Source: https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm511703.htm
Timestamp: 2019-04-24 22:30:50+00:00

Document:
On August 3, 4, and 5, 2015 and August 7 and 12, 2015 an investigator from the U. S. Food and Drug Administration (FDA) conducted an inspection of your drug repackaging, relabeling and own-label distribution facility, GenPak Solutions, LLC at 4324 Reynolds Drive, Hilliard, Ohio 43026-1260.
During this inspection, our investigators 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, Cosmetic Act (the FD&C 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.
Additionally, the inspection revealed that your firm repackages, relabels, and distributes unapproved new drugs in violation of section 505(a) of the FD&C Act [21 U.S.C. § 355(a)]. Furthermore, these products are also misbranded drugs in violation of section 502(f)(1) of the FD&C Act [21 U.S.C. § 352)] as detailed below.
We reviewed your August 27, 2015 response to the form FDA 483 in detail. Our investigator observed specific violations during the inspection, including, but not limited to, the following.
1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).
You have not validated the cleaning processes for the (b)(4) and the (b)(4). These non-dedicated pieces of equipment are used to repackage drugs such as steroids, anticonvulsants, statins, and antidepressants. You have no assurance that your cleaning processes are adequate to prevent unacceptable levels of residual product and cleaner on product contact surfaces for this equipment.
• Schedule and completion dates for executing your cleaning master validation plan and your completion date.
• Detailed cleaning procedures for manufacturing equipment including cleaning agent concentrations, hold times before cleaning, equipment disassembly instructions, cleaning frequencies, rinse times, water temperatures, visual inspection, dates of cleaning, and names of persons performing the cleaning.
• Repackaging line clearance procedures.
2. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166).
• A summary of your stability testing program, with scientific rationale. Include the program protocols, your testing methods, the stability test data to be collected, and how you will analyze the data to support your expiration dating.
3. Your firm failed to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)).
Your quality control unit failed to review 42 of the 104 batch production records that we looked at during the inspection for accuracy and completeness before you released drug products. Records lacked critical in-process control inspection results for tracking lot information, expiration dates, seal integrity, and broken or missing tablets/capsules. For example, your firm distributed prednisone 2mg tablets lot 15010127 on March 19, 2015, but the batch production record for this lot did not include in-process control inspection results and the batch production record was not signed by quality control unit personnel to indicate quality control unit review before release.
• Your steps to ensure that production records are reviewed and approved prior to lot release.
• Your steps to review all previously released lots when you find missing in-process data. Include your range of actions and your selection criteria.
4. Your firm failed to establish adequate written procedures for production and process controls, including validation protocols and reports, designed to assure that your drug products have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
You have no evidence that you validated the filling and sealing processes you use for repackaging at least 74 different drug products into unit dose containers.
• A master validation plan which includes specific strategies, protocols, and data generated to support your process validations. Specify your schedule and completion date for executing this validation master plan.
• A revised master batch record which no longer substitutes wherein bottle weights are no longer substituted for the visual inspection which is intended to verify bottle counts and that tablets/capsules are intact.
The CGMP violations discussed above are similar to those that FDA identified during our May 2013 inspection of your facility, yet your firm continued to release multiple batches of repackaged drug products for distribution. Your August 27, 2015, response promises the same corrective actions as your response to our May 2013 inspection. You failed to implement adequate controls to ensure that the drug products you repackage and sell, such as steroids and statins, are integral, free of contamination, and stable throughout their shelf life.
Failure to correct CGMP violations may result in enforcement action. We recommend that you engage a third party consultant with appropriate CGMP expertise to assess your facility and assist with your remediation.
Further, we request that you submit quarterly reports to the FDA with sufficient detail so that we can assess your progress as you correct these violations and ensure that you implement corrective actions globally.
Based on the information collected during the August 2015 inspection, we have determined that you repackage, relabel, and distribute unapproved new drugs in violation of sections 505(a) and 301(d) of the FD&C Act [21 U.S.C. §§ 355 and 331(d)].
The AnodyneRx product is indicated for the “temporary relief of minor aches and muscle strains associated with arthritis, simple backache, strains, muscle soreness and stiffness. Therefore, it is a drug within the meaning of section 201(g)(1) of the FD&C Act [21 U.S.C. § 321(g)(1)], because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and because it is intended to affect the structure or function of the body of man or other animals. Further, as labeled, this drug is a “new drug” within the meaning of section 201(p) of the FD&C Act [21 U.S.C. § 321(p)] because it is not generally recognized as safe and effective under the conditions prescribed, recommended, or suggested in the labeled uses.
Under sections 301(d) and 505(a) of the FD&C Act, 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 FD&C Act [21 U.S.C. § 355(b) or (j)] is in effect for the drug. There are no FDA-approved applications on file for the drug listed above. The marketing of this drug, or other new drugs, without an approved application constitutes a violation of these provisions of the FD&C Act.
The AdonyneRx product is a “prescription drug” as defined in section 503(b)(1)(A) of the FD&C Act [21 U.S.C. § 353(b)(1)(A)], because, in light of its toxicity or potential for harmful effects, or the method of its use, or the collateral measures necessary for its use, it is not safe for use except under the supervision of a practitioner licensed by law to administer it.
Because the AnodyneRx product is not safe for use except under the supervision of a practitioner licensed by law to administer them, adequate directions cannot be written for the drug product so that a layman can use it safely for its intended use. Consequently, the labeling of your AnodyneRx product fails to bear adequate directions for its intended use, causing it to be misbranded under section 502(f)(l) of the FD&C Act. Because this drug lacks a required FDA-approved application, it is not exempt under 21 CFR 201.115 from the requirements of section 502(f)(1) of the FD&C Act. The introduction or delivery for introduction into interstate commerce of these misbranded products therefore violates section 301(a) of the FD&C Act [21 U.S.C. § 331(a)].
Our review also found that you repackage nearly ninety-eight different drug products that are misbranded under section 502(o), [21 U.S.C. § 352(o)] in that the articles have not been listed as required by section 510(j) of the FD&C Act, [21 U.S.C. § 360(j)].
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 review all your products and their associated labeling for claims that may be in violation of the FD&C Act. It is your responsibility to assure compliance with all requirements of federal law and 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. You should discontinue manufacturing and distributing all of your firm’s unapproved drugs immediately.
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.
All firms are required to electronically update the listing of their products under section 510(j) of the FD&C Act to reflect the discontinuation of unapproved products (21 CFR 207.21(b)). Questions about the electronic drug listing updates should be sent to eDRLS@fda.hhs.gov. In addition to the required update, firms can also notify the Agency of product discontinuation by sending a letter, signed by the firm’s chief executive officer and fully identifying the discontinued product(s), including the product NDC number(s), and stating that the manufacturing and/or distribution of the product(s) have been discontinued. FDA plans to rely on its existing records, including its drug listing records, the results of future inspections, or other available information when considering enforcement action.
Within fifteen (15) 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 the related documentation. If you cannot complete corrective action within fifteen (15) working days, state the reason for the delay and the date by which you will have completed the corrections.
If you have any questions about the content of this letter, please contact Mr. Rabe at 513-679-2700 ext. 2163.

References: § 351
 § 355
 § 352
 § 321
 § 321
 § 355
 § 353
 § 331
 § 352
 § 360