Inspections, Compliance, Enforcement, and Criminal Investigations
Pharma Pac LLC 4/27/09
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
New Orleans District
April 27, 2009
WARNING LETTER NO. 2009-NOL-08
Delivery Signature Requested
Neil S. Sirkin, President
Pharma Pac LLC
110 Industrial Park Road
De Kalb, Mississippi 39328
Dear Mr. Sirkin:
During an inspection of your pharmaceutical manufacturing facility, located at 110 Industrial Park Road, De Kalb, Mississippi, on June 23-26 and July 16, 2008, investigators from the United States Food and Drug Administration (FDA) found your firm is manufacturing and marketing unapproved new drugs in violation of Sections 301(d) and 505(a) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 USC 331(d) and 355(a)], and these drugs are misbranded in violation of Sections, 301(a), 502(c), (e)(1)(A)(ii) and (iii), (f)(1), and (0) of the Act [21 USC 301(a), 352(c), (e)(1)(A)(ii) and (iii), (f)(1), and (0)]. In addition, the inspection revealed deviations from the Current Good Manufacturing Practice (CGMP) requirements of the regulations found at Title 21, Code of Federal Regulation (21 CFR), Parts 210 and 211. Failure to conform to the CGMP regulations causes the products manufactured by your facility to be adulterated within the meaning of Section 501(a)(2)(B) of the Act [21 USC 351(a)(2)(B)].
Unapproved and Misbranded Prescription Drugs
Based on the information collected during the inspection, you manufacture the following prescription drugs, not limited to:
• (b)(4) (each 1 mL contains: Brompheniramine Maleate, USP, 1 mg; Dextromethorphan HBr USP, 3 mg; Pseudoephedrine HCl USP, 12.5 mg); and,
• (b)(4) Antihistamine/Nasal Decongestant (each 5 mL contains: Phenylephrine Tannate 5 mg; Chlorpheniramine Tannate 4.5 mg).
The above products are drugs within the meaning of Section 201(g) of the Act, [21 USC 321(g)] because 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 USC 321(p)] because they are not generally recognized as safe and effective for their labeled uses. Under Sections 301(a) and (d) and 505(a) of the Act [21 USC 331(a) and (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 USC 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 which are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written for them so 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 USC 352(f)(1)], and because the products lack required approved applications, they are not exempt from this requirement under 21 CFR 201.115.
Your firm's drug products are further misbranded under Section 502(0) of the Act [21 USC 352(o)], because they have not been listed, as required by Section 510(j) of the Act [21 USC 360(j)]. Your facility is not exempt from drug listing requirements under 21 CFR 207.10 or Section 510(g) of the Act [21 USC 360(g)]. We note you provided copies of Drug Product Listing Form FDA 2657 to the investigator during the February 2006 inspection; however, your forms do not have receipt stamps from the FDA and based upon our research of the drug products listed on the forms, they are not listed with the FDA.
Your firm's prescription drug (b)(4) are misbranded because its finished product label does not declare the inactive ingredients contained in those drug products, as required by Section 502(e)(1)(A)(iii) of the Act [21 USC 352(e)(1)(A)(iii)].
Unapproved and Misbranded Over-the-Counter (OTC) Drugs
Your firm manufactures numerous drug products for OTC use. Specifically, based on the labeling collected during the inspection of your facility and as described in detail below, healing skin therapy lotion, manufactured by your firm is a "drug" and a "new drug" which requires approval of a new drug application under the Act to be legally marketed in the United States.
The labeling of healing skin therapy lotion includes the following statements:
• "Hydrates... irritated skin... problem skin... to promote speed of healing"
• "Vitamin A - Improves elasticity..."
• "Vitamin C - Promotes skin development & collagen formation"
• "Vitamin E - Enhances protective function of skin..."
Based on the labeling claims, healing skin therapy lotion is a "drug" as defined by Section 201 (g)(1) of the Act [21 USC 321 (g)], because it is intended to affect the structure or any function of the body of man.
The labeled claims noted above relating to the treatment of irritated and problem skin and the healing thereof go beyond cosmetic claims and subject healing skin therapy lotion to the final monograph for Skin Protectant OTC Drug Products. While cosmetics are intended to be "applied to the human body... for cleansing, beautifying, promoting attractiveness, or altering the appearance ...",21 USC 321(i), healing skin therapy lotion's labeling goes beyond cosmetic claims and states the product "Hydrates... irritated skin... problem skin... to promote speed of healing." The OTC skin protectant advisory panel designated skin protectant drug products to include topical medications for irritated skin, including those which "decrease the irritation that is caused by drying of the stratum corneum [outermost layer of the skin]" 43 Fed. Reg. 34630 (Aug. 4, 1978). In addition, healing skin therapy lotion's label prominently displays the inclusion of "Vitamin E" and states" Vitamin E-Enhances protective function of skin...." OTC topical products intended to temporarily protect skin from harmful or annoying stimuli are subject to the requirements of the final monograph for Skin Protectant OTC Drug Products (21 CFR 347.1). We note three of the first four ingredients listed on the label ("Glycerin," "Dimethicone," and "Petrolatum") are allowable active skin protectant ingredients at specific concentrations under the OTC Skin Protectant monograph. Therefore, for the reasons discussed, healing skin therapy lotion is subject to the final monograph for Skin Protectant OTC Drug Products at 21 CFR 347.
However, as labeled, healing skin therapy lotion does not conform to the final monograph for Skin Protectant OTC Drug Products. Not all of the intended uses referenced above, such as "promote[s] speed of healing," "Hydrates ... problem skin," "Improves elasticity" and "Promotes skin development & collagen formation" are included in the final monograph for OTC Skin Protectants as appropriate labeled uses. In fact, under FDA's OTC Drug Review, the skin protectant advisory panel explicitly stated "No skin protectants... have been proven to promote healing..." with respect to minor superficial bums (which could be considered one type of "problem skin" under healing skin therapy lotion's labeling) 43 Fed. Reg. 34631.
Furthermore, the combination of ingredients identified on the label is not authorized under the OTC skin protectant monograph. The ingredients identified under the heading "Ingredients" on the label for healing skin therapy lotion are not differentiated as active or inactive ingredients. The ingredients are listed on the label as follows:
"Ingredients: Water, Glycerin, Dimethicone, Petrolatum, Jojoba Esters, Cetyl Alcohol, Aloe Barbadensis Leaf Juice, Stearyl Alcohol, Distearyldimonium Chloride, Cetearyl Alcohol, Steareath-21, Steareth-2, Propylene Glycol, Chamomilla Recutita (Matricaria) Flower Extract, Polysorbate 60, Stearamidopropyl PG Dimonium Chloride Phosphate, Methyl Gluceth-20, Tocopheryl Acetate, Magnesium Ascorbyl Phosphate, Hydrolyzed Collagen, Hydrolyzed Elastin, Retinyl Palmitate, Hydrolyzed Jojoba Esters, Glyceryl Stearate, Dipotassium EDTA, Fragrance, Triethanolamine, Diazolidinyl Urea, Methylparaben, Propylparaben."
Since these ingredients are not differentiated as active or inactive ingredients, they are all represented as contributing to the claimed effect and, thus, "active ingredients" as defined by 21 CFR 201.66(b)(2). This combination of active ingredients is not authorized in the final monograph for Skin Protectant OTC Drug Products or any other final or tentative final monograph.
As such, we are not aware of any evidence establishing that "healing skin therapy lotion," as formu1ated and labeled, is generally recognized among scientific experts as safe and effective. We are unaware of any evidence documenting a product so formu1ated and labeled was marketed in the United States on or before the inception of FDA's OTC Drug Review. Therefore, healing skin therapy lotion does not qualify for inclusion in any of the ongoing rulemakings under the OTC Drug Review. In addition, this product's formulation and claims described above are not discussed in any of the rulemakings which are being considered under the OTC Drug Review. Therefore, healing skin therapy lotion is a "new drug" under Section 201(p) of the Act [21 USC 321(p)] and because healing skin therapy lotion is not the subject of an FDA-approved application, its marketing in the United States violates Sections 301(d) and 505(a) of the Act [21 USC 331(d) and 355(a)].
In addition to the above violations, healing skin therapy lotion is misbranded under Section 502(c) of the Act [21 USC 352(c)], because the product is not labeled in accordance with the "Drug Facts" labeling requirements described in 21 CFR 201.66 and is misbranded under Section 502(e)(1)(A)(ii) of the Act [21 USC 352(e)(1)(A)(ii)] because it fails to declare the quantity of active ingredients. Additionally, healing skin therapy lotion is misbranded under Section 502(0) of the Act [21 USC 352(o)], because it is not listed, as required by Section 510(j) of the Act [21 USC 360(j)], and your facility is not exempted from drug listing requirements under 21 CFR 207.10 and Section 510(g) of the Act [21 USC 360(g)].
The introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under Section 301(a) of the Act [21 USC 331(a)]. The marketing of healing skin therapy lotion in the United States violates this provision of the Act.
Deviations from CGMP Regulations
During the inspection, our investigator observed deviations from CGMP regulations in the manufacture of drug products at your facility. As a manufacturer of human drugs, it is your responsibility to assure your firm's products are manufactured in conformance with CGMP as delineated in 21 CFR 210 and 211.
For example, your finn had not established an adequate quality control unit which sufficiently controls written procedures and specifications as required by 21 CFR 211.22(c). In addition, written procedures applicable to the quality control unit and production processes were not followed, as required by 21 CFR 211.22( d) and 21 CFR 211.100(b). Furthermore, your firm did not establish adequate procedures, as required by 21 CFR 211.110(a), for in-process control during the manufacture of the Meclizine HCI product and the testing and release of this product did not include appropriate laboratory determination of satisfactory conformance to final specifications prior to release, as required by 21 CFR 211.165(a). Also, the Meclizine HCI product failed to bear an expiration date determined by appropriate stability data, as required by 21 CFR 211.137(a).
Finally, your firm did not provide equipment for the adequate control of humidity and other environmental factors impacting on the manufacture of the Meclizine HCL product as required by 21 CFR 211.46(b), and had not established adequate written procedures for the handling of complaints, as required by 21 CFR 211.198(a).
We acknowledge your correspondence of July 31, 2008, sent in response to the observations described in the Form FDA 483, stating manufacture of the Meclizine HCI product is discontinued and detailing other corrective actions. In addition, we acknowledge your correspondence of September 24, 2008, announcing the cessation of the manufacture of all Papain debridement ointments (See 73 FR 54831, September 23, 2008), including the (b)(4) product. Be aware, however, it is your responsibility as a drug manufacturer, to proactively assure all drug products manufactured in your facility, now or in the future, are manufactured in accordance with all CGMP regulations and the products meet the requirements of the Act as to safety, and have the identity and strength and meet the quality and purity characteristics they purport or are represented to possess.
The violations and issues cited in this letter are not intended to be an all-inclusive list of violations existing at your facility. 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 conduct a comprehensive audit of your facility and operations and assure compliance with all requirements of the Act and FDA regulations. Federal agencies are advised of the issuance of all warning letters about drugs so they may take this information into account when considering the award of contracts.
You should take prompt action to correct all the violations noted in this letter, and you should establish procedures whereby such violations do not recur. Failure to promptly correct violations may result in regulatory action without further notice, such as seizure and/or injunction.
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 follow-up inspection may be necessary. If you no longer manufacture or market any of your drug products, your response should so indicate including the reasons for and the date on which you ceased production.
Please notify this office in writing, within fifteen (15) working days from your receipt of this letter, of the specific steps you have taken to correct the noted violations, including an explanation of each step taken to prevent recurrence of similar violations. You should include in your response documentation or other useful information to assist us in evaluating your corrections. If you cannot complete all corrections before you respond, you must explain the reason for your delay and state when you will correct any remaining deviations. You can find guidance and information for the regulated industry regarding regulations for drug products through links at FDA's website at http://www.fda.gov/oc/industry/.
Your reply should be directed to the U.S. Food and Drug Administration, Attention: Cynthia R. Gibson, Compliance Officer, at the above address. If you have questions regarding any issue in this letter, please contact Ms. Gibson at (251) 344-8208, extension 105.
H. Tyler Thornburg
New Orleans District
Enclosure: Form FDA 483