Inspections, Compliance, Enforcement, and Criminal Investigations
Jenahexal Pharm GmbH 10/19/11
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
Silver Spring MD 20993
VIA UPS MAIL WL: 320-12-02
October 19, 2011
Dr. Adalbert Lembcke
Chief Executive Officer and Pharmacist
Jenahexal Pharm GmbH
Dear Dr. Lembcke;
During our October 25 - 29, 2010 inspection of your pharmaceutical manufacturing facility, Jenahexal Pharm GmbH, located at Otto-Schott-Strasse 15, Jena, Germany, 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.
We acknowledge your written response to the Form FDA 483, submitted on November 26, 2010, and note that it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
1. Your firm has not established appropriate written testing procedures designed to assure the sterility of drug products purporting to be sterile [21 C.F.R. §211.167(a)].
For example, your firm released homeopathic injectables for distribution in the United States without performing adequate release testing. Specifically, you failed to test for bacterial endotoxin in the products you manufactured for your customer GUNA S.p.a. Such testing is essential to assure safety of your products.
In your response you stated that you tested the retain samples, and that they met your specifications for bacterial endotoxins. However, we are concerned that your firm is not taking full responsibility to fully adhere to applicable CGMP requirements for the operations you perform. For example, in your response you state that you had conducted bacterial endotoxin testing for homeopathic injectable drug products that you manufacture for other customers (e.g., (b)(4)) . Please note that you are responsible for the adequacy of all CGMP operations that you perform, including assuring that each batch you distribute is not microbiologically contaminated.
2. Your quality control unit has not established and documented the analytical methods used within your laboratory are adequate for their intended use [21 C.F.R. §211.165(e)].
For example, your sterility test method validation (Suitabilty Testing by (b)(4) Filtration) for the “GUNA-HIP” and “GUNA-ISCHIAL” injectable drug products is inadequate because it lacks verification of bacteriostasis and fungistatis activity in the product. In addition, you did not validate the sterility test method for other products that you manufacture.
In your response you stated that you use a (b)(4) approach for the sterility test method validation. However, you failed to provide a scientific rationale for this approach.
3. Your firm has not established a written assessment of stability of homeopathic drug products based at least on testing or examination of the drug product for compatibility of the ingredients and marketing experience with the drug product to indicate that there is no degradation of the product for the normal or expected period of use [21 C.F.R. §211.166(c)(1)].
In your response you indicated that homeopathic drug products are exempt from the requirements under §211.137. While expiration dating is not required for homeopathic products, evidence of the product stability over the expected shelf life is required. Your response failed to provide an assessment of the stability of the homeopathic injectable products that you manufacture.
Also, as noted below under the caption “Unapproved New Drug Violations,” several of your products use non-homeopathic drug ingredients, and are therefore not considered homeopathic drug products. These products are not exempt from expiration dating and related requirements.
4. Your firm failed to test each component for conformity with all appropriate written specifications for purity, strength, and quality [21 C.F.R. §211.84(d)(2)].
For example, your firm does not test the incoming (b)(4) solution to verify it is acceptable for use before using it in the manufacture of homeopathic sterile products.
Your response indicates that your facility accepts for use the incoming materials already released by your customers. However, the certificate of analysis (COA) you accept from your customers does not include a test for identity. In addition, you provided no information to show that the shipping of the incoming (b)(4) solution does not alter its quality.
UNAPPROVED NEW DRUG VIOLATIONS
FDA has reviewed the labeling for several of your firm’s products including: “Guna-Collagen,” “Guna-Handfoot,” “Guna-Shoulder,” and “Guna-Hip.” These products are unapproved new drugs in violation of sections 301 and 505 of the Act) [21 U.S.C. §§ 331 and 355].
Statements on the product labeling and package insert document the intended uses of your products, including but not limited to the following:
Guna-Collagen: “GUNA®-COLLAGEN is a homeopathic medicament indicated for: skin tone improvement; treatment of face and neck wrinkles; stimulation of connective tissue metabolism;”
Guna-Handfoot: “GUNA®-HANDFOOT is a homeopathic medicament indicated for: osteoarthritis of fingers pain; rhizoarthrosis of the thumb (Forestier disease); arthrosis pain due to hammer toe; Carpal-tunnel syndrome (in association with GUNA®-NEURAL); De Quervain disease (in association with GUNA®-NEURAL); Metatarsal pain; Morton disease (in association with GUNA®-NEURAL); Rheumatoid arthritis of the hand/foot (in association with GUNA®-POLYARTHRITIS); Hand/Foot tendon pain due to prolonged immobilization (casts tendon pain);”
Guna-Shoulder: “GUNA®-SHOULDER is a homeopathic medicament indicated for: Shoulder-arm syndrome; Shoulder pain; Shoulder-arm syndrome (in association with GUNA®-NEURAL); Frozen shoulder; Shoulder pain due to dislocation, therapeutic rest; Epicondylitis;” and
Guna-Hip: “GUNA®-HIP is a homeopathic medicament indicated for: Hip joint osteoarthritis; Hip joint capsule inflammation; Hip joint osteoarthritis with rheumatoid arthritis (in association with GUNA®-POLYARTHRITIS); Hip joint pain of muscle origin (in association with GUNA®-MUSCLE); Hip joint pain of nerve origin (burning hip, in association with GUNA®-NEURAL); Hip joint pain due to prolonged bed rest.”
Based on the above labeling and claims, these products are drugs under section 201 (g)(1)(B) of the Act (21 U.S.C. § 321 (g)(1)(B)), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man, and under section 201 (g)(1)(C) of the Act (21 U.S.C. § 321 (g)(1)(C)), because they are intended to affect the structure or any function of the body.
Further, “Guna-Collagen,” “Guna-Handfoot,” “Guna-Shoulder,” and “Guna-Hip” 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 intended 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 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 product. There are no FDA-approved applications on file for the above listed products. Therefore, the marketing of “Guna-Collagen,” “Guna-Handfoot,” “Guna-Shoulder,” and “Guna-Hip” without approved applications constitutes a violation of these provisions of the Act.
We recognize that these products are labeled as homeopathic drugs with active ingredients measured in homeopathic strengths. The definition of “drug” in section 201(g)(1) of the Act [21 U.S.C. 321(g)(1)] includes articles recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States (HPUS), or official National Formulary, or any supplement to any of them. The definition of homeopathic drug as set out in the Agency’s Compliance Policy Guide entitled “Conditions Under Which Homeopathic Drugs May be Marketed (CPG 7132.15)” (the CPG) states that a homeopathic drug is any drug labeled as being homeopathic which is listed in the HPUS, an addendum to it, or its supplements. Homeopathic drugs are subject to the same regulatory requirements as other drugs; nothing in the Act exempts homeopathic drugs from any of the requirements related to adulteration, labeling, misbranding, or approval. We recognize that many homeopathic drugs are manufactured and distributed without FDA approval; these homeopathic drugs are regulated by the enforcement policies set forth in the CPG. The CPG also states that “drug products containing homeopathic ingredients in combination with non-homeopathic active ingredients are not homeopathic drug products.”
FDA reviewed the labeling and active ingredients for the following products:
- “Guna-Collagen” includes “Collagen, Porcine 6X” as an active ingredient;
- “Guna-Handfoot” includes “Anti interleukin 1 alpha 4C,” “Anti interleukin 1 beta 4C,” and “Beta-Endorphin 4C” as active ingredients;
- “Guna-Shoulder” includes “Anti interleukin 1 alpha 4C,” “Anti interleukin 1 beta 4C,” “Beta-Endorphin 4C” and “Tendon, Porcine 6X 2 parts” as active ingredients; and
- “Guna-Hip” includes “Anti interleukin 1 alpha 4C, Anti interleukin 1 beta 4C, and Beta-Endorphin 4C” as active ingredients.
The above listed ingredients are not established homeopathic active ingredients included in the HPUS or any of the addenda or supplements. Furthermore, to our knowledge, these ingredients are not listed in any recognized materia medica containing information on the preparation of homeopathic medicines. Therefore, these ingredients are not considered homeopathic drug ingredients and “Guna-Collagen,” “Guna-Handfoot,” “Guna-Shoulder,” and “Guna-Hip” are not considered homeopathic drug products under the CPG. Accordingly the policies set forth in the CPG for the marketing of homeopathic drug products do not apply to “Guna-Collagen,” “Guna-Handfoot,” “Guna-Shoulder,” and “Guna-Hip.” Please note that these products are only examples of products your firm is marketing as homeopathic that contain active ingredients that do not conform to the CPG. It is your responsibility to ensure that all of your products marketed as homeopathic follow the enforcement policies set forth in the CPG.
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. If you wish to continue to ship your products to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.
Additionally, your firm is neither registered nor has it listed every product in commercial distribution in the United States with FDA, as required by 21 C.F.R. § 207.40 and section 510(i) of the Act [21 U.S.C. § 360(i)]. Information on how to register and list is available at the following internet website: http://www.fda.gov/cder/drls/registration_listing.htm. You must complete the required registration and listing and provide evidence that you have fulfilled these requirements in your response to this letter.
Our inspection also indicated that your process validation may be inadequate. An effective process validation contributes significantly to assuring that a drug manufactured is fit for its intended use and can be distributed. Adequate manufacturing process knowledge and validation is critical to assure the physical and chemical stability, as well as a robust sterility assurance for your homeopathic drugs.
Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, failure to correct these violations may result in FDA refusing admission of articles manufactured at Jenahexal Pharma GmbH into the United States. The articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)], in that, the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practice within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].
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. Please identify your response with FEI # 1000414342.
If you have questions or concerns regarding this letter, contact Milva E. Melendez, Compliance Officer, at the below address and telephone number.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing and Product Quality
Division of International Drug Quality
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-0662
Fax: (301) 847-8741
Michael Smedley on behalf of Steve Lynn
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research