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Tuesday, September 16, 2008

Ranbaxy Laboratories, Ltd., Paonta Sahib, India 16-Sep-08


Department of Health and Human Services' logoDepartmentof Health and Human Services

Public Health Service
Food and Drug Administration

 

White Oak, Bldg. 51

Silver Spring, MD 20993


 


 


Warning Letter


September 16, 2008


Via FedEx


WL: 320-08-02


Mr. Malvinder Singh, CEO and Managing Director
Ranbaxy Laboratories Limited
Corporate Office
Plot 90; Sector 32,
Gurgaon - 122001 (Haryana), INDIA


Dear Mr. Singh,


This is regarding an inspection of your pharmaceutical manufacturing facility, Batamandi (Unit II), in Paonta Sahib, India by Investigator Jose R. Hernandez and Chemist Susanna E. Ford, during the period of March 3 -7, 2008. The inspection revealed significant deviations from U.S. Current Good Manufacturing Practice (CGMP) Regulations (Title 21, Code of Federal Regulations, Parts 210 and 211) in the manufacture of finished drug products.


These deviations were listed on an Inspectional Observations (FDA-483) form issued to Dr. T.G. Chandrashekhar, Vice President Global Quality and Analytical Research, at the close of the inspection. These CGMP deviations 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)]. Section 501(a)(2)(B) of the Act requires that all drugs be manufactured, processed, packed, and held according to current good manufacturing practices.


The March 2008 inspection also found that the Batamandi (Unit II) site is under the same production and quality management as the existing Paonta Sahib site. In addition, the inspection found that the existing Paonta Sahib site was involved in various aspects of testing and production for the Batamandi site. In a letter dated May 12, 2008, FDA informed you that the duplicative drug registration for the Batamandi (Unit II) facility had been withdrawn by the agency, because we consider the Batamandi (Unit II) facility to be a part of the existing Paonta Sahib facility. As such, the violations observed during the March 2008 inspection are indications of continuing CGMP deficiencies in thequality systems at the Paonta Sahib facility, including the failure of production and quality management to prevent such deficiencies. We issued a Warning Letter to the Paonta Sahib facility on June 15, 2006 citing significant deficiencies related to your stability testing program, including: failure to maintain complete records of data related to stability sample testing, and deficiencies related to storage, inventory management, and testing of stability samples at defined intervals.


Our review included your May 1, 2008 response to the FDA 483 Inspectional Observations. We acknowledge that some corrections have been implemented, including your withdrawal of the [redacted] ANDA due to deficiencies noted in equipment cleaning logs and batch production and control records for the exhibit batches of [redacted] manufactured in July - August, 2006. However, we are concerned that these instances of discrepancies observed during the March 2008 inspection, are indications of continuing, systemic CGMP deficiencies at the Paonta Sahib facility. These include:


1 . Written records of major equipment cleaning and use are inaccurate and do not provide assurance that persons double-checked the performance of equipment cleaning, because there is no assurance that those persons responsible for determining that work was performed were present at the time of equipment cleaning [21 CFR 211.182].



During the inspection, our investigative team uncovered fourteen (14) instances (Observation# la, b, c, e, f, g, h, k, l, m p, q, t, and u on the FDA 483) wherecleaning records for equipment used in manufacturing operations (V-blender, [redacted], etc) included initials or signatures of employees who reportedly verified cleaning of equipment but were not shown as present by security log records. According to the security log used to record the entry of all personnel entering and exiting the Batamandi (Unit II) facility, the supervisors who initialed or signed the "Checked by Production Executive" or "Cleared by QA Executive" block were not present in the Batamandi facility on the days this equipment was cleaned. For example, two of these records each involved entries for five separate dates where the employee signing for verification (hereafter "Employee 1") was not present according to the security log records (Observations #1(a) and (b)).


With regard to entries made by another employee (hereafter "Employee 2"), your May 1, 2008 response states, "An investigation conducted following the issuance of the 483 revealed that the handwritten logs maintained by the security detail at the gate to the Batamandi (Unit II) facility were not intended to and cannot be assumed to provide an accurate accounting of entry in and out of the facility on any given day." You maintain that the security log was not intended to be accurate, yet you acknowledge its accuracy in the same paragraph of the response when you state, "The security log and other records show that [Employee 2] was present at the facility on every other day on which his signature appears on batch documents."


Your response also acknowledges the accuracy of the security log when referring to entries made by Employee 1 and another employee (hereafter "Employee 3"). With regard to multiple entries made by Employee 3, your response states that this individual was not present to verify cleaning operations . With regard to numerous entries made by Employee 1, your response states:"[Employee 1] apparently was not present during the manufacturing of the exhibit batches and related equipment cleaning. [Employee 1] believed that he did not have to be physically present during an activity in order to sign off as having checked the activity on batch records. Instead, he asked [Employee 4] to bring the batch records to him at the Paonta Sahib facility so he could check and sign them."


This statement in your response regarding Employee 1 demonstrates a lack of knowledge by the employee regarding the fundamental purpose of independent verification under CGMP, and the failure of your firm to ensure that employees conducting and recording these checks understood these essential requirements. The requirement for independent verification applies to functions during drugmanufacturing that involve human judgment and consequently are susceptible to human error. Verification of equipment cleaning operations and other critical drug manufacturing operations (e.g., weighing of raw materials, formulation, laboratory calculations) is fundamental to assuring that procedures or work are adequately performed to reduce the risk of human error. This basic function in the manufacture of drug products is an essential part of U.S. CGMP regulations and is one importantexample of the necessary steps your company needs to implement to ensure product quality.


Incomplete or inadequate cleaning of equipment can lead to cross contamination or inadvertent contamination of drug products with residual cleaning agents or solvents. The purpose of 21 CFR 211.182 is to assure that a second person determine that appropriate cleaning and maintenance was performed on equipment. Simply reviewing the cleaning log afterwards, without being present at the time of cleaning, does not meet this requirement. We also note that for the multiple examples whereyou admit that Employee 3 was not present at the time of cleaning, you have failed to provide any explanation for this significant deviation from CGMP requirements.


In your response to this Warning Letter, please explain how the supervisor responsible for verifying the cleanliness of equipment handles verification of cleaning, including whether this individual must inspect the equipment. Please also include documentation regarding your investigation into these incidents, and possible similar incidents not observed by FDA, where employees signed or initialed cleaning records as having verified the steps when, in reality, they were not present at the plantto conduct this verification. Please also describe the steps you have taken to preventrecurrence of these and similar events.


2. Batch production and control records prepared for each batch of drug product produced do not include complete information relating to the production and control of each batch, in that the persons performing, directly supervising or checking each significant step in the operation may not have been present on the dates or times these steps or operations were conducted [21 CFR 211.188(b)(11)].



Our investigative team found four instances (Observation# 1d, j, o, and s on the FDA-483) of batch production records containing the initials for Employee 1 in the "Checked by" column for manufacturing steps. According to the security log, though, this employee was not in the Batamandi (Unit II) facility on the dates when he reportedly supervised these manufacturing activities. One record involved six separate dates where the employee signing for verification was not present accordingto the security log records. These instances include manufacturing steps related to charging of components.


In three instances (Observation# li, n, and r on the FDA 483), the batch production records include the initials of Employee 4 and another employee (hereafter "Employee 5") in the "Carried out by" column after a recorded "Start Time" and "Finish Time." However, according to the security log, these employees were not present at the Batamandi (Unit II) facility at the actual times these operations were conducted.


In these last three instances, your response relies on an interview with the employees to determine that the employee was present on the dates and times specified in the batch record. Your response does not include documentation related to these interviews and the investigation. Moreover, in each instance, the security log documents that Employee 4 and Employee 5 were present on the dates in question, but specifically documents the time of their departure before the time the manufacturing operations were conducted, as recorded on the batch record with their initials.


Your response included a copy of the revised SOP# BPR018-01 "Good Documentation Practices and Correction of Wrong Entries," effective as of April 20, 2008. This SOP indicates, under Section 6.10, that persons performing the checking functions must be "at the place where activity is actually performed." However, your response did not include details on what actions will be taken to ensure that employees supervising or checking significant steps in manufacturing operations are actually present during such operations and that batch production records include complete and accurate information related to the production of each batch.


In addition, our review of SOP#BPR018-01 found that the latter provides instructions, under Section 6.9, whereby "If for some reason the authorized document is not immediately available and immediate recording is [sic] must it can be recorded on blank paper and attach this record with QA approval as raw data with original record. In this case transcribe the entry with reason of transcribing."


This procedure appears to allow manufacturing activities to proceed when an accurate reproduction of the appropriate master production and control record has not been authorized and issued and is not available. This practice violates 21 CFR 211.188(a).


The purpose of this requirement is to ensure that the correct master production and control record has been provided and is available for use in the production of a drug product. Your proposed SOP is inadequate, in that it provides for manufacturing without the use of a batch production and control record. Further, the proposed SOP is inadequate because the practice of transcribing data from blank paper to a batch production and control record is unacceptable.


Please provide proposed corrective actions related to this specific deficiency in SOP BPR018-01 and what corrective actions you will take to ensure that the batch production and control records are an accurate reproduction of the master production and control records, and that these include complete information relating to the production and control of each batch.


3. The firm's procedures for review and approval of drug product production and control records by the quality unit, including those for packaging and labeling, are inadequate to determine compliance with all established, approved written procedures before a batch is released or distributed. Also, investigations into any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications are not extended to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy whether or not the batch has already been distributed [21 CFR 211.192].

During the March 2008 inspection, as explained previously, our investigative team documented numerous instances where persons or supervisors reportedly verifying equipment cleaning activities or supervising or checking significant manufacturing steps were not present at the Batamandi (Unit II) facility on the dates or times that these activities occurred. Please explain why your firm's Quality Control Unit (QCU) did not detect and document these deficiencies during their batch productionand control record review and what actions will be taken to assure these deficiencies do not extend to other batches of the same or other drug products manufactured at the Paonta Sahib facility and to improve the QCU's handling of such issues.

These deficiencies in equipment cleaning and batch production and control records heighten our concerns regarding the conduct, adequacy, and oversight of the Quality System at the Paonta Sahib site, in particular the integrity and reliability of records for equipment cleaning and batch production and control.



The CGMP deviations identified above or on the FDA-483 issued to your firm are not to be considered an all-inclusive list of the deficiencies at your facility. FDA inspections are audits, which are not intended to determine all deviations from CGMP that exist at a firm. If you wish to continue to ship your products to the United States, it is the responsibility of your firm to assure compliance with all U.S. standards for Current Good Manufacturing Practices.


Until FDA has confirmed correction of the deficiencies and compliance with CGMP, this office will continue to recommend disapproval of any new applications listing the Paonta Sahib facility as the manufacturing location for finished pharmaceutical drug products. In addition, shipments of articles manufactured at the Paonta Sahib site are subject to refusal of admission pursuant to Section 801(a)(3) of the FD&C 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 FD&C Act [21 U.S.C 351(a)(2)(B)].


While all shipments of articles manufactured at the Paonta Sahib site are subject to refusal of admission, under the circumstances FDA generally would not refuse shipments of Ganciclovir oral capsules. Because you are the sole source supplier of Ganciclovir oral capsules, FDA considers it important to maintain a sufficient supply of this drug product. Please contact the International Compliance Team immediately to discuss arrangements for your firm to continue importing Ganciclovir oral capsules, which would likely include third-party supervision and verification of each batch prior to release.


Please respond to this letter within 30 days of receipt. Please identify your response with FEI #3002807978. Contact Douglas A. Campbell, Compliance Officer, at the address and telephone numbers shown below, if you have any questions, further information, or further proposals regarding this letter.


U.S. Food & Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Team
White Oak Building 51, Room 4224
10903 New Hampshire Avenue
Silver Spring, Maryland 20993
Tel: (301) 796-3201
FAX: (301) 301-847-8742


To schedule a re-inspection of your facility, after corrections have been completed and yourfirm is in compliance with CGMP requirements, send your request to: Director, Division of Field Investigations HFC 130, 5600 Fisher's Lane, Rockville, MD 20857. You can also contact that office by telephone at (301) 827-5655 or by fax at (301) 443-6919.


Sincerely,


/S/


Richard L. Friedman
Director
Division of Manufacturing and Product Quality
Office of Compliance

Center for Drug Evaluation and Research


 

-

Ranbaxy Laboratories, Ltd., Dewas, India 16-Sep-08


Department of Health and Human Services' logoDepartmentof Health and Human Services

Public Health Service
Food and Drug Administration

 



White Oak, Bldg. 51

Silver Spring, MD 20993


Warning Letter


Via FedEx


September 16, 2008
WL: 320-08-03


Mr. Malvinder Singh, CEO and Managing Director
Ranbaxy Laboratories Limited
Corporate Office
Plot 90, Sector 32,
Gurgaon -122001 (Haryana), INDIA


Dear Mr. Singh,


This is regarding an inspection of your pharmaceutical manufacturing facility in Dewas, India by Investigators Thomas J. Arista and Robert D. Tollefsen during the period of January 28 - February 12, 2008. The inspection revealed significant deviations from U.S. current good manufacturing practice (CGMP) Regulations (Title 21, Code of Federal Regulations, Parts 210 and 211) in the manufacture of sterile and non-sterile finished products. In addition, violations of statutory requirements, Section 501(a)(2)(B) of the Act, were documented with respect to the manufacturing and control of active pharmaceutical ingredients (APIs).


These CGMP deviations were listed on an Inspectional Observations (FDA-483) form issued to Dr. T.G. Chandrashekhar, Vice President Global Quality and Analytical Research, at the close of the inspection. These deviations 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)]. Section 501(a)(2)(B) of the Act requires that all drugs be manufactured, processed, packed, and held in compliance with current good manufacturing practice.


We have reviewed the Established Inspection Report (EIR) and your April 3, 2008 response to the FDA-483 observations. We acknowledge that some corrections appear to have been completed, or will soon be implemented. However, your response fails to adequately address multiple, serious deficiencies. Specific areas of concern include the following: beta-lactam containment program and inadequacies in batch production and control records, failure investigations, quality control program and aseptic operations.


Beta-Lactam Containment Control Program


Interim controls for the containment of beta-lactam antibiotics such as penicillins, cephalosporins, and penems are inadequate. Specifically:


1. Failure to adequately establish separate or defined areas for the manufacture and processing of non-penicillin beta-lactam products to prevent contamination or mix-ups [21 CFR 211.42(c)(5)]. Operations related to the manufacturing, processing, and packaging of penicillins are not adequately separated from non-penicillin products [21 CFR 211.42(d)].

A. During the inspection, our investigators observed inadequate containment practices regarding the handling and movement of personnel, equipment, and materials as follows:

1. QC personnel move about freely collecting samples and engaging in other activities (i.e., documentation) between the manufacturing blocks for betalactam (penicillin, cephalosporin, and penem) and non-beta-lactam products.

2. Batch production and control records for beta-lactam (penicillin and cephalosporin) products were moved from their respective manufacturing blocks through the campus to the administration building for storage.

3. Personnel that dispatch and work in the beta-lactam API warehouses (penicillin and cephalosporin) move about freely on the manufacturing campus.

4. Personnel working in the cephalosporin API [redacted] dispensing area were observed with powder on their gowns and coming in direct contact with the outer surface of a bulk material bag that was then placed on transport equipment that can enter non-beta-lactam areas.

5. Operators and transport equipment (i.e., forklift) used to convey beta-lactam and non-beta-lactam materials to their respective manufacturing blocks on the manufacturing campus were observed interacting with and in very close proximity to other personnel that move about freely on the campus.



In your response, you reported that personnel in beta-lactam dispensing areas are required to decontaminate their gowns by wiping with [redacted] when powder is observed on their gowns before leaving the dispensing booth with bagged material. However, your response lacked data to ensure that all gown parts can be adequately decontaminated, and the procedures (SOPs) provided in your response (attachment #s 16[i] and [ii]) have no instructions on how the operators ensure adequate decontamination of their gowns. Furthermore, these SOPs do not provide the wiping steps intended to render operator gowns, plastic bags, corrugated cardboard boxes, and other surfaces mentioned in the SOPs, free of beta-lactam contamination. In your response to this Warning Letter, please provide an explanation of this approach, its capacity for robustness, methods and qualification of the wiping techniques on the aforementioned materials to ensure decontamination of beta-lactam residues with the [redacted]. Your response also failed to address the decontamination [redacted] effectiveness in neutralizing beta-lactams on the items that procedures require to be wiped with [redacted]. The effectiveness of this neutralizing [redacted] on different materials should be demonstrated through lab studies.


B. Your containment control and monitoring programs are inadequate to prevent cross contamination of non-penicillin pharmaceutical products (APIs and finished dosage forms) with possible residues of penicillin, cephalosporin, or penem compounds, as follows:

1. The containment monitoring program failed to include monitoring (surface sampling/testing) for residual traces of penem (i.e., imipenem) type betalactams in non-penem manufacturing blocks [redacted] and [redacted].

2. Surface monitoring (sampling/testing) for residual traces of penicillin type beta-lactams is not performed in the Penem Block where penem sterile parenterals are manufactured or in Block [redacted] where multiple cephalosporin finished products are manufactured.

3. Surface monitoring for residual traces of cephalosporin type beta-lactams is not performed in the General Block [redacted] where multiple non-beta-lactam finished products are manufactured or in the Penem Block where sterile parenterals are manufactured.

4. There was no written documentation reflecting the decontamination of materials, documents, and sample containers prior to removal from the penicillin or cephalosporin manufacturing blocks through the [redacted]

5. There were no written procedures established to address decontamination methods with the [redacted]

6. The containment control program does not include contingency (corrective action) procedures when beta-lactam contamination is found exceeding established action levels in the manufacturing blocks.



Your April 3, 2008 response, although lengthy, raised many concerns. For example, your response indicates that you are aware, as reported in your Environmental Control Program (Attachment 16.d [ii]), that beta-lactam compounds such as penicillins (i.e., amoxicillin), cephalosporins (i.e., cefaclor, cefadroxil), and penems (i.e., imipenem) have human sensitizing and cross-reactivity properties that require manufacturing controls to prevent cross contamination of non-penicillin (non-beta-lactams and among beta-lactams) products in your multi-product manufacturing campus. However, your procedures lack any sampling of production areas for traces of penem compounds, and various production locations were not sampled for the penicillins and cephalosporins you process.


Furthermore, your response did not include procedures addressing how to respond to a situation in which beta-lactams are found in the plant. Containment control program procedures should include provisions for detecting and correcting containment deficiencies. Beta-lactam contamination on surfaces alerts a firm that contamination is present in the manufacturing environment due to poor containment practices. This can lead to cross contamination of pharmaceutical products that were exposed in that environment. Your procedures should require adequate investigations to determine the cause of a positive residue finding and the extent of any contamination. In addition, the procedures should define the steps to be taken to determine the extent of the contamination and for identifying products potentially affected if such a breach occurs.


Aside from the above, additional information is needed regarding the validity of the reported negative test result findings from the site assessments for residues of penicillins and cephalosporins performed during July 2006 through March 2008, as follows:


i. Your response lacked data showing that surface testing is capable of reflecting true levels of contamination. The swab surface sampling recovery studies should establish that a valid swab sampling technique is in place for penicillins and cephalosporins on all types of surface substrate material mentioned in your firm's reports. Also, the surface recovery studies should demonstrate recovery of the [redacted] different types of cephalosporin compounds processed in Block [redacted]. Your response only provided data on 2 of the [redacted] products. The sampling procedures should address sampling from qualified surfaces. Validation data should show that surface sampling is capable of reflecting true levels of contamination and include the percentage of recovery for each type of surface sampled. Recovery study results should be provided in your response.

We are concerned that it could be difficult to detect beta-lactam contamination on porous surface materials such as operator gowns, corrugated cardboard boxes, and other types of materials mentioned in these reports. Furthermore, the sites identified by your firm for sampling should be sufficient, representative, and include worst case areas. Justification for the selected sampling sites should be provided in your response.

ii. We are concerned about the units reported in your response letter for sample test results of air, product and surfaces. For example, the air samples were reported in surface area units [redacted] and not in the volume of air sampled (see response page 51). Product testing was also reported in surface area units [redacted] and not in weight, volume amounts, or dosage type sampled (see response page 50). The surface sampling was reported in [redacted] and not [redacted] (see response page 52). The larger swab sampling area provides more reliable detection of contamination. It is important to note that the purpose of the swabbing program is to detect low levels of a sensitizing drug in the environment and sampling smaller areas may not ensure detection.

iii. We are concerned with your justification for decontaminating an area a month after the prior site assessment reported no traces of beta-lactam contamination (see response page 52). For example, this assessment reports that the archival room that stored beta-lactam batch production records (located in the Administration block) had no traces of beta-lactam contamination [Attachments 16a (iii) through 16a (vi)] in February 2008. However, your March 2008 reports states that the archival room was decontaminated and re-assessed for beta-lactam contamination [see Attachments 16a (viii) and (ix)].

iv. Your response (page 50) indicates that testing of non-penicillin products for traces of penicillin or cehalosporin contamination indicated results below the limit of detection (e.g., [redacted] for penicillin). We are concerned with your response since testing for residues of beta-lactams in other beta-lactams usually requires much more sophisticated test methodology than the [redacted] method you are currently employing. (We note that you are using a method similar to FDA's codified method under 21 CFR 211.176). However, as reported in your Environmental Control Program (Attachment 16d (ii)), the codified method is limited to detection of a few penicillins in a limited number of products. Therefore unless you can demonstrate to the contrary, this method is not appropriate. In your response to this Warning Letter, please indicate which products were tested, and specify whether testing included traces of penicillin residues in cephalosporin products or cephalosporin residues in penem products or any other drug products.

v. The Contamination Control and Risk Analysis provided in your response [Attachment 16d (i)] failed to address potential contamination between betalactams to include all the deficiencies mentioned above under item 1 of this letter.



Production Records


2. Batch production and control records do not include complete information relating to the production and control of each batch produced [21 CFR 211.188(b)] in that:


A. Production records failed to document weight or measure of excipients dispensed and used in production of non-sterile finished drug products that are manufactured in the following plants: Semi-synthetic Penicillin Block ([redacted]-Block), General Block ([redacted]-Block), and Cephalosporin Block ([redacted]-Block).

B. Production records also lack second person verification to ensure that the weight or measure of excipients was correct.

C. Media fill batch production records for sterile finished products lacked complete information. For example, records did not document the name or initials of the individual operators who executed the manufacturing instructions, nor the individuals who performed the visual inspection of the media filled vials. These media fill batches were submitted in support of the ANDA.

D. Media fill batch production records for sterile APIs also were incomplete in that they failed to document whether the required [redacted] integrity test was executed. These media fill batches were provided as supportive information to the ANDA.



Your response only addresses procedural improvements and discusses some related training. It failed to include an assessment of all batches shipped to the U.S. market with production records that lacked documentation of weight or measure of excipients dispensed in production of non-sterile finished drug products manufactured in the following plants: Semisynthetic Penicillin Block [redacted] Block), General Block [redacted] Block and Cephalosporin Block [redacted] Block). Our records indicate that batches produced in Blocks are being shipped to the U.S. market for distribution. Please provide an assessment or a affected US batches.


Failure Investigations


3. Your procedures do not provide for a thorough review of unexplained discrepancies or failure of a batch or any of its components to meet its specifications whether or not the batch has been already distributed [21CFR 211.192].


A. Sterility failures of four sterile API batches were inadequately investigated, as follows:

1. The investigation failed to confirm the root cause conclusion that microbes found in [redacted] water samples were the cause of the contamination, in that these isolates were not shown (characterized to their genus and species level) to be related to the batch sterility failure isolate [redacted].

2. The investigation failed to accurately report results. The investigation report dated September 4, 2007 inaccurately states that isolates from each of the 4 batches were further identified to their genus and species level. However the contaminant of one of the API batches that failed sterility [Batch [redacted]] was never characterized to genus and species level.

3. Environmental and personnel monitoring microbial sample results were not addressed by the sterility failure investigation reports. We note that your firm collects numerous samples with results from personnel, equipment, and air, from within the sterile API production area, and identifies these microbes. However, these data were not assessed or reported and the failure investigation reports are missing this testing.



Your response to the FDA 483 observation concerning the root cause conclusion in the investigation commits to implementing procedural changes that will address future sterility failures to ensure full characterization of investigational isolates. However, your response does not address how you intend to complete the failure investigation for the four API batches that failed sterility testing, to ensure the root cause for the failures is identified and appropriate corrective and preventive measures are implemented. Your response to the inaccuracy of your records for sterile API batch [redacted] does not address which controls will be implemented to ensure completeness and accuracy in reports. Your response to unreported data in failure investigation reports also does not address FDA's concern on the existence of unreported data associated with the manufacture of other drug products that may be in the U.S. market. Please provide this information in your response.


B. Your rejection of two (2) non-sterile finished product batches for failing to meet release specifications for [redacted] was inadequately investigated in that:

1. There were no records identifying assignable cause, nor implementation of corrective measures. For example, the investigation report did not identify any assignable cause or follow-up measures to determine the cause.

2. Review of the batch production records for the rejected batches found that the actual weights or measures of the [redacted] excipient was not documented in the batch production records of the two (2) failed batches. This information was not noted by the failure investigation.



Your response failed to address the reason the actual weight or measure of the [redacted] excipient was not documented in batch production records and was not addressed by the failure investigation reports. The lack of weight or measurement information in records prevents verification that the correct amounts of excipients were dispensed for the two failed lots. Additionally, your April 3, 2008, response indicates that the Quality Assurance Unit will complete a review of other investigation reports lacking root cause and response action, and supplement these reports if necessary by April 30, 2008. Please provide this information in your response to this letter.


Quality Control Unit


4. The Quality Control Unit (QCU) failed to ensure that its organizational structure, procedures, processes, resources, and activities are adequate to ensure that APIs and drug products, sterile and non-sterile, meet their intended specifications for quality and purity [21 CFR 211.22]. This same issue also applies to APIs produced at this site.


A. The QCU regularly signs off and approves production records although the records are incomplete for weight or measure of excipients used in non-sterile finished drug products as reported under item 2.A. of this letter.

B. The QCU failed to evaluate cleaning and sanitizing of the [redacted]. Additionally, the CU did not evaluate microbial and non-viable particle ingress from the [redacted] into the aseptic filling areas where finished sterile drugs are processed as reported under item 5.D.2.of this letter.

C. The QCU regularly signs off and approves inadequate failure investigation reports related to sterility failures of sterile APIs and rejections of non-sterile drug products as reported under items 3.A. and 3.B. of this letter.



Furthermore, we are concerned that deviations regarding inadequate recordkeeping and failure investigations cited on the current FDA-483 are similar to the deviations from the previous FDA-483 issued to your site on March 2, 2006. For example, the previous inspection conducted 2/27 - 3/2/06 resulted in the issuance of a 6-item FDA-483, which included inadequate failure investigations and lack of controls for analytical test records and batch production records. It is evident that your firm has not corrected the documentation and investigative practices at this site.


The FDA-483 observations and your previous responses indicate that the Quality Control Unit (QCU) was not independent and did not properly discharge its quality assurance and quality control responsibilities. We recognize the commitments to improve the quality organization in your response. However, your response failed to address global corrections to prevent reoccurrence.


Aseptic Operations


5. Procedures designed to prevent microbiological contamination of drug products and APIs purported to be sterile are not adequately written and followed to include adequate validation of the aseptic process. [21 CFR 211.113(b)]


A. Process simulations (media fills) for sterile API processes do not simulate actual commercial production procedures in that the 2005 2006 and 2007 media fills failed to include a media fill with the operator held [redacted] product loading lines from the API sterile [redacted] train to the [redacted].

Your response indicates that the revised media fill protocols now include the loading lines. Your response indicates that the new media fills would be completed by May 15, 2008 in the API facility, although we have not received further updates on the conduct and findings of these media fills.

B. Media fills for parenteral (sterile drug products) filling operations were inadequately performed to qualify aseptic processes in that documentation failed to include the specific reasons (assignable cause) filled vials were removed and not [redacted] during the media fill operation. The removal and destruction of filled vials [integral units] can present a bias to the final media fill results.

Your response indicates that the corrected media fill protocols and procedures will account (reconciliation) for all filled units during media fill runs. Your response indicates that the new media fills would be completed by April 30, 2008 in the finished dosage facility. However, you have not provided updates on the latest media fills.

C. Various instances of poor aseptic practices were observed throughout the manual unloading and transferring processes of the [redacted] sterile API during aseptic processing. These include:

1. Production personnel were observed handling a [redacted] hose without sanitizing its outer surfaces. The exterior surface of this [redacted] hose comes in direct contact with the [redacted] sterile API.

2. Operators were observed handling or touching various work surfaces, equipment, small stools, and tables, which were not wiped with sanitizing [redacted].

3. There were no records to document that the [redacted] door or external surfaces of the [redacted] are sanitized as required by procedures.

D. Various instances of poor aseptic practices during aseptic parenteral filling were also observed during the manual installation of the [redacted] transfer tubes, and the [redacted] flowing device as part of the aseptic transfer of the sterile API (in the [redacted]) to the finished dosage aseptic filling line. These include:

1. During the aseptic connection of the [redacted] and electrical connection an operator was observed coming in direct contact with the unsanitized [redacted] surfaces of the [redacted].

2. The aseptic equipment and areas where aseptic connections were performed were positioned below the [redacted] and within close proximity of its [redacted], which were not cleaned and sanitized, exposing this area to possible contamination.

3. There is also a contamination risk during aseptic filling due to the unsanitized equipment (e.g., possible contamination due to ingress from access panel and [redacted])



Your response to 5.D.2 above a ears to provide adequate corrective actions for the cleaning and sanitization of the [redacted]. However, the lifting of the [redacted] above, and in close proximity to the filing line, is unacceptable. This practice promotes ingress of microbial and non-viable contamination. Your response does not address the effect of the [redacted] position on the unidirectional airflow and maintenance of ISO [redacted] conditions during aseptic manual connections, transfer and filling of sterile product.


E. Utensils and equipment that directly contact sterile API during transfer and [redacted] of the [redacted] are inadequate to ensure that these APIs are maintained sterile and pyrogen-free. For example:

1. Several pits/holes were observed in the weld at the end of the large [redacted]. Additionally, there was a crack observed between the handle and the end of the large [redacted]. These holes and crack create a challenge for sterilization of this [redacted].

2. There were no written standard operating procedures or records documenting that the small [redacted] a.k.a., "Product Uniformity Tool"), that contacts sterile API during the [redacted] process, was depyrogenated prior to use.



Your response failed to include the actual depyrogenation qualification of the Product Uniformity Tool. Provide an assessment for all utensils and equipment to determine possible effects of inadequate design for use with sterile products and a corrective action plan to ensure repair or replacement with proper design and function.


6. The controls to prevent contamination or mix-ups in defined (critical and supporting clean) areas are deficient regarding operations related to aseptic processing of drug products [21 CFR 211.42(c)(10)].


A. For parenteral operations, smoke studies were not conducted to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions during numerous aseptic operations in classified areas of the vial filling facility. For example:

1. Various manual operations performed with the [redacted] such as dispensing sterile API and connecting equipment to this [redacted] were not included in smoke studies.

2. Other significant manual aseptic activities that can affect airflow, including opening and closing the fill equipment access panels during routine aseptic filling operations, were not evaluated in smoke studies.

3. There was no evaluation performed to demonstrate that personnel activities (e.g., manual transfer of material into or out of the ISO [redacted] and ISO [redacted] areas) do not compromise the unidirectional airflow pattern.

4. There was no evaluation performed to demonstrate that the horizontal airflow from the [redacted] does not negatively impact upon the vertical airflow within the aseptic Willing areas.



Your response indicates that you have prepared a comprehensive protocol for performing airflow pattern testing to include all aseptic operations in both the dispensing and filling areas and hope to video record these tests. Your response also indicates that the Quality Review of these smoke studies will be completed and approved prior to initiation of media fill studies, which were targeted to be completed by April 30, 2008. However, your firm has not provided an update on all airflow pattern findings and your evaluation of these study results.


B. For sterile API operations, smoke studies were not representative of actual operations to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions during numerous aseptic operations in classified areas processing sterile APIs. For example:

1. There are no smoke study evaluations to demonstrate that the personnel activities during the [redacted] of sterile API from the [redacted] do not disturb the unidirectional airflow in front of the to prevent compromising the sterile API.

2. The smoke study performed for the set up of the [redacted] equipment did not actually reflect the manner with which the equipment and manual aseptic connections are made.

3. There are no controls (e.g. physical barrier, curtains) in place to ensure that the [redacted] room's ISO [redacted] unidirectional airflow conditions were not compromised during routine operations performed within the ISO [redacted] area.

4. The smoke study performed for the [redacted] steps did not accurately reflect the manner in which routine aseptic connections are made.



Your response indicates that you have prepared comprehensive protocols for performing airflow pattern testing to include all aseptic operations in line with sterile API production and hope to video record these tests. According to your protocol, smoke studies were to be completed prior to the next media fills which were targeted to be completed by May 15, 2008. However, your firm has not provided an update on all airflow pattern findings and your evaluation of these study results.


C. Failure to conduct aseptic connections of sterile API materials in critical areas (ISO [redacted]) and demonstrate providing [redacted] unidirectional air flow over the connections. For example, the manual aseptic connections for sterile APIs performed prior to [redacted] were done in an ISO [redacted] (supporting clean) area.



Your response indicates that your new [redacted] unidirectional air flow (UAF) unit would be qualified by April 7, 2008 and the smoke study would be completed prior to media fills that were targeted to be completed by May 15, 2008. However, your firm has not provided an update on the airflow pattern findings for the [redacted] UAF unit and your evaluation of these studies.


D. Viewing locations are inadequate to assess processing operations in ISO [redacted] sterile API and drug product operations. The aseptic processing facility lacks appropriate viewing facilities for aseptic operations in order to assess the control systems necessary to prevent contamination or mix-ups during the course of aseptic processing. For example, the door windows and their locations, used to observe routine operations, precludes the In-Process Quality Assurance (IPQA) and Management from observing all phases of either the [redacted] aseptic API processes or the aseptic finished drug product processes.



Your response indicates that new procedures are being prepared with respect to activities to be reviewed, identification of all critical operations, and locations from where each operation has to be viewed (whether from view panel or inside critical areas). However, your response fails to indicate the adequacy of the facility to provide appropriate viewing of sterile processing operations in critical areas for both sterile APIs and finished dosage forms. Placing additional personnel such as IPQA personnel in critical areas can increase the risk of contamination and require additional operational qualifications. Please indicate if you intend to improve your viewing facilities.


In summary, we are concerned that your aseptic operations are conducted under extensive steps, manual handling, and inadequate equipment usage as reported above under S.C., D. and E., and 6.C. For example, manual operations under aseptic conditions should be conducted with minimum operator intervention and no exposed critical surfaces and product. Therefore, it is not appropriate to try to overcome major flaws in clean room design and equipment by attempting to validate difficult to perform, intensive manual procedures. These manual practices have the potential to increase the risk of contamination on critical surfaces and are considered inadequate manufacturing practices which can not be justified nor validated. Furthermore, design concepts and use of contemporary equipment and automation technologies should be explored and assessed for suitability to prevent unnecessary activities that could increase the potential for introducing contaminants into the aseptic environment. We recommend that you conduct an extensive evaluation of your facilities for opportunities to minimize steps and manual handling. Additionally, appropriate equipment and usage in all related aseptic operations for APIs and finished dosage forms should be evaluated. Please provide this evaluation in your response showing improvements to current operations.


The CGMP deviations identified above or on the FDA-483 issued to your firm are not to be considered an all-inclusive list of the deficiencies at your facility. FDA inspections are audits, which are not intended to determine all deviations from CGMP that exist at a firm. If you wish to continue to ship your products to the United States, it is your firm's responsibility to ensure compliance with all U.S. standards for current good manufacturing practice.


Until all corrections have been completed and FDA can confirm your firm's compliance with CGMPs, this office will recommend disapproval of any new applications or supplements listing your firm as a manufacturing location of finished dosage forms and active pharmaceutical ingredients. In addition, shipments of articles manufactured by your firm are subject to refusal of admission pursuant to Section 801(a)(3) of the FD&C 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 FD&C Act [21 U.S.C 351(a)(2)(B)].


While all shipments of articles manufactured at the Dewas site are subject to refusal of admission, under the circumstances FDA generally would not refuse shipments of Ganciclovir API. Because you are the sole source supplier of Ganciclovir API, FDA considers it important to maintain a sufficient supply of this drug product. Please contact the International Compliance Team immediately to discuss arrangements for your firm to continue importing Ganciclovir API, which would likely include third-party supervision and verification of each batch prior to release.


Please respond to this letter within 30 days of receipt. Identify your response with FEI #3002807977. Please contact Edwin Melendez, Compliance Officer, at the address and telephone numbers shown below if you have any questions, further information, or further proposals regarding this letter.


U.S. Food & Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Team
White Oak Building 51, Room 4224
10903 New Hampshire Avenue
Silver Spring, Maryland 20993


Tel: (301) 796-3201
FAX: (301) 847-8742


To schedule a re-inspection of your facility, after corrections have been completed and your firm is in compliance with CGMP requirements, send your request to: Director, Division of Field Investigations, HFC 130 Room 13-74, 5600 Fishers Lane, Rockville, MD 20857. You may also contact that office by telephone at (301) 827-5655 or by fax at (301) 443-6919.


Sincerely,


/S/


Richard L. Friedman
Director
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research

-

Thursday, September 11, 2008

A1 Discount Vitamins 11-Sep-08


Department of Health and Human Services' logoDepartmentof Health and Human Services

Public Health Service
Food and Drug Administration

 

Dallas District

4040 North Central Expressway

Dallas, Texas 75204-3128


September 11, 2008


2008-DAL-WL-22


CERTIFIED MAIL
RETURN RECEIPT REQUESTED


WARNING LETTER


Al Discount Vitamins
3180 NW 206
Edmond, OK 73003


Dear Sir or Madam:


This is to advise you that the Food and Drug Administration (FDA) has reviewed your website at the Internet address www.a1discountvitamins.com and has determined that the products "C-1000," "Colloidal Silver," "Graviola," "Red Raspberry Extract," "Juice Complex," " Lycopene," and "Pomegranate" are promoted for conditions that cause the products to be drugs under section 201(g)(1)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 321 (g)(1)(13)]. The therapeutic claims on your website establish that the products are drugs because they are intended for use in the cure, mitigation, treatment, or prevention of disease. The marketing of these products with these claims violates the Act.


Examples of some of the claims observed on your web site include:


C-1000


• "(C Vitamin 1000 with Quertin [sic] 50mg! ) To Help Prevent & Fight Cancer."
• "Vitamin C with bioflavonoids is also a powerful anticancer agent that promotes the production of interferon in the body."
• "Vita-Labs has combined Vitamin C, with Queretin [sic) to help prevent and fight cancer."
• "Lab studies suggest that it may have anti-cancer effects, help prevent heart disease by reducing the oxidation of LDL ("bad") cholesterol, and act as an antihistamine."
• "[M]ay help treat or even prevent prostate cancer by blocking male hormones that encourage the growth of prostate cancer cells, according to preliminary laboratory research at the Mayo Clinic."
• "Population studies have found that people with high intakes of foods containing quercetin and other flavonoids tend to have lower rates of heart disease and lung cancer."



Colloidal Silver


• "Colloidal silver appears to be a powerful, natural antibiotic and preventative against infections."
• "The following is a partial list of the more than 650 diseases that colloidal silver has been reputed to be successful against: ... AIDS ... allergies, appendicitis, arthritis, athlete's foot, bladder inflammation, blood parasites, blood poisoning, boils, burns, cancer ... cholera, colitis, conjunctivitis, cystitis, dermatitis, diabetes ... dysentery, eczema, fibrositis; gastritis, gonorrhea, hay fever, herpes, impetigo, indigestion, keratitis, leprosy, leukemia, lupus, lymphangitis, Lyme disease, malaria, meningitis ... parasitic infections: viral, fungal and bacterial pneumonia, pleurisy ... psoriasis, purulent opthalmia, rhinitis, rheumatism, ringworm, scarlet fever, septic conditions of the eyes, ears, mouth, and throat ... septicemia, shingles, skin cancer, staphylococcus and streptococcus infections, stomach flu, syphilis ... tuberculosis, tonsillitis, toxemia, trachoma, all forms of virus, warts, whooping cough, yeast infection, stomach ulcer ..."
• "Dr. Bjorn Nordstrom, of the Karolinska Institute, Sweden, has used silver in his cancer treatment method .... This brought rapid remission in patients given up on by other doctors."



Graviola (650 mg)


• "Graviola All Natural Cancer Treatment From South America ... Can Help Prevent and Fight Cancer!"
• "Graviola Cancer Fighting Herb From South America!"
• "Graviola, the powerful herb . .. is helping millions of people fight through their cancer treatment."
• "Can help kill cancer cells!"
• "Can help slow tumor growth!"
• "Purdue University researcher Jerry McLaughlin, working with doctoral student Nicholas Oberlies, found compounds in the Graviola tree that have shown preliminary success in fighting some drug-resistant cancers. The studies, published in two separate journal articles, show that the Graviola ... compounds not only are effective in killing tumors that have resistance to anticancer agents, but also seem to have a special affinity for such resistant cells. The findings were detailed in the journal Cancer Letters and the Journal of Medicinal Chemistry."
• "Graviola contains Annonaceous Acetogenins which have remarkable cytotoxic, anti-tumor activities .... [R]esearch identified more than 40 compounds with anti-cancer properties capable of killing cancer cells."
• "Excellent studies and information exists about Graviola's cancer killing abilities such as conducted at Purdue University in West Lafayette Ind, Health Science Institutes press release, the Skaggs Scientific Report from the Scripps Research Institute, Kaohsiung Medical University in Taiwan ... In a study conducted in 1976 by the National Cancer Institute, the leaves and stem of Graviola showed active cytotoxicity against cancer cells."
• "Scientists doing in vitro tests discovered that graviola was capable of killing the malignant cells of twelve different types of cancer."
• "Graviola is effective against all types of cancer, and is a broad spectrum anti-microbial for bacterial and fungal infections, internal parasites, and worms."
• "Graviola main uses: 1. Cancer (all types)."
• "CONQUER CANCER SAFELY and effectively with an all-natural therapy that doesn't cause extreme nausea, weight loss and hair loss."
• "EFFECTIVELY TARGET AND KILL MALIGNANT CELLS in 12 different types of cancer, including colon, breast, prostate, lung, and pancreatic cancer"
• "BE 10,000 TIMES STRONGER IN KILLING COLON CANCER CELLS than Adriamycin, a commonly used chemotherapeutic drug"
• "SELECTIVELY HUNT DOWN AND KILL CANCER CELLS without harming healthy cells, unlike chemotherapy."



Red Raspberry Extract


• "Red Raspberry Complex ... Powerful Cancer Fighter -'Ellagic Acid' - Helps Prevent & Fight Cancer!"
• "Ellagic Acid may be one of the most potent ways to fight Cancer. Ellagic Acid, a phenolic compound, is a proven anti-carcinogen, anti-mutagen, and anti-cancer initiator!"
• "Clinical tests conducted at the Hollings. Cancer Institute at the Medical University of South Carolina (MUSC) show that ellagic acid, a naturally occurring plant phenol with highest concentrations in red raspberries may be the most potent way to prevent cancer, inhibit the growth of cancer cells, and arrest the growth of cancer in persons with a genetic predisposition for the disease."
• "Dr. Daniel Nixon, MUSC, began studying the ellagic acid in red raspberries in 1993. His recently published results show:

o Cervical Cancer Cells -„HPV (human papilloma virus) exposed to ellagic acid from red raspberries experienced apoptosis (normal cell death).
o Ellagic acid leads to G1 arrest of cancer cells, thus inhibiting and stopping mitosis (cancer cell division).
o Ellagic acid from red raspberries prevents destruction of the P53 gene by cancer cells. P53 is regarded as the safeguard of mutagenic activity in cervical cells.
o Tests reveal similar results for breast, pancreas, esophageal, skin, colon, and prostate cancer cells.
o Consuming one cup (150 grams) of red raspberries per day prevents the development of cancer cells."

• "ELLAGIC ACID REDUCES THE INCIDENCE OF CANCER! Ellagic acid acts as a scavenger to bind cancer-causing chemicals, making them inactive!
...[E]Ilagic Acid from red raspberries prevents binding of carcinogens to DNA, and reduces the incidence of cancer in cultured human cells exposed to carcinogens."

• "Ellagic Acid is also considered to be a cancer inhibitor which has the ability to cause apoptosis or normal cell death in cancer cells."
• "Ellagic acid may be one the most [sic] potent substances yet found to help fight and prevent Cancer!"
• "Multiple studies have discovered that phytonutrients found in raspberries can protect us from cancer and can even shrink some types of cancer tumors."
• "Recent work (2001), published by Dr. Gary Stoner at Ohio State University, showed that components in the seeds and berry, but particularly ellagitannins, inhibited the initiation and promotion/progression stages of esophageal cancer."



In addition, the "Graviola & Ellagic Acid" page of your website lists several claims that promote your "Graviola" and "Red Raspberry Extract" products together for the treatment or prevention of cancer. Examples of some of the claims observed on this
page include:


• "(Cancer Fighting Combination)' Graviola & Ellagic Acid - Natural Cancer Fighting Products That Can Help Fight Cancer!"
• "Now you can help fight cancer with the combination of the two most powerfully know [sic] natural cancer fighting supplements 'Graviola 650 mgs 100 capsules and Ellagic Acid (Red Raspberry) 700 mg 120 capsules ..."
• "In an [sic] 1976 plant screening program by the National Cancer Institute, graviola leaves and stem showed active cytotoxicity against cancer cells and researchers have been following up on these findings since .... Three separate research groups have isolated these acetogenin compounds in graviola which have demonstrated significant antitumorous and anticancerous properties, and selective toxicity against various types of cancer cells (without harming healthy cells) publishing eight clinical studies on their findings. Many of the acetogenins have demonstrated selective toxicity to tumor cells at very low dosages as little as 1 part per million."
• "Four studies were published in 1998 which further specify phytochemicals and acetogenins which are demonstrating the strongest anticancerous, antitumorous, and antiviral properties. Thus far, specific acetogenins in graviola have been reported to be selectively toxic to these types of tumor cells: lung carcinoma cell lines; human breast solid tumor lines; prostate adenocarcinoma; pancreatic carcinoma cell lines; colon adenocarcinoma cell lines; liver cancer cell lines; human lymphoma cell lines; and multi-drug resistant human breast adenocarcinoma."



Juice Complex


• "Benefits You Can Have By Taking Juice Complex! ...

o Fights cancerous cells
o Alleviates diabetes
o Normalizes and regulates cholesterol levels
o Minimizes inflammation
o Prevents artherosclerosis [sic]"



Lycopene


• "(Lycopene Maximum Strength 25mg Per Tab - 21 Century!)' Reduces The Risk of Many Cancers Including Prostate Cancer!"
• "Studies have shown that lycopene may reduce the risk of many cancers and may greatly reduce the risk of prostate cancer in men."
• "Epidemiological studies have shown that high intake of lycopene-containing vegetables is inversely associated with the incidence of certain types of cancer. For example, habitual intake of tomato products has been found to help decrease the risk of cancer of the digestive tract among Italians."
• "Ongoing research suggests that lycopene may help reduce the risk of macular degenerative disease, serum lipid oxidation and cancers of the lung, bladder, cervix and skin."
• "In 2002, a Harvard Medical School follow-up study confirmed the previous results revealing frequent tomato product consumption is associated with a lower risk of prostate cancer. Data compiled from 1986 to 1998 show two or more servings a week of tomato sauce is associated with up to a 36 per cent lower risk of prostate cancer."
• "Researchers from the University of Illinois suggest tomato sauce, and possibly the lycopene present in tomato sauce, may play a role in the prevention and treatment of prostate cancer. In 32 prostate cancer patients, recruited from the Westside Department of Veterans Affairs Hospital in Chicago, the consumption of tomato sauce-based pasta dishes for three weeks (30 mg of lycopene per day) resulted in reduced oxidative DNA damage in prostate tissue and leukocytes."
• "There is evidence that the intake of lycopene may positively impact chronic health concerns that are important to women. These include breast cancer, ovarian cancer, cervical cancer, cardiovascular disease ...."



Further, the "Lycopene" product page of your website www.a1discountvitamins.com cites numerous articles about studies of the "lycopene" ingredient used in your products. These articles concern the use of this ingredient for treatment or prevention of cancer.


When scientific publications are used commercially by the seller of a product to promote the product to consumers, such publications may become evidence of the product's intended use. For example, under 21 CFR 101.93(g)(2)(iv)(C), a citation of a publication or reference in the labeling of a product is considered to be a claim about disease treatment or prevention if the citation refers to a disease use and if, in the context of the labeling as a whole, the citation implies treatment or prevention of a disease. The following are examples of reference citations used to market your "Lycopene" product for disease treatment and prevention on your website:


• "American Cancer Society. Cancer Facts & Figures 2002, 4"
• "Zhang S, Tang G, Russell RM, Mayzel KA, Stampfer MJ, Willett WC, Hunter DJ. Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer cases and control subjects. Am J Clin Nutr 1997; 66:626-632."

• "Levy J, Bosin E, Feldman B, Giat Y, Miinster, Daniienko M, Sharoni Y. Lycopene is more potent inhibitor, of human cancer cell proliferation than either Aâ€"carotene or betaâ€"carotene. Nutr Cancer 1995; 24:257-266"
• Levi F, Pasche C, Lucchini F, La Vecchia C. Dietary intake of selected micronutrients and breast-cancer risk. Int'l J. of Cancer 2001; 91:260-263."
• "Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, Stephenson HE Jr. Relationships of serum carotenoids, retinal, a-tocopherol and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri. Cancer Causes Control 1998; 9:89-97."
• "Cramer DW, Kuper H, Harlow BL, Titus-Ernstoff L. Carotenoids, antioxidants, and ovarian cancer risk in pre- and postmenopausal women. Int'l J. of Cancer 2001; 94: 128-134"
• "Goodman MT, Kiviat N, McDuffie K, Hankin JH, Hernandez B, Wilkens LR, Franke A, Kuypers J, Kolonel LN, Nakamura J, Ing G, Branch B, Bertram CC, Kamemoto L, Sharma S, Killeen. J. The association of plasma micronutrients with the risk of cervical dysplasia in Hawaii. Cancer Epidemiol Biomark Prev 7:537-544, 1998"
• "Kanetsky PA, Gammon MD, Mandelblatt J, Zhang ZF, Ramsey E, Dnistrian A, Norkus EP, Wright TC Jr. Dietary intake and blood levels of lycopene: association with cervical dysplasia among non-hispanic, black women. Nutr Cancer 31 :31-40, 1998."



Pomegranate


• "Powerful Anti-Oxidant To Fight Cancer ..."
• "Keep Prostate Cancer From Returning"

o "A study found that pomegranate juice may help fight the return of prostate cancer among men who have had surgery or radiation for the disease....'Pomegranate juice contains antioxidant chemicals that may have cancer-preventing benefits,' the researchers said."

• "Fight Breast Cancer"

o "Israeli researchers found that pomegranate seed oil causes breast cancer cells to self-destruct, while leaving healthy cells unharmed."



Finally, your website promotes the products listed above for cancer treatment or prevention through the "Cancer Fighting Products" link on the home page of your website as well as the "Cancer Supplements," "Natural Cancer Products," and "Prevent Cancer Products" links in the "Products Menu" listing on the left side of each page. Clicking on any of these links brings you to a product directory where these products are offered for sale. You also promote "Colloidal Silver," "Graviola," "Red Raspberry Extract," "Juice Complex," "Lycopene," and "Pomegranate" on the "Cancer Prevention" page of your website.


Your products are not generally recognized as safe and effective for the above referenced uses and, therefore, the products are "new drugs" under section 201(p) of the Act [21 U.S.C. § 321(p)]. New drugs may not be legally marketed in the U.S. without prior approval from FDA as described in section 505(a) of the Act [21 U.S.C. § 355(a)]. FDA approves a new drug on the basis of scientific data submitted by a drug sponsor to demonstrate that the drug is safe and effective. Your products "C1000," "Colloidal Silver," "Graviola," "Red Raspberry Extract," "Juice Complex," "Lycopene," and "Pomegranate" are also misbranded within the meaning of section 502(f)(1) of the Act in that labeling for these drugs fails to bear adequate directions for use [21 U.S.C. § 352(f)(1)].


The above violations are not meant to be an all-inclusive list of deficiencies in your products and their labeling. While reviewing your website, we noticed that you were promoting these products for treatment and/or prevention of diseases other than cancer and that you were also promoting other products for disease treatment and/or prevention. It is your responsibility to ensure that products marketed by your firm comply with the Act and its implementing regulations. We advise you to review your website, product labels, and other labeling and promotional materials for your products to ensure that the claims you make for your products do not cause them to violate the Act.


You should take prompt action to correct the violations described above and prevent their future recurrence. Failure to do so may result in enforcement action without further notice. The Act authorizes the seizure of, illegal products and injunctions against manufacturers and distributors of those products [21 U.S.C. §§ 332 and 334].


Please notify this office, in writing, within fifteen (15) working days of the receipt of this letter, as to the specific steps you have taken to correct the violations noted above and to assure that similar violations do not occur. Include any documentation necessary to show that correction has been achieved. If corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time within which the corrections will be completed.


Your response should be directed to Sherrie L. Krolczyk, Compliance Officer, at the letterhead address.


Sincerely,


/S/


Reynaldo R. Rodriquez Jr
Dallas District Director


 

-

Monday, August 25, 2008

A. Tarantino and Sons, Inc. 25-Aug-08


Department of Health and Human Services' logoDepartmentof Health and Human Services

Public Health Service
Food and Drug Administration

 

San Francisco District

1431 Harbor Bay Parkway

Alameda, CA 94502-7070

Telephone: 510/337-6700


WARNING LETTER


August 25, 2008


Via Federal Express


Our Reference: 1000161244


Anthony J. Tarantino, President
A. Tarantino and Sons, Inc.
2275 Jennings Street
San Francisco, CA 94124


Dear Mr. Tarantino:


We inspected your seafood processing facility, located at 2275 Jennings Street, San Francisco,California, on April 3 and 8, 2008. We found that you have serious violations of the seafoodHazard Analysis and Critical Control Point (HACCP) regulation, Title 21, Code of FederalRegulations, Part 123, and the Current Good Manufacturing Practice regulation for foods, Title21, Code of Federal Regulations, Part 110 (21 CFR 123 & 110). In accordance with 21 CFR123.6(g), failure of a processor of fish or fishery products to have and implement a HACCP planthat complies with this section or otherwise operate in accordance with the requirements of Part 123, renders the fish or fishery products adulterated within the meaning of Section 402(a)(4) ofthe, Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 342(a)(4). Accordingly, yourrefrigerated canned wild crabmeat, vacuum packed smoked salmon, vacuum packed smoked trout and histamine-forming fishery products are adulterated, in that they have been prepared, packed, or held under insanitary conditions whereby they may have been rendered injurious to health. You may find the Act, the seafood HACCP regulation and the Fish and Fisheries Products Hazards & Controls Guidance through links in FDA's home page at www.fda.gov.


Your significant violations were as follows:


1. You must conduct or have conducted for you a hazard analysis for each kind of fish and fishery product that you produce to determine whether there are food safety hazards that are reasonably likely to occur and you must have and implement a written HACCP plan to control any food safety hazards that are reasonably likely to occur, to comply with 21 CFR 123.6(a) and (b). However your firm does not have a HACCP plan for your reduced oxygen packaged seafood products, including but not limited to, refrigerated canned wild crabmeat, refrigerated vacuum packed smoked salmon, and refrigerated vacuum packed smoked trout, to control the food safety hazard of pathogen growth and toxin formation including that of Clostridium botulinum.

Once you have conducted a hazard analysis for refrigerated, reduced oxygen packaged seafood products, your HACCP plan must, at a minimum, list hazards that are reasonably likely to occur, and include appropriate critical control points, critical limits, monitoring procedures, recordkeeping activities, etc., to ensure that the food safety hazards are controlled. For example, your hazard analysis should consider the hazard of pathogen growth and toxin formation, including Clostridium botulinumtoxin formation, which is a reasonably likely hazard associated with these products. Preventative measures should be implemented at receipt and during refrigerated storage to ensure that the product is continuously maintained at or below 40° F. For example, upon receipt receiving your firm should consider monitoring the presence of ice or cooling media if product is received on ice or cooling media. Your firm should also consider a means to ensure that adequate storage temperatures are continuously maintained by monitoring the presence of ice or cooling media daily; or monitoringcooler temperatures on a continuous basis.

2. You must have a HACCP plan that, at a minimum, lists monitoring procedures and their frequency for each critical control point (CCP), to comply with 21 CFR 123.6 (c)(4). However, your firm's HACCP plan for [redacted] lists a monitoring procedure and a frequency at the refrigerated storage CCP that is not adequate to control histamines. Specifically, the HACCP plan for [redacted] lists a monitoring procedure of [redacted] by the [redacted] at a frequency of which is not appropriate to ensure continuous monitoring of your refrigerated fishery products. Intermittent temperature checks as a monitoring procedure during extended refrigerated storage is not adequate to ensure that products are not exposed to elevated temperatures for extended time periods due to fluctuations occurringbetween those checks.

FDA recommends the use of a continuous monitoring device such as a continuous temperature data logger for monitoring refrigerated cooler storage. In addition, we recommend a daily check of the recorded temperatures to ensure that proper temperatures have been maintained, and a daily check of the monitoring equipment itself to ensure that it is operating properly. Alternatively, you may choose toperform a daily visual check of the adequacy of ice or cooling media surrounding product during refrigerated storage; however, your HACCP plan and monitoring records should reflect this monitoring activity accordingly.

3. Because you chose to include a corrective action plan in your HACCP plan, your described corrective actions must be appropriate, to comply with 21 CFR 123.7(b). However, your corrective action plans for [redacted] at the [redacted] and [redacted] CCPs to control histamine formation are not appropriate. Specially, your corrective action plans do not resolve how the cause of the deviation will be corrected.



We may take further action if you do not promptly correct these violations. For instance, wemay take further action to seize your product(s) and/or enjoin your firm from operating.

You should respond in writing within fifteen (15) working days from your receipt of this letter.Your response should outline the specific things you are doing to correct these violations. Youshould include in your response documentation such as HACCP and verification records, or other useful information that would assist us in evaluating your corrections. If you cannot complete all corrections before you respond, you should explain the reason for your delay and state when you will correct any remaining violations.


This letter may not list all the violations at your facility. You are responsible for ensuring thatyour processing plant operates in compliance with the Act, the seafood HACCP regulation (21CFR Part 123) and the Current Good Manufacturing Practice regulation (2) CFR Part 110) . Youalso have a responsibility to use procedures to prevent further violations of the Act and allapplicable regulations.


Please send your reply to the Food and Drug Administration, Attention: Juliane Jung-Lau,Compliance Officer, San Francisco District, 1431 Harbor Bay Parkway, Alameda, CA 94502. If you have questions regarding any issues in this letter, please contact Ms. Jung-Lau at 510-337-6193.


Sincerely,


/S/


Barbara J. Cassens
District Director
San Francisco District

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Friday, May 2, 2008

Immucor, Inc. 02-May-08


Department of Health and Human Services' logoDepartmentof Health and Human Services

Public Health Service
Food and Drug Administration

 

Rockville MD 20857


MAY 0 2 2008


WARNING LETTER


OEWL-08-03


Express Mail


Gioacchino DeChirico
President and CEO
Immucor, Inc.
3130 Gateway Drive
P.O. Box 5625
Norcross, Georgia 30091


Dear Mr. DeChirico:


The Food and Drug Administration (FDA) conducted an inspection of Immucor, Inc., 3130 Gateway Drive, Norcross, Georgia, between January 8 and January 17, 2008 and determined that your firm manufactures serological reagents which are medical devices as defined under section 201(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) because they are intended for use in diagnosis of disease or other conditions. During the inspection, FDA investigators documented violations of Section 501(h) of the FD&C Act and deviations from applicable standards and requirements of Subchapter H, Part 820, Title 21, Code of Federal Relations (CFR). At the close of the inspection, our investigators issued a Form FDA 483, Inspectional Observations, which described anumber of significant objectionable conditions relating to your facility's compliance withcurrent good manufacturing practice (CGMP). Significant deviations in the manufacture of serological reagents observed during the inspection include, but are not limited to, thefollowing:


1. You failed to establish and maintain procedures to control product that does not conform to specified requirements [21 CFR 820.90). For example:

a. Panocell-16 lot 17154 tested out of specifications for reactivity of the cells on May 16, 2006. The lot was released to inventory prior to completion of the investigation on May 23, 2006.

b. Panocell-10 lot 02722 was placed on hold alert after testing positive for microbial growth. The hold was removed, and the product was released for distribution on February 7, 2007, prior to completion of the investigation on April 9, 2007.

c. Ficin Panocell-10 lot 50664-E was placed on hold alert after testing positive for microbial growth . The hold was removed, and the product was released for distribution on January 17, 2007, prior to completion of the investigation on February 20, 2007.

d. Panoscreen lot 03739 was placed on hold alert after testing positive for microbial growth. The hold alert was removed, and the product was released for distribution on February 13, 2007, prior to completion of the investigation on February 21, 2007.

e. Panoscreen I & II, Lot 41500 was removed from inventory on November 10, 2006, due to complaints of clots and unexpected color from a related lot. Sales were made from this lot on November 14, 2006, and November 20, 2006, prior to your discarding the remaining inventory on November
30, 2006.



2. You failed to establish and maintain procedures for changes to a specification, method, process, or procedure [21 CFR 820.70(b)]. Your SOP GEN 118 entitled "Change Order" requires approval of change orders by [redacted] before implementation of a change. However, you initiated Change Order CO-06-014 for a process change in the manufacture of Capture-R-Screen/Ready-ID plates, lots ID069 and ID070. These lots were distributed prior to approval of the change by the quality unit on March 23, 2006.


3. You failed to establish and maintain complaint handling procedures to ensure that all complaint files are evaluated to determine whether the complaint represents an event which is required to be reported to FDA under part 803 of this chapter, Medical Device Reporting (MDR) [21 CFR 820.198 (a (3). For example, your SOP GEN.162, entitled, [redacted] requires MDR assessments in Risk Evaluation Summaries was not followed for the below-mentioned complaints:


a. Complaint relating to Panocell-16, lot 21210.

b. Complaints relating to Panoscreen II &111, lots 41500, 41507, 41508, 41489.

c. Complaint relating to Capture-R RID Extend II, lot DN017.



4. You failed to establish and maintain procedures for implementing corrective and preventive action, including requirements for investigating the cause of nonconforming product and identifying the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems (21 CFR 820.100]. For example:


a. Your SOP GEN 106 entitled "Deviation Reporting" recommends a review of Customer Complaint Logs for similar deviations to determine product impact. However, investigations into deviations of Capture-R Ready Screen Plates, lots X155, X157, N097, N095, did not include a review of complaint files for similar deviations.

b. Your SOP BQA.101 entitled "Handling Microbiological Out of Specification Test Results" requires an investigation to be initiated as a result of a confirmed microbiological out-of-specification result. However, you did not investigate out-of-specfication microbial results for Panocell-l0, Lot 10832.

c. An investigation was not conducted for Panoscreen 1& II lot 41500, which was included in a recall initiated on November 29, 2006.



5. You failed to submit an MDR to FDA within 30 days of receiving information that reasonably suggests that your marketed device may have malfunctioned and would be likely to cause or contribute to a death or serious injury if the malfunction were to recur [21 CFR 803.50(a) (2)J . Specifically, a complaint for an unexpected positive reaction with Immucor Anti-D, Series 4, lot 504694 was deemed MDR reportable on August 28, 2007. This report was not submitted to FDA until January 9, 2008.

We acknowledge receipt of your written responses dated February 5, 2007, February 7, 2007, and March 14, 2007, which address the inspectional observations on the Form FDA 483 issued at the close of the inspection. We have reviewed your responses and accompanying documents. Corrective actions addressed in your responses may be referenced in your reply to this letter, as appropriate. However, your responses did not provide sufficient detail to fully assess the adequacy of your corrective actions. For example, your responses fail to discuss implementation of adequate quality assurance oversight to ensure prompt identification, correction, and follow up to problems associated with the manufacture of your products.


Neither this letter nor the list of inspectional observations (Form FDA 483) is meant to bean all-inclusive list of deficiencies that may exist at your facility. It is your responsibilityas management to assure that your establishment is in compliance with the provisions of the FD&C Act, and applicable federal regulations. Federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts.


You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action without further notice. Such action includes license suspension and/or revocation, seizure and/or injunction.


Please notify us in writing, within 15 working days of receipt of this letter, of anyadditional steps you have taken or will take to correct the noted violations and to preventtheir recurrence. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.


Your reply should be sent to the Food and Drug Administration, ORA/OE/Division of Compliance Management and Operations, HFC-210, 15800 Crabbs Branch Way, Rockville, MD 20855. If you have any questions regarding this letter, please contact Jacqueline Little, Ph.D., Team Biologics Compliance, Division of Compliance Management and Operations, at (240) 632-6863.


Sincerely,


/S/


David K. Elder
Director

Office of Enforcement

-

Monday, April 28, 2008

Merck & Company, Inc. 28-Apr-08


Department of Health and Human Services' logoDepartmentof Health and Human Services

Public Health Service
Food and Drug Administration

 

Rockville, MD 20857


April 28, 2008


WARNING LETTER


OEWL-08-02


EXPRESS MAIL
Richard T. Clark
President and Chief Executive Officer
Merck and Company, Inc.
770 Sumneytown Pike
West Point, Pennsylvania19486-004


Dear Mr. Clark:


The Food and Drug Administration (FDA) conducted an inspection of Merck and Company, Inc., West Point, Pennsylvania, between November 26, 2007, and January 17, 2008.During the inspection, the FDA investigators documented significant deviations from current good manufacturing practice (CGMP) in the manufacture of licensed biological vaccine products, bulk drug substances, and drug components.These products include Liquid PedvaxHIB®, RECOMBIVAX HB®, ProQuad®, Gardasil®, VAQTA®, and COMVAX®.These deviations from CGMP include non-compliance with Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the requirements of your biologics license application approved under Section 351 of the Public Health Service Act (PHS Act), and Title 21, Code of Federal Regulations (21 CFR) Parts 210 and 211.


At the close of the inspection, the FDA investigators issued a Form FDA 483, Inspectional Observations, which described a number of significant objectionable conditions relating to your firm’s compliance with CGMP.Significant deviations observed during the inspection include, but are not limited to, the following:


CGMP DEFICIENCIES CONCERNING DRUG PRODUCTS


1.You failed to thoroughly investigate any unexplained discrepancy of a batch or any of its components to meet any of its specifications whether or not the batch has already been distributed and to extend the investigation to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy [21 CFR 211.192].For example:


a. You submitted a Biological Product Deviation Report to FDA in October 2006, due to the [redacted] of Varivax III being out-of-specification at the two month stability time point.This product had been shipped to [redacted] and then returned to the United States before being placed on stability.The product was not licensed in the United States at the time of the deviation.Your investigation concluded that the failure was due to the ingress of [redacted] into the vial headspace during shipment [redacted].Your investigation did not include testing of other potentially affected products shipped [redacted], for example, ProQuad®, to determine if there were any detrimental effects on these products.

b. Numerous customer complaints have been received citing over-pressurization of vials.For example, Complaints 48891 and 53106 for Zostavax®, lot [redacted], concerned over-pressurization of vials.The investigations did not address the possibility of [redacted] ingress as the reason for over-pressurization of vials.The investigation also did not consider the possibility that the packing method might not be functioning as validated.

c. Not all lots of product that may have been affected by fibers being shed from [redacted] lot [redacted] were assessed.Only [redacted] lots of product, where the fibers were observed during filling, were quarantined and assessed.Approximately [redacted] lots of lyophilized product and [redacted] lots of liquid products were filled during the time of receipt and use of [redacted] lot [redacted].

d. Product lots that failed the initial [redacted] visual inspection for critical defects such as [redacted] and [redacted] were not thoroughly investigated.For example, MMR II® lots [redacted] and [redacted] failed the critical defect category for [redacted] and no investigations were performed.These lots were subsequently distributed.



2.You failed to establish adequate written procedures describing the handling of all written and oral complaints regarding a drug product [21 CFR 211.198].For example, Standard Operating Procedure (SOP) 283-316, [redacted] directs that a lot history be performed.This lot history is performed for the final finish lot number, which is the packaging/labeling lot number.However, complaints such as leaking vials/syringes and various container/closure defects would be associated with a fill lot number, and a fill lot number may be associated with several final finish lot numbers.


3.Your firm failed to assure that there are written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 CFR 211.100(a)].For example:


a. The validation performed in December 2006 for [redacted] machines 2, 3, and 4 is not representative of the actual automated inspection process for detection of [redacted] defects, in that there was no assessment of acceptably filled vials.This equipment is used to inspect multiple vaccine products from filling lines 131 and 138.

b. Process control limits were not evaluated and re-established for filling line defects for Zostavax® as required by SOP 300-103X.The SOP states that the Process Control Limits (PCL) should be evaluated after the first [redacted] lots and again after [redacted] lots or sooner if changes were made to the process.[Redacted] lots were inspected by the [redacted] from February 2006 to September 2007, yet the limits have not been evaluated.



4.You failed to assure that equipment used in the manufacture, processing, packing and holding of a drug product is calibrated, inspected, or checked according to a written program designed to assure proper performance [21CFR 211.68(a)].Specifically, a set of control samples representing defect types are examined by the automated inspection equipment prior to beginning each inspection process.The reject set testing allows high rates of known rejects to be accepted by the equipment.In addition, the first time non-accepts are sent back through the equipment and only those rejected a second time are discarded.


5.You failed to exercise appropriate controls over computer or related systems to assure that changes in master production are instituted and input and output from the computer or related system of formulas are checked for accuracy and maintained [21 CFR 211.68(b)], in that there is no documentation to support software manufacturing change performed to the [redacted] used in the manufacture of Gardasil®, lots [redacted] and [redacted].


6.You failed to establish test procedures or other laboratory control mechanisms designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity and to assure that any deviation from the written test procedures or laboratory control mechanisms shall be recorded and justified [21 CFR 211.160(a) and (b)].For example:


a. During review of atypical process reports (APR’s), QA release personnel may edit the number of occurrences calculated by the software.This practice is not addressed in the product release SOP.In addition, the practice has been used inconsistently.The number of occurrences is reportedly decreased if the root causes of the multiple deviations are not related; however, the opposite logic was applied to nine test failures for VAQTA®.These nine test failures, although related, were recorded as a single occurrence in the deviation tracking system.

b. CP 9110.001, [redacted] does not direct that any anomaly concerning the product or sample preparation such as leaking vials or test canisters, over-pressurized vials, or particles be documented on the testing worksheet.The procedure only addresses foreign material in test media and the inability to reconstitute lyophilized product.In these cases, the instructions are to notify the supervisor.

c. There are no data to support extension of expiration for preservative-free RECOMBIVAX HB® Reference Standard Lot [redacted] to [redacted] years, as [redacted] year stability data are not yet available.



CGMP DEFICIENCIES CONCERNING BULK DRUG SUBSTANCES AND DRUG COMPONENTS


Additionally, significant deviations in manufacture of your bulk drug substances and drug components were observed during the inspection.These deviations cause your bulk drug substances and drug components to be adulterated within the meaning of Section 501(a)(2) (B) of the FD&C Act.Specific areas of concern include, but are not limited to:


Production and Process Controls


1.You failed to assure that there are written production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.For example:


a. SOP 209-205X, [redacted] allows for a maximum of three re-dispensing operations prior to filling.To date, there have been no stability studies initiated for [redacted] re-dispensed bulk.


b. There are no data to support the [redacted] post [redacted] hold time for tanks used in the [redacted] Manufacturing Complex [redacted].Specifically, the tanks used for media challenges to support the [redacted] post [redacted] hold were not equivalent to the PedvaxHIB® processing tanks.The tanks used are [redacted] with [redacted] while the PedvaxHIB® tanks have [redacted] with [redacted].Additionally, the tanks used in PedvaxHIB® production include assemblies that are connected to the tank and [redacted] in place.


Failure Investigations


2.Failures are not fully investigated and documented, nor extended to other batches as appropriate.For example:


a. You failed to quarantine numerous process intermediates associated with the use of [redacted] filter membranes that were identified to cause foaming during filtration.This foaming was found to be associated with leaching of [redacted] into process intermediates.These process intermediates were used to further manufacture MMR®II, PedvaxHIB®, VAQTA®, VARIVAX® product lots.


b. Your investigation into leaks discovered in the [redacted] during [redacted] recharge for lot [redacted] concluded that the leaks resulted from a small hole in the [redacted]. The investigation also concluded there was no impact “due to the isolation of the leak and immediate remediation of the leak.” Attached to the investigation was an unsigned and undated chronology of events, estimated to the second.This information was derived from a notebook maintained by the production operator.However, these pages from the notebook are no longer available.


c. APR 2006-204C-0034 dated 8/24/2006 was issued for the sterility failure of Pedvax bulk lot [redacted].The contaminant was noted as [redacted]. The investigation failed to assess a recent change in the SIP cycle for [redacted] tank [redacted] in [redacted]. The validation of this SIP change was subsequently implicated during investigation of the failure of a [redacted] media challenge, which led to the recall of several PedVaxHIB® and COMVAX® lots.


Laboratory Controls


3. Laboratory controls do not include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure components and products conform to appropriate standards of identity, strength, quality and purity.For example, there has been no evaluation of the stability of [redacted] measles, mumps and rubella drug components over the multiple year storage and use periods.Existing stability data for the drug components are limited to potency of the vaccine components and sterility testing.


Building and Facilities


4. Written procedures for the use of cleaning and sanitizing agents designed to prevent contamination of your facility are incomplete. Specifically, SOP 204-608X, [redacted] does not provide a frequency for performance of the multi-step decontamination with [redacted].


Maintenance of Equipment


5. Written procedures are not followed for the maintenance of equipment used in manufacture, processing, packing or holding. Specifically:


a. Work order 1400076, dated August 29, 2007, issued for the 6-month maintenance on the PedvaxHIB® [redacted] tank [redacted], required a check of the condition of the [redacted]. This action was documented as "NA". However, there was no documentation as to why this prescribed action was not completed.


b. Work order 1415800, dated September 9, 2007, issued for the annual maintenance of the PedvaxHIB® [redacted] on [redacted], documented the first (10) inspections on the work order as "NA".However, there was no documented reason for the failure to complete these activities.


Containers and Closures


6. You failed to assure that container closure systems provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of bulk drug substances and sterile solutions used in production. For example:


a. Study FR #99-053, [redacted] did not include an assessment of the effect of storage conditions.This container/closure is used for bulk drug substances including Pedvax®HIB, RECOMBIVAX®, and [redacted].


b. [Redacted] sterile filtered solutions used in the manufacture of vaccines are stored in containers for [redacted].Validation studies have not been conducted to assure container/closure integrity.


The deficiencies described in this letter are indicative of your quality control unit’s inability to fulfill its responsibility to assure the identity, strength, quality, and purity of your drug product and drug substance.


We acknowledge receipt of your written response dated February 15, 2008, which addresses the inspectional observations on the Form FDA 483 issued at the close of the inspection, and we have reviewed its contents. Corrective actions addressed in your letter may be referenced in your response to this Warning Letter; however, we believe that your response(s) did not provide sufficient detail to fully assess the adequacy of the corrective actions. Our comments and requests for further information regarding corrective action are detailed below.The items correspond to the observations listed on the Form FDA 483:


Observation 2

Your response indicates that although direct testing of other products susceptible to [redacted] ingress was limited in scope, there was no detrimental affect on product potency and/or sterility.However, your investigation states that impact to vaccine potency for MMR can not be extrapolated from the results obtained for the Varivax III product. In addition, your investigation states that due to the limited [redacted] capacity of the ProQuad® single dose product (04984-00), [redacted] impacts the vial headspace and the resulting lower [redacted] upon reconstitution. Please provide an explanation to clarify these statements.


Observation 3

Please note that the investigation report dated December 20, 2007, for MMR Lot [redacted] is referred to as the final investigation report in the letter preceding the report. This report was also presented to the investigator as the Final Manufacturing Investigation. Alternatively, you refer to this report in your response as “a summary of your comprehensive investigation…in response to the request from [redacted]. Please explain if this is a final report or a summary of the final report.


Observation 14

Your response did not provide any documentation of the inputs and outputs generated during your investigation of the incident that caused the omission of the coding observed during the manufacture of Gardasil® lots. Additionally, your response did not include an explanation of the code, which controls the updates and downloads in the [redacted].


Observation 15

In your response you state “Independent of the high antigen content, an analysis of the Enzyme ImmunoAssay (EIA) method indicates that it is performing within historical parameters….” you also state that the findings from your investigation to date conclude that: “The EIA was underestimating the antigen content at the [redacted] step.This measurement is used to determine the antigen concentration taken into the [redacted].”As these statements seem to contradict each other, please provide a detailed explanation to clarify these statements.


Observation 16

In your response you acknowledge the importance of effective glass management in vial filling areas and the need to ensure that the line clearance procedures address the removal of broken glass from critical processing areas and equipment. We acknowledge the formation of a Glass Breakage Management Team and the issuance of a guidance document entitled, “Management of Glass Breakage,” on October 15, 2007.Please provide an update relating to your divisional glass breakage initiative.Please include the status of the three action items mentioned at the end of your response to this observation.


Observation 18

Your response seems to be adequate and will be followed up at the next inspection.However, we noted that during the inspection, information was given that does not correlate with the information in your response.During the inspection, your production supervisor indicated that the [redacted] system recorded the data but that there was no review of the monitoring data collected by the system.Also, at two different times during the inspection your production supervisor was unable to provide any information to explain the cited pressure losses.


Observation 20 C

Your response indicates that no marketed product has been manufactured with measles drug components held for more than[redacted] years and that all measles drug components in inventory at or greater than [redacted] years have been quarantined.However, your response does not address how the potency out-of-specification stability result will affect the expiration dating of measles drug components and vaccine drug products made from these drug components.Please comment.


Observation 25

Your response stated that independent of the validation of [redacted] #2 and #3 for volume of fill, there was no impact to product quality for all lots produced since there is an additional 100% manual inspection for [redacted].Please provide the procedure(s) in place prior to and after the current inspection covering the 100% manual inspection for volume of fill.


Observation 34

Your response states that you have verified that none of the data entry errors impacted the [redacted] leak test results or resulted in the incorrect use of the [redacted] within your manufacturing areas.Furthermore, you state that you conducted and completed a thorough investigation into the root cause for these errors and you list several corrective actions that will be implemented to address the causes.Please provide information on how you verified the [redacted] leak test results or that no [redacted] were used in manufacturing. Additionally, the investigation and relevant documents as well as the updated SOPs you mention in your response should be available for review at the next inspection.


Observation 37

Your response included the same historical data for two of the markers [redacted] in CP9110.780 and the Historical Reference Curve ed 50 Values in CP9110.780) that were reviewed during the inspection.Furthermore, updated data submitted in support of the historical [redacted] parameter in CP9110.780 continue to show a downward trend with respect to the upper and lower control limits.These data are also inadequate to support the expiry extension. Commitments to evaluate the expiry date for the November 2006 and November 2007 extensions (based on historical performance evaluation markers) and update the extension parameters in SOP 129.022 [redacted] are noted; however, these do not address the problems with IVRP assay. Please provide the results from the investigation of the 48 month stability time point investigation and additional information regarding storage of the gold standard reference material (Lot [redacted]).


Observation 38

Your response indicates that you will establish a [redacted] re-evaluation date on [redacted] based on the supplier’s [redacted] years stability data at [redacted]. If this critical reagent has a re-evaluation date, please explain your criteria for extending the date.Also, please clarify whether or not the[redacted] is stored at -20 ?C and whether there is data to support the [redacted] year storage at [redacted].


Observation 43

Your response indicates that by March 31, 2008, you will have established the following: 1) a procedure clearly defining those individuals that had authority to delete tests in [redacted] (would coincide with modification of [redacted] users accounts) and what documented approvals would be required prior to deletion of a test; and 2) a report which will summarize all deleted tests, which will be reviewed and approved by laboratory management and then forwarded for approval to the Director/Associate Director of Product Release on a monthly basis.Copies of the relevant SOPs as they relate to your enhancements regarding test deletions and reports summarizing all deleted tests should be available for review at the next inspection. Finally, it was stated during the inspection that your firm was also going to conduct an evaluation of the need to assess all pharmaceutical products to confirm that all release tests were performed.What is the status of that evaluation?


Neither this letter nor the observations noted on the Form FDA 483, which were discussed with you at the conclusion of the inspection, are intended to be an all-inclusive list of deficiencies that may exist at your facility. It is your responsibility as management to assure that your establishment is in compliance with the provisions of the Federal Food, Drug, and Cosmetic Act, Public Health Service Act, all applicable federal laws and regulations, and the standards in your license. Federal agencies are advised of the issuance of all Warning Letters about biological products so that they may take this information into account when considering the award of contracts.


To facilitate your remediation efforts we request a meeting with you and other senior management at Merck to further discuss the issues cited in this letter and your proposed responses to address them.Given the potential contributions of safe, pure, and potent vaccines to the public health, we encourage frequent interactions between your technical staff and FDA in an effort to help Merck move forward with corrective actions as rapidly as possible.


Please notify this office in writing, within 15 working days of receipt of this letter, of any steps you have taken or will take to correct the noted violations and to prevent their recurrence. Include any documentation necessary to show that correction has been achieved. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. Failure to promptly correct these deviations may result in regulatory action without further notice. Such actions may include license suspension and/or revocation, seizure or injunction.


Your response should be sent to Food and Drug Administration, Office of Regulatory Affairs/Office of Enforcement/Division of Compliance Management and Operations, HFC-210, 15800 Crabbs Branch Way, Rockville, Maryland 20855.

If you have any questions regarding this letter, please contact Jacqueline Little, Ph.D., Team Biologics Compliance, Division of Compliance Management and Operations, at (240) 632-6863.To schedule a meeting at your earliest convenience, please telephone Julie D. Bringger, Compliance Officer, Team Biologics Compliance, at (904) 281-1924, ext. 104, to discuss an appropriate date and time for the meeting.


Sincerely,


/S/


David K. Elder
Director
Office of Enforcement


Office of Regulatory Affairs


 


 

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