handwritten changes resulted in packaging errors.
For example, lot (b)(4) of Morphine Sulfate Immediate Release 30 mg tablets was packaged on October 13, 2010. The description of the embossing on the tablet in the BPCR was not the same as that found on the drug being packaged. The employee changed the description on the BPCR and added a note to change the MPCR. As a result, your firm mislabeled this lot of Morphine Sulfate Extended Release 30 mg tablets as an immediate release drug. Subsequently, your firm recalled this lot.In addition, your firm performed the following packaging operations without approved MPCRs and BPCRs:
• Lot (b)(4) of Amoxicillin 875 mg tablets packaged on December 29, 2011.
• Lot (b)(4) of Amlodipine/Benazepril 10 mg/20 mg capsules packaged on September 13, 2011.
• Lot (b)(4) of Famotidine 40 mg tablets packaged on September 13, 2011.
• Lot (b)(4) of Dilantin Capsules 30 mg' packaged on September 28, 2011.
In your response, you stated that you re-trained your employees, that you will ensure all BPCRs match the MPCRs, and that you will approve all MPCRs following any changes. You also stated that you added version numbers to both the MPCR and the BPCR in order to track such changes. Your response is inadequate because you failed to conduct a review of all BPCRs used to manufacture products within expiry to ensure unapproved changes did not lead to manufacturing errors.
In addition to the CGMP violations, you repackage and distribute prescription drugs without an approved application at your facility in Tulsa, Oklahoma. Based on the information your firm submitted to FDA's Drug Registration and Listing System and information collected during the inspection, you repackage and distribute prescription drugs, including, but not limited to:
• Oxycodone Hydrochloride 5mg capsules
• Pilocarpine Hydrochloride Ophthalmic Solution, USP 1% and 4%
As labeled, the above products are drugs within the meaning of section 201(g)(1)(B) and (C) of the Act [21 U.S.C. §§ 321 (g)(1)(B) and (C)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and because they are intended to affect the structure or function of the body. Further, these drugs, as marketed by your firm, are "new drugs" within the meaning of section 201(p) of the Act [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses. Under sections 301(d) and 505(a) of the Act [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 either section 505(b) or (j) of the Act [21 U.S.C. § 355(b) or (j)] is in effect for the drug. Based upon our information, there are no FDA-approved applications on file for the above drugs. The marketing of these drugs, or other applicable drugs, without approved applications constitutes a violation of these provisions of the Act.
Because the above drugs 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 drugs 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 Act [21 U.S.C. § 352(f)(1)]. Because your drugs lack the required approved applications, they are not exempt under 21 CFR 201.115 from the requirements of section 502(f)(1) of the Act. The introduction or delivery for introduction into interstate commerce of these drugs therefore violates section 301(a) of the Act [21 U.S.C. § 331(a)].
To ensure that all prescription and over-the-counter drugs marketed in the U.S have been shown to be safe and effective, FDA published a Compliance Policy Guide (CPG) Section 440.100, Marketed Unapproved Drugs.1 The CPG outlines the Agency's enforcement policies aimed at efficiently and rationally bringing all drugs requiring approved applications into the approval process without adversely affecting public health, imposing undue burdens on consumers, or unnecessarily disrupting the market. Upon receiving this warning letter, FDA requests that you contact CDER's Drug Shortages Program at email@example.com immediately, as you begin your internal discussions on discontinuation of your marketed unapproved drugs. This will ensure your actions do not adversely affect the public health and cause a disruption to the marketplace.
We acknowledge your commitment to cease packaging operations for penicillin and cephalosporin products. Please notify FDA if you decide to resume packaging operations for penicillin, penicillin-based, and/or beta-Iactam products at your establishment and describe the separate facilities used to prevent crosscontamination. Please note that you are responsible for ensuring that the packaging conducted for your firm pursuant to contract meets CGMP requirements.
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Other federal agencies may take this warning letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/UCM070290.pdf
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections, and indicate your progress in updating the Drug Listing files in accordance with 21 CFR 207.30(a) along with the name and address of any other manufacturer, distributor, or supplier of these products. Additionally, if you no longer manufacture or distribute the drug product(s) at issue, provide the date(s) and reason(s) you ceased production.
Please send your reply to the following address: Thao X. Ta, Compliance Officer, U.S. Food and Drug Administration, 4040 N. Central Expressway, Suite 300, Dallas, Texas 75204.
If you have any questions about the contents of this letter, please contact Mr. Ta at (214) 253-5217.
Reynaldo R. Rodriguez, Jr.
Dallas District Director