|
FDA Warning Letter/ Notice of Violation Letter |
Link:
Pharm/Biotech Resources
Posted by FDA:
2011
Dr. Adalbert Lembcke
Chief Executive Officer and Pharmacist
Jenahexal Pharm GmbH
Otto-Schott-Strasse 15
Jena, Germany
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.
CGMP VIOLATIONS
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.
CONCLUSION
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
Sincerely,
Michael Smedley on behalf of Steve Lynn
Director
Office of Manufacturing and Product Quality
Office
of Compliance
Center
for Drug Evaluation and Research
|
|
| [
Outsourcing Guide
] [
Cont. Education
] [
Software/Reports
] [
Training Courses ]
[ Web Seminars ] [ Jobs ] [ Consultants ] [ Buyer's Guide ] [ Advertiser Info ] [ Home ] [ Pharm Patents / Licensing ] [ Pharm News ] [ Federal Register ] [ FDA Links ] [ FDA Warning Letters ] [ Pharm/Biotech Events ] [ Newsletter Subscription ] [ Web Links ] [ Suggestions ] [ Site Map ] |