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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Legacy Pharmaceuticals International 07-May-08

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

Public Health Service
Food and Drug Administration


San Juan District
466 Fernandez Juncos Avenue
San Juan PR 00901-3223

Telephone: (787) 474-9500
FAX: (787) 729-6658

May 7, 2008



Mr. Michael R. Danzi, CEO
Legacy Pharmaceuticals International
Ruhrbergstrasse 21, CH-4127
Birsfelden, Switzerland

Dear Mr. Danzi:

This letter is in reference to the inspection of your manufacturing facility Legacy Pharmaceuticals Puerto Rico located at Carretera #909 Km 1.1 Bo. Mariana Humacao, PR 00791, conducted between September 10-28, 2007, by an investigator from the Food and Drug Administration (FDA). The inspection revealed that your firm's manufacture, processing, packing or holding of the human drug product Efudex Topical Cream 5% deviates from the Current Good Manufacturing Practice (CGMP) Regulations as stated within 21 CFR Parts 210 and 211, rendering the drug adulterated within the meaning of 21 U.S.C. § 351(a)(2)(B) (Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act)). The manufacture and processing of the drug do not conform with CGMP to assure that the drug product meets the requirements of the Act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess.

At the conclusion of the inspection a List of Inspectional Observations (Form FDA-483) was issued and presented to Zaida Berrios, Manufacturing Site Director at the facility. Ms. Berrios responded to the FDA-483 by letter dated October 18, 2007 (October 18 Letter). We address this response below, in relation to each of the noted violations where appropriate.

The deviations observed during the inspection demonstrating your firm's failure to comply with 21 CFR parts 210 and 211 include, but are not limited to, the following:

1. Failure to establish written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess as required by 21 CFR § 211.100(a).

Information obtained during the September inspection and from your Field Alert Reports (FAR) indicates a pattern of variability in key quality attributes of your Efudex Topical Cream 5% drug product in the last two and one-half years. Since August 2005 your analyses of retained lots (as part of complaint investigations) and stability samples (as part of your ongoing stability program) revealed at least 11 instances of failure to meet specifications for assay, appearance and/or [redacted] content. Other samples (i.e., different tubes) from some of these same lots met specifications, which indicates that your manufacturing process is not well-controlled and/or is not designed to ensure that all dosage units within a lot are of appropriate quality throughout their expiry period. These failures are detailed below in additional charges, but their quantity and quality, and your responses to those failures, indicate a more fundamental problem with your manufacturing processes. Our inspection revealed that you lack understanding of what constitutes adequate control over process design, i.e., what steps, process parameters, and raw material attributes are necessary to assure final product quality over the three-year expiry period.

We understand from the October 18 Letter that you are not the applicant or original manufacturer of Efudex Topical Cream 5% (New Drug Application (NDA) 16-831). Rather, Hoffman La-Roche Inc. owned the NDA, which was approved on July 29, 1970. Hoffman La-Roche transferred ownership to ICN Ducth Holdings ( now Valeant Pharmaceuticals International) located in Aliso Viejo, California in 1997 . At that time the product was only filled into 25 gm tubes. Manufacturing operations were moved to your Humacao Puerto Rico site in 2001. In 2004, you added an additional packaging configuration, the [redacted]

Manufacturing this cream involves an [redacted] and an [redacted] and a complex set of process steps and processing parameters such as [redacted] and [redacted] for specified times and at specified temperatures. It also involves the transfer of raw materials and intermediate materials to, from, and between [redacted] until the final bulk material is pumped into drums that are filled into the final marketed dosage form, [redacted] Although you did not design the original manufacturing process, as the current manufacturer of Efudex Topical Cream 5% you must have a thorough understanding of the process parameters necessary to assure that the product has the identity, strength, quality, and purity it purports or represents to possess. It is evident that you do not have this requisite understanding.

For example, in the course of your investigations into complaints related to product consistency, you reviewed manufacturing and control records (e.g., temperature cycle charts, batch worksheets) and observed anomalies, or differences in times or temperatures for the different steps in the process such as heating, cooling, dispersion, mixing, and/or material transfer. These empirical observations suggested possible correlations or connections to quality issues. You did not take the next step necessary to correct this problem on a process-wide level, however, which is to determine the root cause of these anomalies through scientific study of your particular drug formulation and process.

Your subsequent "[redacted] Final Report -- Plant Test Process Monitoring for Efudex Topical Cream 5% Commercial Lots," again illustrates this deficiency. See FDA-483 Observation 1. This "plant test" was conducted after implementation in April 2007 of several corrective and preventive actions such as changes to tank heating and cooling systems, clarification of batch record steps, and the addition of operators for handling material transfers. The evaluation revealed variability in the [redacted] and [redacted] of the in-process and final bulk product, which reasonably can be thought to impact the physical stability of the product over time. You concluded in the final report that an assignable cause for the variable [redacted] behavior has not been identified. The report only recommends continued monitoring of the Efudex manufacturing process, further evaluation of the discharge process, and monitoring assays at different points in the processing of this cream.

Such empirical analysis did not identify the underlying process flaws causing these problems. As a result, you cannot make process adjustments, and evaluate those adjustments, to address the root causes. You therefore cannot assure the quality, strength, identity, and purity of existing and future product. It is essential that you establish and apply control procedures for identifying and remediating such problems.

In addition, the lack of adequate process controls extends beyond the manufacturing phase. All of these lots tested ultimately were released because they met their release specifications. It is clear that your firm intends to monitor these lots. However, an understanding of the impact of the processing "differences" and variable viscosity and penetrability characteristics on the physical stability and/or chemical attributes of this cream throughout its shelf life appears to be unknown. You must determine this impact as well through established process controls.

2. Failure to establish scientifically sound and appropriate specifications, standards and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity, as required by 21 CFR § 211.160(b). Specifically, you have not evaluated whether a viscosity specification for the Efudex Topical Cream 5% drug product needs to be established.

You concluded from information and data gathered during both the 2006 process validation with lots C0726, C0727 and C0738 conducted to qualify a change in active ingredient supplier and your investigations into complaints related to product consistency that a relationship or correlation exists between initial [redacted] and [redacted] of the cream at release and its physical stability over time.

You acknowledge that [redacted] specification exists for this product in the NDA and you therefore concluded that the [redacted] results would be used for information only. In light of the recent information and out-of-specification (OOS) analytical results of stability and retain samples however, it is your company's obligation to determine if such specifications are relevant and appropriate for this product. While you indicate in your October 18 Letter that a [redacted] test at time of release and during stability has been included in an internal specification to establish a baseline to assist in monitoring cream thickness, this does not address the larger issues raised by your [redacted] analyses. It is essential that these issues are evaluated scientifically and incorporated in your validation process if necessary.

Based on statements made during the inspection and in your correspondence, it appears that your company believes that the NDA processing approach and specifications cannot be revisited over the life-cycle of a product. For example, you emphasize in the October 18 Letter that no changes have been made to the formulation, manufacturing process, equipment or batch size since approval. Manufacturing procedures and specifications must be changed if warranted to assure product quality, however. It is essential that all the issues recently raised are evaluated scientifically. You are not limited to process validation procedures established almost forty years ago for another configuration.

As a general matter, it is your responsibility under the CGMP regulations to establish appropriate specifications for your product and to continually improve your process based on information accumulated from batch manufacturing, monitoring, and testing. As new information arises that has the potential to impact product specifications, you are obligated to investigate and implement scientifically sound changes as appropriate. Current good manufacturing practice is an ongoing requirement.

Finally, we find your reference in the October 18 Letter to statements made by FDA's [redacted] at the March 12, 2002 Advisory Committee for Pharmaceutical Science related to the systematic classification of dosage forms for topical drugs inapposite. While [redacted] specifications of other cream products might be helpful to know, ultimately, your company must determine scientifically the appropriate [redacted] range for your product to ensure its chemical and physical quality throughout its expiry period, and whether a [redacted] specification for release and stability is necessary to achieve that quality.

3. Failure to assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use by establishing an expiration date required by 21 CFR § 211.137(a) as determined by appropriate stability testing.

Various lots of Efudex Topical Cream 5% drug product have failed to meet product specifications during their expiry period. The three-year expiration period for this product therefore is not valid because it is not supported by reliable stability data. Analyses of retained lots (as part of complaint investigations into claims that the product was "watery," "liquidy" and/or had a "thinner consistency") and stability samples (as part of your ongoing stability program revealed that, as detailed below, at least [redacted] lots that were out-of-specification for assay and/or [redacted] content. Specifically, a portion (either the top-to-middle or middle-to-bottom) of the sample tubes, which must be within the product specification limit of 90.0% to 110.0%, was sub-potent in all of the lots listed below. In addition, [redacted] content in a stability sample of Lot C1033, which content must be between 80% - 120%, was found recently as indicated in your FAR dated January 17, 2008.

This product is labeled with a three-year (36 month) expiry period. These lots, all packaged in [redacted] were distributed and some are still within expiration:

Lot C0424 - expired March 2008
Failed individual portion assay [redacted] at stability interval [redacted]

Lot C0397 - expired March 2008
Failed individual portion assay [redacted] at stability interval [redacted]

Lot C0398 - expired March 2008
Failed individual portion assay [redacted] at stability interval [redacted]

Lot C0399 - expired March 2008
Failed individual portion assay [redacted] at stability interval [redacted]

Lot C0892 - expires July 2009
Failed both portion assays [redacted] and [redacted]. Tested as part of a complaint investigation.

Lot C042201 (distributed in Canada) - expired March 2008
Failed both portion assays [redacted] and [redacted] at stability interval [redacted]

Lot C0898 - expires November 2009
Failed individual portion assay [redacted] and mean assay [redacted] Tested as part of a complaint investigation. Additional testing of this lot also failed assay with values of [redacted] and [redacted]. These values are up to [redacted] its accepted release specifications.

Lot C1033 - expires March 2010
Failed individual portion for [redacted] content at stability interval [redacted]

We understand that medical assessments were conducted by Valeant's Director of Medical Affairs and by the Vice President of Global Safety and Pharmacovigilance regarding the OOS findings as part of the FARs. These individuals concluded that "there should be no efficacy issue with product." One medical assessment states that:

The typical treatment duration for the approved indication of actinic keratosis is 2-4 weeks. The clinical assessment of efficacy with this product can typically be determined by the visual inspection of response by the treating physician, enabling any variability in response to be identified and addressed. Based on this information, we do not believe that this event [the OOS results for Lot C0898] represents a significant safety or efficacy issue at this time.

Please note that notwithstanding the foregoing medical officer assessments, your product is marketed and labeled as having 100% potency. As patients apply this cream daily to their lesion(s), it is their reasonable expectation that all portions of the cream in every tube are homogenous and equally potent. Our inspection found that the consistency and uniformity of your drug product's quality is not assured.

In your response to this letter, please explain your intention regarding the above-referenced lots on the market and your plan in the future if additional distributed lots of Efudex Topical Cream 5% do not meet their assay, appearance, and/or preservative content specifications. Specifically regarding complaints related to consistency, you stated in your October 18 Letter that no additional complaints related to "thinner consistency" have been received as of October 18, 2007. Your earlier experience is that physical instability may begin approximately [redacted] Your preventive action to eliminate abrupt temperature fluctuations was implemented in April 2007, [redacted] Please submit a summary of complaints your company has received for Efudex since the conclusion of the inspection on September 28, 2007.

4. Failure of your quality control unit to review production records to assure that errors have not occurred, and to fully investigate errors that have occurred during the manufacturing of your Efudex Topical Cream products, as required under 21 CFR § 211.22(a); and failure of your quality control unit to ensure appropriate procedures impacting on the identity, strength, quality, and purity of the drug product are approved and implemented as required by 21 CFR § 211.22(c).

During your investigations of complaints, your firm appropriately reviewed various charts that recorded vessel jacket temperature and product temperature during the oleous manufacturing phase. Excursions from vessel jacket set-point temperatures during stearyl alcohol addition as well as product temperature excursions outside of the range specified were noted.

In the October 18 Letter you indicated with regard to FDA-483 Observation 3 that prior to the investigations:

Documentation review of Efudex lots consisted in [sic] reviewing the executed manufacturing batch records to confirm that each step was executed by the process operators in compliance with batch records requirements including target temperatures and times required in the validated batch worksheet. Since the batch record required documenting the temperatures at the moment of material addition and critical steps, the tank charts were only evaluated to identify that set points were achieved. Therefore, investigations were not requested for temperature fluctuations in the charts since this was considered [redacted] behavior inherent to the process as a result of jacket temperature set point changes by the operator and excipients addition. These temperature fluctuations on the chart profile were always observed on lots manufactured since the technology transfer of this product from Roche to ICN Humacao. Therefore, these temperature fluctuations were considered a normal chart profile behavior during the batch record review.

As stated in Item 1 above, it is essential that the impact of processing parameters on the final product quality is understood in order implement the appropriate manufacturing controls. Your statements that the temperature fluctuations in the charts were "considered [redacted] behavior inherent to the process as a result of jacket temperature set point. . ." and that "temperature fluctuations were considered a normal chart profile behavior," do not explain the impact of these fluctuations on the product. Your Quality Control Unit must ensure that systems (e.g., comprehensive control record review procedures) are in place so that anomalies of this sort are scientifically evaluated by the proper organizational units within your company.

Regarding your responses to FDA-483 for Observation 3 (with respect to procedures established to reduce temperature excursions) and for Observation 4, your corrective and preventive actions appear to be adequate and will be evaluated during the next inspection.

Neither this letter nor the observations noted on the FDA-483 are intended to be an all-inclusive list of the deficiencies that may exist at your facility. It is your responsibility to ensure that your operations at this facility and all other facilities under your control are in full compliance with all applicable 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 new drug applications listing your facility as a manufacturer until the above violations are corrected. A reinspection may be necessary.

Within 15 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, as well as copies of related documentation. If you cannot complete corrective action within 15 working days, state the reason for the delay and the time within which you will complete the correction. If you no longer manufacture or market Efudex Topical Cream 5%, your response should so indicate, including the reasons for, and the date on which, you ceased production.

Your reply should be sent to the Food & Drug Administration, San Juan District Office, 466 Fernandez Juncos Ave., San Juan, PR 00901-3223, to the attention of Margarita Santiago, Compliance Officer.



Maridalia Torres
District Director
San Juan District

Ms. Zaida Berrios Berrios
Site Director
Legacy Pharmaceuticals Puerto Rico
Carretera #909 Km 1.1 Bo. Mariana
Humacao, PR 00791-9731