Inspections, Compliance, Enforcement, and Criminal Investigations
Apotheca Inc 6/23/09
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|Los Angeles District
Irvine, California 92612-2506
Telephone (949) 608-2900
Fax (949) 608-4401
RETURN RECEIPT REQUESTED
June 23, 2009
Mr. Mitchel Herseth, President
1622 N. 16th Street
Phoenix, AZ 85006-1901
Dear Mr. Herseth:
We have completed our review of the inspection report for the inspection conducted at your manufacturing (repackaging) facility in Phoenix, Arizona, by the U.S. Food and Drug Administration (FDA) on January 28-29,2009. The inspection revealed significant deviations from the current Good Manufacturing Practice (CGMP) regulations in the repackaging of various drug products, including penicillin and non-penicillin beta-lactam drug products. These deviations were listed on the Form FDA 483, List of Inspectional Observations, issued to you at the close of the inspection.
The inspection revealed that these drug products are 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 with the CGMP regulations, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211.
We acknowledge your written response, received May 27, 2009, addressing our investigator's observations on the Form FDA 483. Our review of the response showed it is not adequate because it does not address the full separation and containment of your repackaging operations, nor was any documentation (e.g., written procedures, decontamination plans, facility schematics, floor plans) provided to demonstrate adequate corrective actions have been implemented. In addition, we acknowledge the Regulatory Meeting that we held with you on June 2, 2009, in which we discussed the need for full separation of your repackaging operations and containment controls, as well as the need for cessation of your repackaging and distribution activities, decontamination of your facility, and recall of repackaged product distributed to your customers.
The violations observed during this inspection include, but are not limited to, the following:
1. Failure to establish separate or defined areas or such other control systems for your film's operations as are necessary to prevent contamination or mix-ups during the course of manufacturing and processing operations, as required by 21 CFR § 211.42(c)(5). In addition, operations related to the manufacturing, processing, and packaging of penicillin are not performed in facilities separate from those used for other drug products for human use, as required by 21 CFR § 211.42(d).
Your firm's repackaging operations for cephalosporin (beta-lactam) and non-beta-lactam drug products (acetaminophen, ibuprofen, and various cough/cold products) are not separate. Due to the nature of these drug products, you must ensure separation of your repackaging operations in order to prevent contamination or mix-ups of these products. Beta-lactam drug products such as penicillin, amoxicillin, and cephalosporins (non-penicillin beta-lactams) present a substantial health hazard to patients. The potential health hazard of non-penicillin beta-lactam drug products is similar to that of penicillin drug products, in that they can be sensitizing agents that trigger a hypersensitive exaggerated allergic immune response in some people, with allergic reactions ranging from skin rash to life-threatening anaphylaxis. Anaphylaxis can result in significant tissue damage or even death. The non-penicillin beta-lactam drug products also have the potential for cross-reactivity resulting in anaphylaxis in some people. Preventing cross contamination and minimizing the potential for life-threatening allergic reactions is clinical when manufacturing non-penicillin beta-lactam drug products. Consequently, the processing of beta-lactam drug products must be separate from non-beta-lactam drug products. In addition, penicillin and non-penicillin beta-lactam drug products (cephalosporins) must also be separate from each other. Your repackaging operations for cephalosporin and non-beta-lactam drug products are not separate. They occur in the same Repack Room, using the same non-dedicated equipment and the same air-handling system (HVAC), as documented in the hand-drawn facility diagram you provided to our investigator. Also, the same employee can repackage cephalosporin and non-beta-lactam drug products on the same day. Containment control procedures (e.g., qualified decontamination, gowning, and flow diagrams) have not been established to prevent cross-contamination. For example, repackaging worksheets (b)(4) document the same employee with initials (b)(4) repackaging five packages of Cephalexin (b)(4) and 20 packages of (b)(4) on December 19, 2008. These observations indicate that you do not have adequate separation or containment control systems in order to prevent cross-contamination of these products, per 21 CFR § 211.42(c)(5).
In addition, your firm conducts repackaging of penicillin and non-penicillin drug products in the same facility without adequate separation of your operations and containment controls (e.g., adequate facility design, differential air pressures, and a monitoring program). Although penicillin is repackaged in a nominally delineated penicillin repack area, your repackaging operations are not adequately separated, per the intent of 21 CFR § 211.42(d), in order to prevent cross contamination of penicillin and non-penicillin drug products. For example, the penicillin repack area lacks a physical barrier (the doorway has no door) to assure its full separation from the rest of your facility. Therefore, the penicillin repack area is readily accessible to all employees. In addition, the same employee can repackage penicillin and non-penicillin products (e.g., cephalosporins) on the same day. Containment control procedures (e.g., qualified decontamination, gowning, and flow diagrams) have not been established to assure that your firm strictly precludes an operator, apparel, equipment, and materials from carrying residue from the penicillin repack area into non-penicillin areas. For example, repackaging worksheets (b)(4) document the same employee with initials (b)(4) repackaging ten packages of (b)(4) and four packages of Cephalexin (b)(4) on January 12, 2009. These examples illustrate that your firm's penicillin repackaging operations are not truly separate from those used for other drug products, nor do you have adequate containment controls in order to prevent cross-contamination of drug products.
To comply with the cited regulations, a comprehensive control strategy towards separation should be taken to prevent cross-contamination during the repackaging of penicillin, non-penicillin beta-lactam, and non-beta-lactam drug products. Adequate separation must include physical facility barriers and separate air-handling (HVAC) systems. In addition, there should be adequate separation of personnel and equipment, with well established written procedures and adequate controls. The separation should be verified by testing, auditing, and adequate monitoring
2. Failure to test non-penicillin drug products for the presence of penicillin, if a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, as required by 21 CFR § 211.176.
This regulation requires that non-penicillin drug products be tested for the presence of penicillin where a reasonable possibility of exposure to cross contamination exists. The non-penicillin drug products should not be marketed if detectable levels of penicillin are found. Your film has not tested non-penicillin drug products for the presence of penicillin. Product testing does not have to be performed if your firm can demonstrate that a reasonable possibility of exposure to traces of penicillin does not exist in your non-penicillin drug products. However, the lack of containment control procedures observed by our investigator leads us to believe that the possibility of contamination exists at your facility; therefore, non-penicillin products must be tested according to 21 CFR § 211.176.
3. Failure to establish and follow written procedures for cleaning and maintenance of equipment as required by 21 CFR § 211.67(b). For example:
a. Your firm has not established adequate written procedures for cleaning equipment, including utensils, used in the repackaging operations for any of the drug products that you repackage. Your pharmacist provided our investigator with a one page reference document, R4-23-604, which states that equipment shall be maintained in a clean and orderly manner. However, there are no written procedures that reference the approved cleaning and sanitizing solutions, assembly-reassembly instructions, solution contact time for surfaces, maintenance and cleaning schedules, assignment of responsibility, and protection of clean equipment from contamination prior to use.
b. In addition to your failure to establish written procedures for cleaning, your firm also has not validated the cleaning methods that you have been using for non-dedicated equipment (e.g., (b)(4) and hand count trays) and surfaces. Your pharmacist stated 70% Isopropyl Alcohol (IPA) was used to clean the (b)(4) and count trays, and counter tops. However, you have not provided any documentation that demonstrates that 70% IPA can effectively neutralize beta-lactams residues on equipment and surfaces such as countertops to prevent cross contamination.
4. Failure to maintain written records of major equipment cleaning, maintenance, and use that show the date, time, product, and lot number of each batch processed as required by 21 CFR § 211.182. For example:
a. Your firm does not maintain individual equipment logs of the cleaning, maintenance, and use of the non-dedicated equipment used in your repackaging operations. In fact, your firm does not maintain any records of the cleaning, maintenance, and use of your non-dedicated equipment.
b. Your firm does not maintain records of the cleaning, maintenance, and use of the dedicated equipment used in your repackaging operations, either in individual equipment logs or in batch records.
5. Failure to maintain batch production and control records that document that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including identification of the individual major equipment and lines used for each batch of drug product packed, as required by 21 CFR § 211.188(b)(2).
Your batch production and control records (i.e. repackaging worksheets) do not document the production lines (e.g., the room) where repackaging operations are conducted, nor the specific equipment used (e.g., (b)(4) hand count trays, beakers, graduated cylinders) during these repackaging operations for any of the drug products that your firm repackages.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility, and in connection with your products. 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.
We acknowledge your statement during the inspection that the penicillin repack area has "its own air conditioning system"; however, the requirement is to have a separate air-handling system for the manufacturing, processing, and packing of penicillin, per 21 CFR § 211.46(d). A separate air-handling system (HVAC) should consist of a separate air-handling unit (which includes heating and cooling elements, filters, humidifier, etc.) and separate ductwork. Also, be advised that distribution records must identify the lot or control number of all drug products shipped and that your firm must have a system by which the distribution of each lot of drug product can be readily determined to facilitate its recall, if necessary, per 21 CFR § 211.196. We are concerned about the potential for cross-contamination at your facility and request that your firm inform us upon receipt of this letter of your plans to assess the hazard to products repacked by your firm.
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 new drug applications listing your facility as a manufacturer until the above violations are corrected. A reinspection may be necessary.
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. Include an explanation of each step taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. Additionally, your response should state the date(s) when you ceased repackaging operations and distribution of drug product(s) repackaged at your facility.
Your response should be sent to:
Director, Compliance Branch
Food and Drug Administration
Los Angeles District Office
Irvine, CA 92612
If you have any questions about the content of this letter, please contact Dr. William Vitale, Compliance Officer, at 949-608-2919.
Alonza E. Cruse
Cc: Jeff Farrar, DVM, PhD, MPH
California Department of Public Health
Food and Drug Branch
1500 Capitol Avenue, MS-7602