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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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River's Edge Pharmaceuticals, LLC 5/20/10


Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
Atlanta District Office
60 8th Street, N.E.
Atlanta, Georgia 30309

May 20, 2010



Brendan Murphy, President
River's Edge Pharmaceuticals, LLC
5400 Laurel Springs Parkway
Building 500, Suite 504
Suwanee, Georgia 30024-6056

Dear Mr. Murphy:

Investigator(s) from the Food and Drug Administration (FDA) conducted an inspection at your pharmaceutical manufacturing facility, River's Edge Pharmaceuticals, LLC, from July 13 thru August 12, 2009, and identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. River's Edge Pharmaceuticals is located at 5400 Laurel Springs Parkway, Building 500, Suites 503 & 504, Suwanee, Georgia, and is an own-label distributor that has entered into agreements with contract manufacturers to manufacture all products. These CGMP 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 prescription drugs are manufactured without an approved application. As described below, these drugs are unapproved new drugs without an approved application, and by introducing them into interstate commerce, you are in violation of sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)]. These unapproved new drugs are misbranded pursuant to section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)], and by introducing them into interstate commerce you are in violation of section 301(a) of the Act [21 U.S.C. § 331(a)].

We have reviewed your firm's response of August 28, 2009, and note that it lacks sufficient corrective actions.

Specific violations observed during the inspection include, but are not limited, to the following:

CGMP Violations

1. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].

For example,

a. Lots 7L2198 and 8I2342 of Lidocaine HCI 3%/Hydrocortisone 0.5% were released and distributed even though they failed stability testing. These lots failed your initial release and shelf-life viscosity specification during stability testing at the 3, 6, and 9 months time points. In your response, your contract manufacturer (b)(4) revised the viscosity specification to a range of (b)(4) cps. In revising your viscosity specification, you do not describe a scientific rationale for making these changes nor do you discuss the impact, if any, to your product quality.

b. Your firm failed to provide a scientific rationale for releasing Selenium Sulfide 2.25% Shampoo, Lot 94200. This lot failed the pH specification (b)(4) as identified in your validation report, but was released and distributed based on the pH specification (b)(4) listed in your stability summary report.

2. Your quality control unit (QCD) has not fulfilled its responsibility to approve or reject 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 QCD failed to reject Lot 6191 of RE Pramoxine HC Otic Drops when the lot failed the assay specification for Chloroxylenol (b)(4) during accelerated stability testing. In our review of the stability data (during the inspection) for this product, we discovered incorrect assay results and brought these findings to your attention. In. your response, you agreed the assay results were incorrectly rounded and that the product did not meet the assay specification. We acknowledge your plan to perform a "safety assessment" for this product. However, your response does not provide a timeline for completing this safety assessment or how your employees will be trained.

3. Your quality control unit has not fulfilled its responsibility nor exercised its authority to approve or reject all drug products manufactured, processed, packed or held under contract by another company [21 C.F.R. § 211.22(a)].

For example, your firm failed to review the Certificate of Analysis (COA) for your products prior to release and distribution. Your current practice for release and distribution of product is to check for the presence of a COA prior to accepting shipment; however, there is no requirement that the COA actually be reviewed. Also, during a separate inspection, your Warehouse Supervisor responded "no" when asked if the receiving employee is required to review the COA for conformance of specifications prior to accepting the shipment.

4. Your firm has not followed written procedures for the handling of written and oral complaints regarding drug products [21 C.F.R. § 211.198(a)], and your quality control unit failed to conduct complaint investigations or include a written record of the reasons that an investigation was found not to be necessary [21 C.F.R. § 211.198(b)(3)].

For example,

a. Your firm failed to review and approve Complaint #'s 548, 575, 583, and 607 as required by your SOP RE-001-001.

b. Your firm failed to investigate over 30 complaints of discoloration of Hydroquinone 4% Cream.

You also failed to provide a written record explaining why these complaints were not investigated.

According to your response, your firm plans to address this discoloration issue by revising the labeling to describe the product as a "tan to slight brown cream on storage." Your response is not adequate since Hydroquinone 4% cream is a prescription drug product and requires approval prior to marketing. The safety and effectiveness of this drug must be evaluated as a part of a New Drug Application (NDA).

FDA understands the need for assistance when securing approval for currently marketed unapproved drugs. As part of our commitment to assist firms through this process, FDA has appointed an unapproved drugs coordinator in the Office of New Drugs, Dr. Sally Loewke, to work with companies trying to bring their products into compliance. Please contact Dr. Loewke, at 301-796-0710, to start the process of obtaining approval for all your marketed unapproved drug products.

c. Your firm did not adequately investigate complaints for the presence of red speckles in Reme-Tussin DM cough Syrup. We acknowledge in your response that you plan to re-open the investigation for the Reme-Tussin DM cough syrup to determine a root cause for the unidentified particles. However, your response is not adequate because you do not provide a timeline for investigating these complaints. Please ensure that your investigation includes a root cause determination and a corrective action plan. Also, for lots that have been distributed, please provide an evaluation of product impact.

5. Your firm failed to conduct current good manufacturing practice (CGMP) training as related to the employees' assigned functions [21 C.F.R. § 211.25(a)].

As evidenced in prior examples, your firm has not trained your employees on CGMP regulations. We acknowledge you have established a procedure for conducting routine CGMP training and have requested a third party expert consulting firm to provide CGMP training to your employees.

We acknowledge your newly generated procedures for your product approval processes, completing vendor audits, annual product reviews, and your plans to perform a comprehensive review of your validation program for all products manufactured by your contract companies. However, we are concerned about your firm's fundamental understanding of what is required by your QCD and the regulatory expectations for a firm that enters into agreements with contract manufacturers to manufacture all drug products. Although you have agreements with other firms that may delineate specific responsibilities to each party (e.g., quality control responsibilities), you are ultimately responsible for the quality of your products. Regardless of who manufactures your products or the agreements in place, you are required to ensure that these products meet predefined specifications prior to distribution and are manufactured in accordance with the Act and its implementing regulations, including CGMP regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Part 211.

Unapproved and Misbranded Prescription Drugs

Based on the information collected during the inspection, you market the following prescription rugs, including but not limited to:

• DiphenMax Chewable Tablets (Diphenhydramine Tannate 25 mg)
• DiphenMaxD Chewable Tablets (Diphenhydramine 25 mg, Phenylephrine Tannate 10 g)
• Dextromethorphan Tannate 30 mg Phenylephrine Tannate 20 mg Dexchlorpheniramine Tannate 2 mg
• Dextromethorphan Tannate 25 mg Phenylephrine Tannate 15.5 mg Pyrilamine Tannate 5.5 mg
• Hyoscyamine Sulfate 0.125 mg IRIHyoscyamine Sulfate 0.250 mg SR Tablets
• Servira Tablets (Phenobarbital, 48.6 mg, Hyoscyamine Sulfate .3111 mg, AtropineSulfate .0582 mg, Scopolamine Hydrobromide .0195 mg)

The above products are drugs within the meaning of section 201(g) of the Act, [21 U.S.C.§ 321(g)] because, as demonstrated by their labeling, they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases. Further, they 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 on our information, there are no FDA-approved applications on file for these drug products.

Additionally, because the above prescription drug products 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 products safely for their intended uses. Consequently, their 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 the products lack required approved applications, they are not exempt from this requirement under 21 C.F.R. §201.115. The introduction or delivery for introduction into interstate commerce of these products without approved new drug applications violates section 301(a) and (d) of the Act [21 U.S.C. §§ 331(a) and (d)].

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. 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. 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.

As stated above, you must cease manufacturing and distributing all your unapproved new drug products. 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 products, and provide the date(s) and reason(s) you ceased production.

Your reply should be sent to Philip S. Campbell, Compliance Officer, at the address noted in the letterhead.

John R. Gridley, Director
Atlanta District