Shanghai Medical Ltd 10-Feb-04

Departmentof Health and Human Services	Public Health Service Food and Drug Administration
	Rockville, MD 20857

WarningLetter

Via Certified andRegistered Mail

WL:320-04-03

FEB 10, 2004

Ding You Xin
Factory Director
Shanghai Medical Ltd.,
No. 15 Pharmaceutical Factory
1440 Bei Di Road
Shanghai, China

Dear Mr. Ding:

We have completed our reviewof the inspection of your pharmaceutical manufacturing facility in Shanghai,China, by Investigator Robert C. Horan, Ph.D. and Chemist Susan W. Ting, duringthe period of 27-31 October 2003. The inspection revealed significant deviationsfrom U.S. current Good Manufacturing Practice (cGMP) in the manufacture of activepharmaceutical ingredients (APIs). The deviations were presented to you on anInspectional Observations (FDA-483) Form, at the close of the inspection. ThesecGMP deviations cause your APls to be adulterated within the meaning of section501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.

We have reviewed your November7, 20 and December 22, 2003, responses to the FDA 483 Inspectional Observationssent through [redacted] Group Vice President, of [redacted] These responsesdo not sufficiently address the deviations observed during the aforementionedinspection.

Specific areas of concerninclude, but are not limited to:

1. Qualifications ofthose working in the Quality Assurance (QA) and Quality Control (QC) unitshave not been demonstrated to be adequate.

In your response datedNovember 20,2003, you state that, “Our parent company has transferredtwo qualified QC supervisors” and that, “The interim head of QChas been replaced with a qualified individual.” In the organization chartthat you provided as Appendix 3, two of these individuals are identified ashaving Bachelor of Science degrees in engineering and one as being a LicensedPharmacist having graduated from a Secondary Technical School. Further, no oneon the organizational chart, including supervisors in QA and QC, are identifiedas having academic or other suitable training in chemistry or microbiology.This is of particular concern because all of the items listed on the FDA 483related to the chemistry and microbiology deviations in the quality controlunit. The investigative team also stated that analysts could not always answertheir questions about testing. For example, a supervisor and QC manager couldnot explain how the calculation was done for the [redacted] assay determinationfor [redacted] and [redacted] In addition, the analyst performing this assaywas unaware that it is necessary to enter the [redacted] in order for the resultto be calculated properly. Lastly, the two microbiologists interviewed wereunable to accurately answer questions about growth promotion and the identificationof microorganisms.

In your recent correspondenceyou offered to provide our office a copy of the internal audit that resultedfrom this inspection. We would like to see your audit findings.

2. One of the discussionpoints with management concerned missing data for the analysis of [redacted]and [redacted] by [redacted] There were six entries in the [redacted] logbookthat could not be found in the correlating computer files.

In your response, you statethat these were samples tested for training purposes and their [redacted] weresubsequently discarded. We fail to see how this could be accurate since theanalyst conducting the test on 2/13/03 conducted 24 other acceptable tests beforethis. In addition, the analyst conducting the tests on 2/21/03, 2/23/03, 2/25/03,2/27/03, and 3/01/03 conducted analyses on 2/20/03, 2/24/03, 2/26/03, and 2/28/03.These test results were entered as acceptable prior to completion of what youare telling us is training. We are concerned about this discrepancy.

3. The microbiologicaltest records all appear to be recently written in spite of the fact that somedate back as far as two years.

You state that the documentsmay appear new because they are kept in plastic folders away from heat and light.The investigative team says they never observed any of the documents they requestedfrom the microbiological laboratory being removed from plastic folders, nordid they observe this practice anywhere else in the firm. In addition, the investigativeteam expressed concerns that the records having one entry per day appeared tohave multiple entries in the same handwriting written at a single time. Also,entries identified as being performed by a single person appeared to be writtenin more than one person’s handwriting. They observed this with virtuallyall of the documents they reviewed in the microbiological laboratory, includingsuch documents as equipment usage logs, logs for record receipt of materials,and for transfer of cultures. You failed to address this in your responses.

4. Individuals responsiblefor overseeing testing, other management, [redacted] technical managers, andthe individual hired by [redacted] as a cGMP consultant were not forthcomingwith testing documents for [redacted] testing by [redacted]

The investigative teamwas together during the interaction with the above mentioned individuals regardingthe test records for [redacted] testing. Both give the same account of whathappened. They have documented a detailed description of who they spoke withand what responses they received. None of the responses from the above mentionedindividuals was accurate until the investigative team found the test resultson the [redacted]computer. All of the above mentioned individuals initiallydenied that the firm has ever tested [redacted] for [redacted] by [redacted]Then, the QC manager said that they had done the test once a long time ago,but did not have record of the test. Later, when the investigative team lookedat the [redacted] computer files, they found that [redacted] testing for [redacted]was routinely performed. In addition, the QC Manager denied having a writtentest method for [redacted] testing for [redacted] by [redacted] but the writtentest method was later found locked in her office desk. Lastly, when asked whythe testing was performed, both the QC Manager and the Assistant Plant Managerboth stated that the test was done for no reason. When the investigative teamspoke with you and your management team the following day (10/30/2003) theysay that you told them the testing was done at a customer’s request. Theinvestigative team also said that you admitted that your firm had been untruthfulabout the testing. As the investigative team expressed to you that they didnot have confidence in the integrity of your test data as a result of this incident,so we also express our concern that your test records may be unreliable.

Another related observation statedthat one [redacted] test result represented as many as five and eight lots offinished [redacted] and [redacted] API, respectively. Although you have respondedto this observation, it nonetheless adds to our concerns about the reliabilityof the records at your firm.

5. Compendial and secondaryreference standards were not properly stored.

The investigative team found thecompendial and secondary reference standards stored in the controlled room temperaturestability room. We do not have assurance that these reference standards usedto test the finished APIs have not degraded as a result of being subjected tothe temperature and humidity conditions in the stability room. In your response,before installing a ceiling fan, you state that the temperature was [redacted]at the outlet of the heater. The observation indicates that this air was blowingdirectly on the reference standards. Reference standards that are not storedunder appropriate conditions could result in false test values. Product thatis out of specification could test within specification. This draws into questionyour test results for product shipped to the United States.

6. Microbiological testingwas inadequate in that the [redacted] samples was not neutralized prior toperforming the [redacted] testing.

In your response you expressed concernthat if the [redacted] in the sample was neutralized, you would not be testingthe [redacted] "as is". It is necessary to neutralize the [redacted] becauseit interferes with microbiological testing. Without the neutralization step,the [redacted] test will likely show a lower number of bacteria than is actuallypresent in the sample.

The procedure you submitted withyour response indicates that you will add a neutralizing agent, [redacted] tothe sampling container prior to [redacted] Please submit to data or scientificrational that the [redacted] does not alter the effectiveness of the neutralizingagent. In addition, the procedure should require swabbing the sample port andrunning [redacted] for five minutes if this is how you draw the [redacted] beforeadding it in the manufacturing process.

The cGMP deviations identifiedabove or on the FDA-483 issued to your firm are not to be considered an all-inclusivelist of the deficiencies at your facility. FDA inspections are audits, whichare not intended to determine all deviations from cGMP that exist at a film.It is the responsibility of your firm to assure compliance with all U.S. standardsfor current Good Manufacturing Practice.

Due to the significance of thesedeficiencies the FDA will deny entry of drugs manufactured by your firm intothe United States. The articles will be subject to refusal of admission pursuantto Section 801(a)(3) of the Act in that the methods and controls used in theirmanufacture do not appear to conform to current Good Manufacturing Practicewithin the meaning of Section 501(a)(2)(b) of the Act.

Until FDA can confirm compliancewith cGMP and correction to the most recent inspection deficiencies, this officewill recommend disapproval of any new applications listing your firm as themanufacturer of active pharmaceutical ingredients.

Please contact Karen K. Moksnes,Compliance Officer, at the address and telephone number shown below if you haveany questions related to human drugs.

U.S. Food & Drug Administration
Center for Drug Evaluation and Research
Foreign Inspection Team, HFD-325
11919 Rockville Pike, 4th Floor
Rockville, MD 20852
Tel: (301) 827-9008; FAX (301) 827-8909

Or, contact Jorge F. Christian,Compliance Officer at the address and telephone number shown below if you haveany questions related to veterinary drugs.

U.S. Food & Drug Administration
Center for Veterinary Medicine
Division of Compliance, HFV-232
7500 Standish Place
Rockville, MD 20855
Tel: (301) 827-0152; FAX (301) 827-1498

Sincerely,

/s/

Nicholas Buhay for

Joseph C. Famulare Director
Division of Manufacturing and Product Quality
Center for Drug Evaluation and Research

/s/

Gloria Dunnavan
Director
Division of Compliance
Office of Surveillance and Compliance
Center for Veterinary Medicine

cc: [redacted]
Group Vice-President
[redacted]

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2bbrands.com/drugstore 09-Sep-03

Public Health Service Food and Drug Administration
	Rockville, MD 20857

Via Express Mail/Return Receipt

& Faxed to (775) 924-4501

Warning Letter

September 9, 2003

Mr. David Anderson

Registrant

2bbrands.com/drugstore

P.O. Box 3567

San Francisco, CA 90266

Dear Mr. Anderson:

The Food and Drug Administration (FDA) has learned that, through the websites www.2bbrands.com and ww.mexican-drugstore.com, you are selling “Accutane topical gel” to United States (U.S.) consumers. Accutane is the trade name for a prescription drug approved for marketing in the United States under an approved new drug qdication submitted by RochePharmaceuticals. Nutley, New Jersey. The only approved Accutane products approved for marketing in the United States are capsules for oral ingestion. Even though the the mexican-drugstore.com order form states that the product offered for sale is Accutane topical gel,” the label of the actual product shipped states that it is “ISOTEX ISOTRENINOINA GEL 0.05%. The labeling for this product is in Spanish. Neither “Accutane topical gel” nor “Isotrex” has an approved new drug application, and they may not be legally marketed in the United States.

You sell “Accutane topical gel" without a prescription to the American consumers from a Mexican pharmacy. As discussed in greater detail below, these actions violate the Federal Food, Drug and Cosmetic Act (FD & C Act or Act), 21 United States Code

(U.S.C.) 301 Et seq.

When a U.S. resident logs onto the Internet site, www.2bbrands.com/drugstore they are automatically taken to that states in part, “***US Corporation enables you to purchase medicines from Mexico***Privately delivered to your address Medicines in Mexico are made from the same quality ingredients, made by the same companies *** in compliance with all U.S. and international laws*** ” Your firm packages the dispensed prescription and mails it directly to the resident in the United States.

The “Accutane” product sold through your web site is labeled in part, “ISOTREX ***ISOTRETlNOINA GEL 0.05 %***Tuba con 30 g Formila: Cada 100 g contiene: Isotretinoina 0.05g Excipiente c.b.p. 100 g. ***Hecho en Mexico por STIEFEL MEXICANA, S.A. DE C.V., Eje Norte Sur. No. 11, Nuevo Parques Industrial, San Juan del Rio Qro., C.P. 76809. Segun Formula y bajo licencia de: STIEFEL LABORATORIES. INC.,. Coral Gables, FL 33134 ***Late. 130002F428 CAD. 15/JUN/2004***.”

Accutane (isotretinoin) is a systemically administered retinoid approved in 1982 to treat severe recalcitrant nodular acne. Isotretinoin carries significant potential risks, including that it may cause severe birth defects. The approved Accutane labeling states in part.

“Accutane must not be used by females who me pregnant...must be prescribed under the System to manage Accutane Related Teratogenicity (S.M.A.R.T.), a yellow Accutane Qualification Sticker must be on each prescription,“ (meaning special training has been given to the prescribin, tr licensed practitioner and the patient) “and no telephone or computerized prescriptions are permitted. ” The approved Accutane is for oral ingestion. FDA has not approved a topical gel version of Accutane or any other isotretinoin drug.

Because it has serious risks, isotrctinoin is available in the U.S. only under specially created safety controls. These safety controls are bypassed wbcn this drug is purchased from foreign sources or over the Internet, placing patients wvho use this imported drug at higher risk.

The isotretinoin dispensed through mexcian-drugstore.com is a "new drug” as defined by section 201(p) of the Act. Under Section 505(a) of the Act, a “new drug” may not be introduced or delivered for introduction into interstate commerce unless an FDA-approved new drug application (NDA) is in effect for such drug, The continued distribution of this product into the U.S. withoul an approved NDA is a prohibited act as set forth in Section 301 (d) of the Act.

The isotretinoin dispensed through mexican-drugstore.com is also misbranded under section 502(f)(1) of the Act because its labeling fails to bear adequate directions for the uses for which it is being offered and it is not exempt from this requirement (See 21 CFR 201.115). The drug is also not allowed to bear the required informarion solely in Spanish because it is not distributed solely in the commonwealth of Puerto Rico or in a U.S. Territory where the predominant language is Spanish (See 21 CFR 201.15(c)).

This drug is also misbranded pursuant to section 503(b)(1) of the Act because it is dispensed without a prescription.



In addition, faisc promotional statements are being made by you on www.2bbrands.com and www.mexican-drug.store.com, such as, “All items arc shipped *** in compliance with all U.S. and international laws.” You are giving the incotrect impression that all the drugs sold on your website are approved and/or legal to be sold and shipped to U.S. residents. This is a false and misleading statement on your Internet site causing the drugs you distribute to be misbranded pursuant to section 502(a) of the Act.

This letter is not intended to identify all of the ways in which your activities might be in violation of United States Iaw. For example, in addition to isotretinoin, your pharmacy also offers for sale and shipment to U.S. consumers numerous other prescription drugs.

FDA believes that virtually ail shipments of prescription drugs imported from non-U.S. pharmacies will violate the Act. It is your responsibility to ensure that all drug products dispensed and distributed by you and your website into the United States are in

compliance with applicable legal requirements.

The agency has taken steps to warn our residents that drugs sold via the Internet, from foreign sources, may not be approved for marketing in this country, and may not be legally imported. With copies of this Ietter, we are advising Mexican, New York, and

California drug regulatory officials of these potential violations, In addition, we are advising the U.S. CustomÂ’s Bureau, through an Import Alert, that shipments offered for importation into the U.S. as a result of your activities may bc detained and subject to

refusal of entry.

You are instructed to cease these practices, and you are requestcd within fifteen (15) days of your receipt of this letter, to describe the actions you are taking to assure that your operations are in full compliance with United States law. Please address your

correspondence to Mr. Melvin F. Szymanski. Compliance Officer, at the U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Compliance. HFD-310, 5600 Fishers Lane, Rockville, MD 20857.

You should be aware that violations of the FD&C Act could result in seizure, injunction, and/or prosecution without further notice.

 

Sincerely,

/s/

David J. Horowitz, Esq.

Director

Office of Compliance

Center for Drug Evaluation and Research

 

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2bBrands 09-Sep-03

Public Health Service Food and Drug Administration
	Rockville, MD 20857

Via Express Mail/Return Receipt
& Faxed to (775) 924-4501

Warning Letter

September 9, 2003

Mr. David Anderson
Registrant
2bbrands
P.O. Box 0798
Manhattan Beach, CA 90266

Dear Mr. Anderson:

The Food and Drug Administration (FDA) has learned that, through the websiteswww.2bbrands.com and ww.mexican-drugstore.com, you are selling “Accutanetopical gel” to United States (U.S.) consumers. Accutane is the trade namefor a prescription drug approved for marketing in the United States under anapproved new drug qdication submitted by Roche Pharmaceuticals. Nutley, MewJersey. The only approved Accutane products approved for marketing in the UnitedStates are capsules for oral ingestion. Even though the the mexican-drugstore.comorder form states that the product offered for sale is Accutane topical gel,”the label of the actual product shipped states that it is “ISOTEX ISOTRENINOINAGEL 0.05%. The labeling for this product is in Spanish. Neither “Accutanetopical gel” nor “Isotrex” has an approved new drug application,and they may not be legally marketed in the United States.

You sell “Accutane topical gel" without a prescription to the Americanconsumers from a Mexican pharmacy. As discussed in greater detail below, theseactions violate the Federal Food, Drug and Cosmetic Act (FD & C Act or Act),21 United States Code
(U.S.C.) 301 Et seq.

When a U.S. resident logs onto the Internet site, www.2bbrands.com/drugstorethey are automatically taken to that states in part, “***US Corporationenables you to purchase medicines from Mexico***Privately delivered to youraddress Medicines in Mexico are made from the same quality ingredients, madeby the same companies *** in compliance with all U.S. and international laws***” Your firm packages the dispensed prescription and mails it directly tothe resident in the United States.

The “Accutane” product sold through your web site is labeled in part,“ISOTREX ***ISOTRETlNOINA GEL 0.05 %***Tuba con 30 g Formila: Cada 100g contiene: Isotretinoina 0.05g Excipiente c.b.p. 100 g. ***Hecho en Mexicopor STIEFEL MEXICANA, S.A. DE C.V., Eje Norte Sur. No. 11, Nuevo Parques Industrial,San Juan del Rio Qro., C.P. 76809. Segun Formula y bajo licencia de: STIEFELLABORATORIES. INC.,. Coral Gables, FL 33134 ***Late. 130002F428 CAD. 15/JUN/2004***.”

Accutane (isotretinoin) is a systemically administered retinoid approved in1982 to treat severe recalcitrant nodular acne. Isotretinoin carries significantpotential risks, including that it may cause severe birth defects. The approvedAccutane labeling states in part.
“Accutane must not be used by females who me pregnant...must be prescribedunder the System to manage Accutane Related Teratogenicity (S.M.A.R.T.), a yellowAccutane Qualification Sticker must be on each prescription,“ (meaningspecial training has been given to the prescribin, tr licensed practitionerand the patient) “and no telephone or computerized prescriptions are permitted.” The approved Accutane is for oral ingestion. FDA has not approved a topicalgel version of Accutane or any other isotretinoin drug.

Because it has serious risks, isotrctinoin is available in the U.S. only underspecially created safety controls. These safety controls are bypassed wbcn thisdrug is purchased from foreign sources or over the Internet, placing patientswvho use this imported drug at higher risk.

The isotretinoin dispensed through mexcian-drugstore.com is a "new drug”as defined by section 201(p) of the Act. Under Section 505(a) of the Act, a“new drug” may not be introduced or delivered for introduction intointerstate commerce unless an FDA-approved new drug application (NDA) is ineffect for such drug, The continued distribution of this product into the U.S.withoul an approved NDA is a prohibited act as set forth in Section 301(d) ofthe Act.

The isotretinoin dispensed through mexican-drugstore.com is also misbrandedunder section 502(f)(1) of the Act because its labeling fails to bear adequatedirections for the uses for which it is being offered and it is not exempt fromthis requirement (See 21 CFR 201.115). The drug is also not allowed to bearthe required informarion solely in Spanish because it is not distributed solelyin the commonwealth of Puerto Rico or in a U.S. Territory where the predominantlanguage is Spanish (See 21 CFR 201.15(c)).

This drug is also misbranded pursuant to section 503(b)(1) of the Act becauseit is dispensed without a prescription.

In addition, faisc promotional statements are being made by you on www.2bbrands.comand www.mexican-drug.store.com, such as, “All items arc shipped *** incompliance with all U.S. and international laws.” You are giving the incotrectimpression that all the drugs sold on your website are approved and/or legalto be sold and shipped to U.S. residents. This is a false and misleading statementon your Internet site causing the drugs you distribute to be misbranded pursuantto section 502(a) of the Act.

This letter is not intended to identify all of the ways in which your activitiesmight be in violation of United States Iaw. For example, in addition to isotretinoin,your pharmacy also offers for sale and shipment to U.S. consumers numerous otherprescription drugs.
FDA believes that virtually ail shipments of prescription drugs imported fromnon-U.S. pharmacies will violate the Act. It is your responsibility to ensurethat all drug products dispensed and distributed by you and your website intothe United States are in
compliance with applicable legal requirements.

The agency has taken steps to warn our residents that drugs sold via the Internet,from foreign sources, may not be approved for marketing in this country, andmay not be legally imported. With copies of this Ietter, we are advising Mexican,New York, and
California drug regulatory officials of these potential violations, In addition,we are advising the U.S. Custom’s Bureau, through an Import Alert, thatshipments offered for importation into the U.S. as a result of your activitiesmay bc detained and subject to
refusal of entry.

You are instructed to cease these practices, and you are requestcd within fifteen(15) days of your receipt of this letter, to describe the actions you are takingto assure that your operations are in full compliance with United States law.Please address your
correspondence to Mr. Melvin F. Szymanski. Compliance Officer, at the U.S. Foodand Drug Administration, Center for Drug Evaluation and Research, Office ofCompliance. HFD-310, 5600 Fishers Lane, Rockville, MD 20857.

You should be aware that violations of the FD&C Act could result in seizure,injunction, and/or prosecution without further notice.

 

Sincerely,

/s/

David J. Horowitz, Esq.
Director
Office of Compliance
Center for Drug Evaluation and Research

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