Inspections, Compliance, Enforcement, and Criminal Investigations
Shamrock Medical Solutions Group LLC , 4/8/10
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|New England District
One Montvale Avenue
Stoneham, Massachusetts 02180
FAX: (781) 596-7896
RETURN RECEIPT REQUESTED
April 8, 2010
Mr. James Martin, President
Shamrock Medical Solutions Group
741 Radio Drive
Lewis Center, Ohio 43035
Dear Mr. Martin:
During our July 14-17 and 28-29, 2009, August 11, 2009, September 18, 2009, and October 2, 2009 inspections of your pharmaceutical repackaging and relabeling facility, Shamrock Medical Solutions Group (Shamrock Medical), located at 250 Revolutionary Drive, Suite 200, East Taunton, Massachusetts, investigators from the 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 products 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, the drug products are misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)] and unapproved under section 505(a) of the Act [21 U.S.C. § 355(a)].
We have reviewed your firm’s responses of September 25, 2009 and January 18, 2010 and note that they lack sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited to, the following:
1. Your firm does not have any written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].
For example, your firm has no written procedures for conducting validation studies. Shamrock Medical is splitting and repackaging tablets without conducting validation studies to ensure that the product consistently meets label specifications. In addition, your firm has not established adequate production and process controls for this manufacturing operation, such as tests and specifications for assay, content uniformity, and tablet friability.
In general, we exempt repackagers from the CGMP requirements to test for the identity and assay of repackaged drug products where: (a) the repacking operations are conducted under conditions that ensure that the properties of the incoming drug product are not altered, and (b) the repackaged containers are labeled with the same substantive labeling declarations as the incoming bulk containers of the finished dosage form (e.g. identity, strength, and directions for use). Your firm has not met these conditions in that it has provided no assurance that the split tablets have the same properties as the intact tablets from which they were produced. Additionally, the labeled strengths of the split tablets differ from those of the intact tablets. We are especially concerned regarding your splitting of tablets, particularly for those drug products that have narrow therapeutic ranges and require monitoring of patient blood concentrations. Examples of these medications are (b)(4)™ (b)(4) tablets and (b)(4) tablets.
2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].
For example, no corrective or preventive action was documented regarding Simethicone Infant Gas Relief Drops, a drug product that your firm stated was light-sensitive. Your firm incorrectly packaged this product in non-light resistant packaging. According to your client, the defective product was destroyed, but no certificate of destruction was provided. Your client failed to indicate if the product had been dispensed to patients. A second light-sensitive drug product, Therapeutic Multivitamins with Minerals, was also incorrectly packaged in non-light resistant packaging. The defective product was returned and repackaged, but you did not investigate the effect of light exposure on product quality.
In your response of January 18, 2010, you state that you have revised your procedures for investigating and reporting “incidents.” You also stated that your firm has developed a new SOP to limit the exposure to light of those drugs labeled by the manufacturer as “protect from light” or “dispense in a light-resistant container.” However, we are unable to evaluate these corrective actions because you failed to provide supporting documentation. Additionally, there was no mention of any review of records of light-sensitive repackaged products to ensure that no other similar incidents occurred. We therefore find the response inadequate.
3. Your firm has not cleaned and maintained equipment at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality, or purity of the drug product [21 C.F.R. § 211.67(a)]. For example:
a. Plastic containers used to hold bulk liquid oral drug products during filling operations are washed between uses in a dishwasher without soap. There is no documentation that your firm performed studies to ensure that the cleaning adequately removes residues of the drug product from the containers before their re-use. Furthermore, these plastic containers are not covered during manufacturing operations. Your firm did not perform studies to demonstrate that this practice does not result in solvent loss and change in the concentration of the active ingredient.
b. Disposable silicone tubing sets are cleaned with isopropyl alcohol and distilled water between uses and then reused to fill liquid oral drug products. There is no documentation that your firm performed studies to ensure, for example, that this cleaning procedure (a) is
sufficient to effectively remove residues of the drug product from the tubing and (b) does not adversely affect the quality of the tubing for its re-use. The latter is of particular concern, because, as noted in the minutes from the Shamrock Medical Quality Committee meeting of August 18, 2008, the manufacturer of the tubing sets (b)(4) told your firm that the use of isopropyl alcohol to clean the tubing can “breakdown [sic] the silicone part of the tubing.”
In your response of January 18, 2010, you state that “Shamrock Medical is in the process of reviewing and approving draft procedures for the maintenance and cleaning of the packaging equipment.” This response is inadequate in that it fails to state (a) when the draft procedures will be finalized, (b) what information will be included in the new procedures, (c) what studies have been performed to validate the new cleaning procedures, and (d) whether training on the new procedures will be provided to the affected employees. Additionally, your response did not address interim measures or additional controls for manufacturing until the new procedures could be finalized.
4. Your firm does not have a written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates [21 C.F.R. § 211.166(a)].
For example, your firm split tablets of drug products in half or quarters, but failed to develop or follow a written testing program to conduct the required stability testing on these products. As required by 21 C.F.R. § 211.137, expiration dates must be supported by appropriate stability testing as described in a written program, which your firm has not established. In addition, your firm assigned 12-month expiration dates to all repackaged solid and liquid oral dose products without having any stability studies to support these expiration dates.
The corrective actions cited in your response of January 18, 2010, are inadequate in that you reference a “beyond use date,” rather than an “expiration date.” The CGMP regulations in 21 C.F.R. § 211.137 require adequate expiration dates on drug products packaged by a drug manufacturer. The repackaging activities that you perform constitute a manufacturing operation— regardless of whether you repackage to distribute under your firm’s label or under contract for other firms — and therefore must comply with the CGMP regulations.
5. Your firm failed to ensure that equipment is constructed so that surfaces that contact components, in-process materials, or drug products are not reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements [21 C.F.R. § 211.65(a)]. For example:
a. Plastic pail-type containers purchased at a home improvement store are used as vessels to hold bulk liquid drugs, such as Noxafil Oral Suspension, in filling operations.
There is no documentation of studies to demonstrate that the containers’ surface materials do not react with the drug products while holding the liquid drugs.
b. Disposable silicone tubing sets are cleaned with isopropyl alcohol and distilled water between uses and then reused to fill liquid oral drug products such as Noxafil Oral Suspension. No studies were conducted to demonstrate that the silicone does not react with the drug products when used to dispense the drugs.
In your response of January 18, 2010, you state that Shamrock Medical has stopped using the reusable plastic containers for liquid products and is currently using disposable, single-use polypropylene beakers that meet FDA requirements. However, your response is inadequate in that it fails to address how the cleaning process and period of use of the silicone tubing in the (b)(4)™ dispensing machine might affect the reactivity of the silicone in the tubing when the oral liquid drug products are dispensed through it.
6. Your quality control unit failed to fulfill its responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product [21 C.F.R. § 211.22(c)].
For example, your firm’s quality control unit failed to approve procedures regarding the operation and maintenance of equipment used by your firm to repackage drug products. The specific machines include the (b)(4) unit-dose packaging machine ((b)(4)™), the (b)(4)™
dispensing machine used for liquid oral drug products, and the machine (b)(4) used to repackage solid oral dosage forms. Specifically, your firm’s quality control unit failed to approve the following procedures:
• (b)(4) Production Run, M -0061 – procedures describing the steps required to adjust run-specific functions of the (b)(4) Unit-Dose Packaging Machine.
• (b)(4) unit Dose Packaging Machine Control Panel, M-0022 – procedures describing the functions and operations of the (b)(4) control panel.
• “Bingo Card” Packaging Machine (b)(4), M-0094 – procedures for calibration and maintenance of this machine.
• (b)(4) Unit Dose Packaging Run Procedures, M-0089 – procedures describing the start-up and use of this machine.
In your response of January 18, 2010, you state that “Shamrock Medical is in the process of reviewing and approving draft procedures for the operation and maintenance of various pieces of packaging equipment.” This response is inadequate in that it fails to state (a) when the draft procedures will be finalized, (b) what information will be included in the new procedures, and (c) whether training on the new procedures will be provided to the affected employees. Additionally, your response did not address interim measures or additional controls for manufacturing until the new procedures could be finalized.
7. Your firm failed to routinely calibrate, inspect, or check automatic, mechanical, or electronic equipment according to a written program designed to assure proper performance [21 C.F.R. § 211.68(a)].
For example, your firm has not conducted performance qualification for the (b)(4) unit-dose packaging machine (b)(4)™ to ensure its proper performance. Your firm has also failed to provide documentation to establish that the (b)(4)™ or (b)(4)“ Bingo Card” repackaging
equipment (for liquid and solid oral doses, respectively) has been qualified before use.
In your response of January 18, 2010, you stated that your firm has completed “machine validation” on several pieces of repackaging equipment used in production and will complete the process by the end of February 2010. This response is inadequate in that it fails to adequately describe how and on which pieces of equipment qualification will be performed. Your response provides an intended future date of completion, but fails to address whether manufacturing operations will continue before the machine qualifications are finalized, and, if so, what additional controls will be implemented during this interim period.
8. Your firm failed to provide adequate training in current good manufacturing practice as they relate to employees’ functions to enable employees engaged in the manufacture, processing, or holding of a drug product to perform their assigned functions [21 C.F.R. § 211.25(a)].
For example, our inspections revealed that employees engaged in critical manufacturing operations were not trained in CGMP. This was confirmed by the General Manager (GM), who informed the FDA investigator that no CGMP training is provided to operators and management personnel involved in critical operations. The GM also stated that he was not aware that this training was required. Also, when presented with an unsigned SOP entitled “Training,” which requires CGMP training of employees, both the GM and the Production Supervisor stated that they were unaware of this document.
In your response of January 18, 2010, you state that your firm will revise its training program to provide and track employee training in CGMP and specific job functions. This response is inadequate in that it fails to state when the training will be completed. It also fails to explain the
measures you will take to ensure product quality while operations continue with employees not adequately trained.
In addition to the CGMP violations discussed above, you manufacture and market unapproved new drugs in violation of the Act at your facility at 250 Revolutionary Drive, Suite 200, East Taunton, MA. Based on the information collected during the inspection, you manufacture the following prescription drugs, including, but not limited to:
• (b)(4) 1.5 mg tablet (b)(4) 3 mg tablet split in half and repackaged as 1.5 mg unit dose)
The above product is a drug within the meaning of section 201(g) of the Act, [21 U.S.C. §321(g)] because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases. Further, it is a “new drug” within the meaning of section 201(p) of the Act [21 U.S.C. § 321(p)] because it is not generally recognized as safe and effective for its labeled use(s). Under sections 301(d) and 505(a) of the Act [21 U.S.C. § 331(d), 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 on our information, you do not have any FDA-approved applications on file for this drug product.
Additionally, under section 301(a) of the Act [21 U.S.C. § 331(a)] it is prohibited to introduce into or deliver for introduction into interstate commerce a misbranded drug. The above product is misbranded because, as a prescription drug, adequate directions cannot be written for it so that a layman can use this product safely for its intended use(s). Consequently, its labeling fails to bear adequate directions for use as required under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)] and because it lacks a required approved application, it is not exempt from this requirement under 21 C.F.R. § 201.115. The introduction or delivery for introduction into interstate commerce of this product without an approved new drug application violates section 301(a) and (d) of the Act [21 U.S.C. § 331(a), (d)].
You should discontinue manufacturing and repackaging all of your unapproved drugs at your facility immediately. We also request that you outline the action you are taking to discontinue the manufacturing of the unapproved drug products at your facility, or any other applicable drug that you may manufacture. Also please note that if you are no longer manufacturing this or other unapproved drug products, you must update the Drug Listing files in accordance with 21 C.F.R. § 207.30(a)(2).
The violations cited in this letter are not intended to be an all-inclusive statement 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.
It appears that you have not taken a global quality systems approach to corrective actions at your firm. Several of the CGMP deficiencies observed during the inspection of your Massachusetts facility were also documented during our inspection of your Ohio facility in 2007. Examples of such deficiencies include: (a) failure of the quality control unit to approve or reject standard procedures, (b) failure to properly clean and maintain equipment and utensils, and (c) failure to ensure proper performance of automatic, mechanical, or electronic equipment. The Massachusetts and Ohio facilities share a single Corporate Quality Committee for decision making. It is your responsibility to review your operations at all facilities and apply appropriate corrective actions to address deficiencies present at multiple sites; i.e. the deficiencies cited by FDA in the inspection of your Ohio facility should have been noted and corrected at your Massachusetts facility. It is also your responsibility to ensure compliance with all requirements of federal law and FDA regulations.
Other issues of concern for the FDA include (a) the inadequate use by your operators of head and forearm coverings when working over open containers of oral liquid drug products, (b) the lack of procedure to evaluate environmental data (analyzing and trending) after it has been downloaded from the recording devices in the manufacturing area to a computer storage file, and (c) the assignment of 12-month expiration dates to your repackaged drug products, unsupported by stability studies, when the FDA Compliance Policy Guide 480.200 "Expiration Dating of Unit Dose Repackaged Drugs - Testing/Examination under CGMPs (CPG 7132.13)" provides for a maximum 6-month expiration for pharmaceutical products repackaged into suitable containers, without supporting stability studies.
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 being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute your repacked drug products manufactured at this facility, and provide the date(s) and reason(s) you ceased production. Please direct your response or any questions to Amber Wardwell, Compliance Officer. She may be reached at the address listed above or by telephone at (781) 596-7700.
John R. Marzilli
New England District
U.S. Food & Drug Administration