Inspections, Compliance, Enforcement, and Criminal Investigations
Hawkeye Jensen Inc 2/8/11
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|900 U.S. Customhouse |
2nd and Chestnut Street
Philadelphia, PA 19106
RETURN RECEIPT REQUESTED
February 8, 2011
Wendy M. Shartle
72 Feick Avenue
Shartlesville, PA 19554
Dear Ms. Shartle:
During our June 14 to July 14, 2010 and August 4 to August 10, 2010 inspection of your pharmaceutical manufacturing facility, Hawkeye Jensen, Inc., located at 72 Feick Avenue, Shartlesville, Pennsylvania, 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 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, (b)(4) Antiseptic Wound Cream is an unapproved new drug under section 505(a) of the Act [21 U.S.C. § 355(a)] and misbranded under sections 502(a) and 502(e) of the Act [21 U.S.C. §§ 352(a) and (e)]. Further, (b)(4) (Chloroxylene 0.1%. Pramoxine HCI 0.5%, Zinc Acetate 0.1%) is an unapproved new drug under section 505(a) of the Act [21 U.S.C. 355(a)] and misbranded under section 502(f) (1) of the Act [21 U.S.C. § 352(f)(1)].
We have reviewed your firm’s response of August 2, 2010, and August 20, 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 has not established and/or followed written procedures for cleaning and maintenance of equipment [21 C.F.R. § 211.67(b)]. For example:
a. Your firm has not validated the cleaning process for the (b)(4), a non-dedicated piece of equipment, used to fill products such as (b)(4) Ear Drops, jeweler cleaner, nail polish, and baby lotion. Your firm does not have any assurance that your cleaning process is adequate to prevent unacceptable levels of residual product and cleaner on equipment product contact surfaces.
In your August 20, 2010 response, your firm states that you will validate the cleaning process for the (b)(4) based on your assessment of the worst–to-clean product. Be advised that the test methods used during your cleaning validation activities should be appropriate (e.g., selective and sensitive) to detect residue. Your response is inadequate because you have not provided the timeframe for which the cleaning process for the (b)(4) will be validated. We are concerned about the length of time your firm has needed to develop and implement cleaning validation plans, despite your awareness of our concerns since the February 2006 inspection. Further, your firm has not provided your interim plan to ensure the quality of drug products manufactured and distributed prior to the completion of your cleaning validation activities.
b. Your firm has not validated the (b)(4) water system used in the manufacture of drug products, including (b)(4) and (b)(4) Wound Healing Cream. Your firm does not have any assurance that your system can reliably and consistently produce water of acceptable chemical and microbiological quality.
In your August 2, 2010 and August 20, 2010 responses, your firm states: 1) you have resumed (b)(4) sampling; 2) you are making efforts to validate the (b)(4) water system, and; 3) you have demonstrated the ability of the system to generate water that complies with USP requirements. Your response is inadequate because your water analysis results (i.e., a sample tested on (b)(4) different days from July 2007 to July 2010) are insufficient to demonstrate that your water system is in a state of control. The validation of your (b)(4) water system should demonstrate that the system will consistently produce the desired water quality. The sampling plans and maintenance schedules for your (b)(4) water system should be supported by sufficient data.
Your response is also inadequate because you have not provided your corrective actions for deficiencies noted at the time of inspection for your microbiological testing of water samples. Specifically, you did not perform growth promotion testing on your solid media plates as per USP requirements. In addition, your firm was using (b)(4) media plates for microbiological assessment that were seven years pass expiration with no validation data to support this action. The ability of (b)(4) media plates to promote microbial growth is limited to the parameters specified by the manufacturer. Your firm cannot assure accurate microbiological test results if the media product specifications were not followed. Also, your firm was using a microbiological test method, SOP (b)(4), that was not validated.
This is a repeat observation from the September 2000 inspection.
2. Your firm has failed to follow written responsibilities and procedures applicable to the quality control unit [21 C.F.R. § 211.22(d)].
For example, your Quality Control Unity (QCU) failed to follow Standard Operating Procedure (SOP) (b)(4), that requires the QCU to: 1) (b)(4) 2) (b)(4) and; 3) to (b)(4) regarding the (b)(4) system. In addition, your QCU failed to follow SOP (b)(4) to ensure the documentation of complaints. In your August 2, 2010 response, your firm states that your corrective actions include (b)(4). Your response is inadequate because you have not specifically stated how added personnel (i.e., (b)(4)) will ensure your QCU fulfills its responsibilities (e.g., approval of (b)(4)). At the time of inspection, your Quality Manager repeatedly stated that QCU responsibilities were not fulfilled due to a lack of resources (e.g., money, time, and personnel). Be advised that a lack of resources is not an acceptable response for your firm’s failure to comply with CGMP regulations. It is a requirement under 21 C.F.R. § 211.25(c) to ensure that your firm has an adequate number of qualified personnel to perform daily operations.
3. Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product prior to release, including the identity and strength of each active ingredient [21 C.F.R. § 211.165(a)].
For example, your firm has failed to test each lot of (b)(4) and (b)(4) Wound Healing Cream to determine the strength of the active ingredients, Allantoin (0.5%) and Benalkonium Chloride (0.1%). Your firm’s QCU released lots (b)(4) between (b)(4) and (b)(4) and without such testing.
4. Your firm does not have adequate 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 failed to validate the manufacturing process for (b)(4) and (b)(4) Wound Healing Cream. Your firm has not identified the component attributes (e.g., solubility, viscosity, and particle size) and the process parameters (e.g., speed, temperature, and pH) that are important to produce this cream with a consistent quality. Your firm does not have any assurance that the manufacturing process is adequately controlled to consistently ensure the potency and uniformity of these drug products.
In your August 2, 2010 response, your firm states you will validate the manufacturing process. Your response is not adequate because you do not state the timeframe for completing the process performance qualification.
This is a repeat observation from the September 2000 inspection.
Over-the-Counter (OTC) Drug Products:
The label for (b)(4) Antiseptic Wound Cream includes the following claims:
“(b)(4) Antiseptic Wound Cream”
“Promotes Fast Infection Free Healing”
“Amino Acid Vitamin Complex”
In addition, the “Drug Facts” panel on the product’s label includes the following “Purpose” and “Use”:
“Purpose • Skin Protectant • First aid antiseptic”
“Use • First aid to help prevent infection in minor cuts, scrapes and burns.”
And the “Drug Facts” panel includes the following ingredient listing:
“Active Ingredients…Allantoin 0.5%, Benzalkonium 0.1%”
“Inactive Ingredients: Arginine, Chlorobutanol, Cod liver Oil, Diazolidinyl Urea, Glyceryl Monostearate, Hepes Linoleate, Isoleucine, Leucine, Methionine, Methyl Paraben, Mineral Oil, dl-Panthenol, Petrolatum, Phenylalanine, Propyl Paraben, Purified Water, Sorbitol 70%, Stearic Acid, Tea Tree Oil, Tetrasodium EDTA, Threonine, Trolamine, Valine, Vitamin E Acetate.”
The above statements demonstrate that (b)(4) Antiseptic Wound Cream is a “drug” as defined by section 20l(g)(l) of the Act [21 U.S.C. § 321(g)(l)] because it is intended to prevent disease and to affect the structure or function of the body of man.
The skin protectant claims on the product’s labeling, as well as the listed active ingredient of allantoin—a skin protectant active ingredient—subject (b)(4) Antiseptic Wound Cream to the requirements of the OTC Final Monograph for Skin Protectant Drug Products (21 C.F.R. Part 347). In addition, first aid antiseptic and wound claims are also discussed in the OTC Tentative Final Monograph for First Aid Antiseptic Drug Products (56 Fed. Reg. 33644 (July 22, 1991)). Although skin protectant and first aid antiseptic combination products are permitted under the skin protectant final monograph when formulated and labeled in conformance with the respective rulemakings, (b)(4) Antiseptic Wound Cream is neither formulated nor labeled in conformance with the skin protectant final monograph or any first aid antiseptic rulemaking.
Specifically, the product’s “Drug Facts” panel lists allantoin and benzalkonium chloride as the product’s active ingredients. However, the product’s principal display panel prominently displays the term, “Amino Acid Vitamin Complex,” which suggests these ingredients contribute to the uses attributed to the product. Therefore, it is our position that the amino acids and vitamins listed as inactive ingredients in the product’s “Drug Facts” panel are active ingredients for (b)(4) Antiseptic Wound Cream that are intended to furnish pharmacological activity as defined in 21 C.F.R. § 201.66(b)(2).1 The combination of the amino acid and vitamin ingredients as active ingredients along with the other listed active ingredients is not an acceptable combination under the final monograph for OTC skin protectant drug products (21 C.F.R. § 347.20(d)) nor does it follow any first aid antiseptic rulemaking (56 Fed. Reg. 33644 (July 22, 1991)).
Moreover, the labeling indicates that the drug product can be used for “Fast Infection Free Healing” and as a “Wound Cream.” However, the final monograph for OTC skin protectants does not allow for either an “…Infection Free…” indication or a “…Wound…” indication. (21 C.F.R. §§ 347.50(b) and 347.60(b)(2)). In fact skin protectant products containing allantoin as an active ingredient and making wound healing claims are explicitly not generally recognized as safe and effective under 21 C.F.R. § 310.545(a)(18). Furthermore, wound claims are also not part of the first aid antiseptic rulemaking (56 Fed. Reg. 33644 (July 22, 1991)).
Moreover, we are not aware of sufficient evidence that shows this product as formulated and labeled is generally recognized as safe and effective as a topical skin protectant and first aid antiseptic. Therefore, (b)(4) Antiseptic Wound Cream is a “new drug” under section 201(p) of the Act [21 U.S.C. § 321 (p)] and may not be legally marketed in the United States without an approved application under section 505(a) of the Act [21 U.S.C. § 355(a)].
Finally, as described above, your product’s amino acid and vitamin ingredients are listed as inactive ingredients in the product’s “Drug Facts” panel but your product’s labeling also gives more prominence to these ingredients than your product’s other inactive ingredients (21 C.F.R. § 201.10(c)(1)). Therefore, the amino acid and vitamin ingredients are considered active ingredients for (b)(4) Antiseptic Wound Cream. As a result, the labeling is misleading causing (b)(4) Antiseptic Wound Cream to be misbranded under sections 502(a) and 502(e) of the Act [21 U.S.C. §§ 352(a) and (e)].
Prescription Drug Products:
Based on the information your firm submitted to FDA’s Drug Registration and Listing System you market unapproved drug products, including, but not limited to:
• (b)(4) (Chloroxylene 0.1%. Pramoxine HCl 0.5%, Zinc Acetate 0.1%).
This 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, your product is “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 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, you do not have any FDA-approved application on file for this drug product. The marketing of this product without an approved application constitutes a violation of these provisions of the Act.
Additionally, because (b)(4) is 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 it so that a layman can use this product safely for its intended uses. Consequently, its labeling fails to bear adequate directions for its intended use, causing it to be misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)]. Because your product lacks required approved application, it is not exempt under 21 C.F.R. § 201.115 from the requirements of section 502(f)(1) of the Act. The introduction or delivery for introduction into interstate commerce of this product therefore violates section 301(a) of the Act [21 U.S.C § 331(a)].
FDA remains committed to taking enforcement action against unapproved drugs in an effort to ensure that drugs used by patients are safe and effective, but at the same time seeks to ensure that such actions do not impose an undue burden on patients.
As expressed in Compliance Policy Guide (CPG) Section 440.100, Marketed Unapproved Drugs, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070290.pdf, FDA expects manufacturers of products requiring approval to submit applications to the agency showing that their products are safe and effective. The CPG describes the very strict criteria under which the Act permits drugs to be marketed without approval. The CPG also outlines the Agency’s enforcement policies aimed at efficiently and rationally bringing all drugs requiring approved applications into the approval process.
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.
Your firm acts as a contract manufacturer for various finished OTC drug products. It is essential that you understand your responsibility to operate in full compliance with CGMPs and to inform all of your customers of significant problems encountered during the testing of these 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 the drug product(s) manufactured at this facility, and provide the date(s) and reason(s) you ceased production.
Your response should be sent to Richard C. Cherry, Compliance Officer, at U.S. Customhouse, Room 900, 200 Chestnut Street, Philadelphia, PA 19106.
Kirk D. Sooter
Philadelphia District Office
1 "Active ingredient means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans." 21 CFR § 201.66(b)(2).