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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Monserrat Pharmaceuticals Inc 20-Jan-04

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration


466 Fernandez Juncos Avenue
San Juan PR 00901-3223

Telephone: (787) 474-9659
FAX: (787) 729-6658

January 20, 2004



Mr. Ambrosio Malave
Monserrat Pharmaceuticals, Inc.
#34 Munoz Rivera St.
Aguas Buenas, PR 00703

Dear Mr. Malave:

On July 10, 11, 14, 18, 2003, the Food and Drug Administration (FDA) conducted an inspection of your facility located at Rd. #34 Munoz Rivera St., Aguas Buenas, PR 00703. Our Investigator, accompanied at the end of the inspection by a representative from the Puerto Rico Health Department, Drugs and Pharmacy Division, documented serious violations of the Federal Food, Drug, and Cosmetic Act (the Act). The inhalation solutions, ipratropium bromide 0.02% and albuterol sulfate 0.083%, manufactured by your firm and defined as drugs in the meaning of Section 201(g) of the Act, are unapproved new drugs under section 505, misbranded within the meaning of sections 502(f)(1) and 502(o), and adulterated within the meaning of section 501(a)(2)(B) of the Act.

Although in the FDA Modernization Act of 1997 Congress had provided certain conditions under which compounded drugs could be exempt from particular requirements of the Act, as a result of a Supreme Court ruling in 2002 those exemptions are no longer available for compounded drugs.

With the invalidation of section 503A, FDA determined that it needed to issue guidance to the field and compounding industry on what factors the agency will consider in exercising its enforcement discretion regarding pharmacy compounding. This guidance, in the form of Compliance Policy Guide (CPG), section 460.200, issued on June 7, 2002.

As a result, the agency now applies its longstanding policy to recognize and exercise its enforcement discretion for extemporaneous compounding, where reasonable quantities of drugs are manipulated upon receipt of valid prescriptions from licensed practitioners for individually identified patients. One factor that the agency considers is whether or not there is any documentation that demonstrates a medical need for particular patients for a specific variation between a commercially available drug product an compounded drug products.

Further, the agency remains seriously concerned about the public health risk associated with the large-scale production of massive quantities of inhalation solutions without these products being required to meet all the laws and regulations applicable to a drug manufacturer. This concern exists especially in light of your firm's need to recall the products distributed during the months of June and July 2003 because you did not have adequate testing procedures to determine satisfactory conformance to final specifications for identity and strength of each active ingredient.

Your firm purports to be a compounding pharmacy (as noted in your letter received in our Compliance Branch on August 26, 2003). However, our investigation has determined that your firm exceeds the scope of the regular course of the practice of pharmacy. Our findings include the following:

Your firm produces albuterol sulfate and ipratropium bromide inhalation solution in the same dosage form and strength as the commercially available products. When the FDA Investigator asked company officials about the difference between the firm's products and the commercially available products, the investigator was advised that the commercially available drugs are supplied in [redacted] vials and Monserrat's products are supplied in a [redacted] vials. When asked if the prescription indicated a medical need for the [redacted] vial, an official stated that the prescriptions do not state a need for the [redacted] vial of the drug. As such, we do not believe that the difference between the compounded versions of these two drug products and the commercially available drug products is sufficient to justify use of the compounded versions of these products.

Since your firm initiated operation in February 2003, you have manufactured a significantly large number of batches of drug products that are essentially copies of commercially available products. The inspection showed that your batch sizes are within the range of [redacted] to [redacted] and that for each [redacted] preparation, [redacted] units are prepared. For example, the records collected showed that on 5/15/03, a batch of albuterol sulfate 0.83% consisting of [redacted] was produced. This batch, once filled in [redacted] containers, produced a total batch size of [redacted] units. We do not believe that such production volume is consistent with that of a pharmacy compounding operation.

In addition, the Puerto Rico Department of Health (PRHD) embargoed [redacted] of albuterol sulfate 0.083% and [redacted] of ipratropium bromide 0.02% because your pharmacy operations were not in conformance with the applicable laws of Puerto Rico.

In light of the above, we do not believe that your firm is operating as a retail pharmacy engaged in extemporaneous compounding that would justify our exercising enforcement discretion. As such, your firm appears to be in violation of the following sections of the Federal Food, Drug, and Cosmetic Act:

Section 505
The inhalation solutions manufactured by your firm are drugs within the meaning of section 201(g) of the Act which may not be introduced or delivered for introduction into interstate commerce under section 505(a) of the Act, since they are new drugs within the meaning of section 201(p) of the Act and no approval of an application filed pursuant to section 505(b) is effective for such drugs.

Section 502(f)(1)
Your drug products are unapproved new drugs and as such are subject to the provisions of Section 503(b)(1) and are not exempt from 502(f)(1) because they are not labeled as required under 21 CFR 201.100.

Section 502(o)
Your drug products are misbranded under Section 502(o) of the Act in that they are manufactured in an establishment not duly registered under Section 510, and the articles have not been listed as required by Section 510(j). Your facility is not exempt from registration and drug listing under Section 510(g) of the Act or 21 CFR 207.10 in that your firm exceeds the scope of the regular course of the practice of pharmacy.

Section 501(a)(2)(B)
Your drug products are adulterated within the meaning of Section 501(a)(2)(B) of the Act in that the controls and procedures used in the manufacture, processing, packing, and holding do not conform to current good manufacturing practices regulations, 21 CPR Part 210 and 211.

Deviations from these regulations include, but are not limited to, the following:

1. Failure to test each batch of your oral inhalation drug products to assure they are free of any objectionable microorganisms. In addition, there is no assurance that the water used to produce these products is also free of microbial contamination. 21 CFR 211.84(d)(6)

2. Failure to have appropriate laboratory determination of satisfactory conformance to final specifications of each batch produced. Records reviewed showed that you have manufactured at least [redacted] batches of the above products since February 2003. However, one sample each of albuterol 0.083% and ipratropium bromide 0.02% has been tested for potency. We note that Ipratropium Bromide 0.02% lot FM0020 tested by the firm's contract laboratory failed a potency test. 21 CFR 211.165(a)

3. Failure to have stability data to justify the expiration date assigned to your products. There is no assurance that your products meet the applicable standards of identity, strength, quality and purity at the time of use. For example, batch records collected during the inspection include the following statement: "Store at room temperature up to three months." You fail to have evidence to demonstrate that your products would not be affected within this period of time. 21 CFR 211.137(a); 21CFR 211.166

4. Failure to withhold the drug components, containers and closures until these have been sampled, examined and/or tested, and released by your quality control unit. For example, approximately, [redacted] were filled with ipratropium bromide and [redacted] with albuterol sulfate. There is no evidence to show that the ipratropium bromide bulk ingredient, the water used during the production of your products or the containers were examined and/or tested prior to being used to produce the finished products. The inspection also revealed a failure to verify the identity of each component used and the failure to establish the reliability of your suppliers through appropriate validation of the drug product components and containers used in the production of albuterol sulfate 0.083% and ipratropium bromide 0.02%. 21 CFR 211.84

5. Failure to have written procedures-for the cleaning and maintenance of the equipment and utensils (e.g., beakers and graduated cylinders, filling equipment), used during the production of albuterol sulfate 0.083% and ipratropium bromide 0.02%. 21 CFR 211.67(b)

6. Failure to have personnel trained in the particular manufacturing operations they perform, and in current good manufacturing practice (CGMP). For example, employees engaged in the manufacture (including mixing of solutions), processing and packing of albuterol sulfate 0.083% and ipratropium bromide 0.02%, have not been trained in CGMPs. 21 CFR 211.25(a)

7. Failure to have trained persons responsible for the supervision of the manufacturing, processing, packing and holding of your drug products. Your supervisors lack training in equipment use, cleaning and product preparation. 21 CFR 211.25 (b)

8. Failure to have written procedures for the calibration and verification of your measuring instruments including the balance model [redacted] used in the addition of the active ingredients, and for the dispensing machine us or the filling of [redacted] of ipratropium bromide into the [redacted] unit dose vials. 21 CFR 211.160(b)(4)

9. Failure to have adequate production controls by not recording the amount of active and other ingredients weighed and added during the production of your products as required. 21 CFR. 211.188(a)(4). The inspection also documented that the in-process adjustments are not recorded nor verified by a second person. 21 CFR 211.101(d)

10. Failure to have adequate master production and control records in that the different manufacturing steps related to the production of your products ipratropium bromide 0.02% and albuterol 0.83% are not dated, signed by the operator nor independently checked, dated and signed by a second person. 21 CFR 211.188(b)(11)

We acknowledge the receipt of your written response to the FDA-483, received at the US Food and Drug Administration, San Juan District Office, on August 11, 2003. Contrary to your contention in your response letter that you are operating as a regular pharmacy, our investigation finds that your firm has transcended the level of a regular pharmacy operation and is operating as a drug manufacturer, as stated above. Further, while a recall was initiated and the available inventory was embargoed by the state officials, your firm has not committed to altogether discontinue future manufacture and distribution of such drug products. You should also be aware that, as set forth in 21 CFR 200.51, manufactured aqueous-based drug products for oral inhalation are required to be sterile, and, as set forth in 21 CFR 201.57(a)(iv), if a product is sterile, the labeling must contain a statement of that fact.

In summary, the above violations are not intended to be an all-inclusive list of deficiencies at your facility and may not be limited to the above mentioned products. It is your responsibility to ensure adherence to each requirement of the Act and regulations. Federal agencies are advised of the issuance of all Warning Letters about drugs and services so that they may take this information into account when considering the award of contracts.

You should take prompt action to permanently correct these deviations and prevent their future recurrence. Failure to make prompt corrections may result in regulatory action without further notice. Possible actions include seizure and/or injunction.

Please notify this office in writing, within 15 working days of receipt of this letter, of the specific steps you have taken to correct the noted violation, including an explanation of each step being taken to prevent the recurrence of similar violations. If corrective actions can not be completed within 15 working days, state the reason for delay and the time within which corrections will be completed.

Your reply should be sent to the U.S. Food & Drug Administration, San Juan District Office, 466 Fernandez Juncos Ave., San Juan, PR 00901-3223, Attention: Carmelo Rosa, Compliance Officer.



Donald J Voeller
District Director