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U.S. Department of Health and Human Services

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Enforcement Actions

Medefil, Inc. 29-Dec-04

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

Public Health Service
Food and Drug Administration


Chicago District Office
550 West Jackson Blvd., 15th Floor
Chicago, liilnols 60661


December 29, 2004



Mr. Pradeep Aggarwal, President
Medefil, Inc.
Glendale Heights, IL b0139-3805

Dear Mr. Aggarwal:

During inspection of your firm from August 11 to September 23, 2004, United States Food and Drug Administration (FDA) investigators determined that your firm manufactures prefilled sterile heparin syringes and prefilled sterile saline syringes. These products are devices as defined by Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act).

This inspection revealed that these devices are adulterated within the meaning of Section 501 (h) of the Act, in that the methods used in, or the facilities or controls used for manufacturing, packing, storage, or installation are not in conformance with the Quality System Regulation (QSR), Title 21, Code of Federal Regulations (CFR), Part 820, as follows:

1. Your firm failed to maintain procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria as required by21 CFR 820.80 (d). For example, between January 17, 2004, and August 18, 2004, your firm shipped 24 lots (complete or partial) of product, labeled sterile, before your firm completed final acceptance tests to assure the product met specifications.

2. Your firm failed to establish and maintain procedures to ensure that expired devices or devices deteriorated beyond acceptable fitness for use are not distributed as required by 21 CFR 820.1b0 (a). For example, your firm's standard operating procedure (SOP) for product stability testing did not require placing at least one batch per year of both Heparin Lock Flush product and Saline Lock Flush product into the stability testing program.

3. Your firm failed to maintain procedures for implementing corrective and preventive action that include investigating the cause of nonconformities relating to product, processes, and the quality system as required by 21 CFR 820.100(a)(2). For example, your firm failed to document any type of investigation for the following deviations:

1.Non-viable particle counts that exceeded the alert limit or action limit:

Lot Manufactured


Controlled Area


Lot # [redacted]


OP Area (Class 1, 000)

19 counts over action limit

Lot # [redacted]


Sterilization (Class 100,000)

1 count over action limit

Lot # [redacted]


Clean Room 1 –Hood L (Class 100)

1 count over action limit

Lot # [redacted]


Clean Room 1 –Hood L (Class 100)

1 count over action limit

Lot # [redacted]


Clean Room 1 –Hood L (Class 100)

1 count over action limit

Lot # [redacted]


Clean Room 1 –Hood L (Class 100)

1 count over action limit

Lot # [redacted]


Product Outflow Class 10,000

17 counts over action limit

b) The MET ONE particle counter did not record data from the non-viable probes located throughout the controlled manufacturing area from December 20, 2003, to February 23, 2004. Your firm failed to document a cause, method or repair, or action taken to prevent this deviation from recurring.

4. Your firm failed to monitor and control production processes to ensure your devices conform to specifications as required by 21 CFR 820.70. For example:

a) According to the firms Non-Viable Count Procedure effective June 23, 2002 (Section 5.8), the computer monitor should stand facing the clean room during dynamic conditions so that staff working in the sterile product complex can monitor the non-viable particle counts. On 8/31/2004, the computer monitor did not face the clean room. Your firm was actively manufacturing Normal Saline Flush Syringes, 9mg/ml, lot number [redacted]

b) According to your firm's Non-Viable Particle Count Standard Operating Procedure (Section 5.12),effective June 23, 2002, if the counting any particular area exceeds the action level, then work in that area shall be stopped immediately and the deviation investigated by the department manager as well as the quality control unit. This procedural step was not followed for the following instances:

(1) During the Production of Heparin I.V. Flush Syringe, 100 Units/m1 Lot Number [redacted] the Product Outflow (Class 10,000 Room) reached above the action level 17 times during monitoring.
(2) During production of Normal Saline I.V. Flush Syringe Lot# [redacted] the Hood Left (Class 100) reached above the action level.
(3) During production of Normal Saline Flush I.V. Lot# [redacted] the Hood left (Class 100) reached above the action level once.
(4) During production of Normal Saline Flush 1.V. Syringe Lot# [redacted] the Product Outflow (Class 10,000) reached above the action level once.
(5) During production of Normal Saline Flush I.V. Syringe Lot# [redacted] the Hood Left (Class 100) reached above the action level once.

5. Your firm failed to establish and maintain process control procedures that include control of component characteristics during production as required by 21 CFR 820.70 (a)(2). For example, your firm had no documented limits for pre-filtration bioburden of the Heparin Lock Flush and Saline Lock Flush bulk solutions.

6. Your firm failed to establish and maintain procedures to adequately control environmental conditions that could reasonably be expected to have an adverse effect on product quality as required by 21 CFR 820.70(c). For example:

a) Your firm failed to trend environmental monitoring results of microorganisms isolated from aseptic-processing operators, equipment, and facilities according to specific operators or locations from which samples were taken.

b) Your firm failed to revise SOP709, "NON-VIABLEPARTICLE COUNT", dated 5/29/02, to reflect the current clean room conditions and equipment. SOP709, Section 5.5, indicated that the sterile product complex contains [redacted] nonviable particles counting probes. However, during our inspection the investigator determined that your firm's sterile product complex contained [redacted] nonviable particle counting probes in the sterile product complex.

c) Your firm failed to establish and implement procedures or mapping plans when your firm installed probes for nonviable particle counters.

7. Your firm failed to establish and maintain a process control procedure that describes a process control necessary to ensure conformance to specifications as required by21 CFR 820.70(a). For example, SOP 303, “Bacteriostasis and Fungistasis Testing" does not state that the extent of growth observed for the test specimens should be comparable to that observed for the positive controls. Line 5.12.4 states, "Test Product: There should be growth of microorganisms in all the canisters." The purpose for conducting bacteriostasis and fungistasis testing is to determine whether or not the extent of grow this comparable to that of the positive control.

8. Your firm failed to establish and maintain requirements for the health, cleanliness, personal practices, and clothing of personnel if contact between such personnel and product or environment could reasonably be expected to have an adverse effect on product quality as required by 21 CFR 820.70(d). For example, your firm's personnel engaged in aseptic filling operations, working in the Class 10,000 area, were not required to wear protective goggles. On 9/13/04 and 9/7/04 our investigator observed operators working in the aseptic processing area without wearing protective goggles.

9. Your firm failed to establish and maintain procedures for identifying valid statistical techniques required for establishing, controlling, and verifying the acceptability of process capability and product characteristics as required by 21 CFR 820.250(a). For example, your firm did not categorize filled syringes, which are rejected by the [redacted] and [redacted] automatic inspection machines, into types of defects.

10. Your firm failed to conduct quality audits by individuals who do not have direct responsibility for the matters being audited as required by 21 CFR 820.22. For example, according to your corporate structure flow chart, both you and Mr. Sandeep Aggarwal, Executive Vice President, have joint responsibilities for both product and quality assurance activities. Both you and Mr. Sandeep Aggarwal conducted all parts of your firm's most recent quality audit.

11. Your firm failed to maintain a Device Master Record for each type of device that includes, or refers to the location of, device specifications as required by 21 CFR 820.181(a). For example, your firm lacked physical specifications for syringe components and syringe fluid volume.

12. Your firm failed to maintain Device History Records (DHR) that include, or refer to the locations of, the dates of manufacture as required by 21 CFR 820.184(a). For example, on DHR 42 (saline) and 43 (Heparin) there is one space on page 2 that documents the date of manufacture and is not signed. In addition, there are numerous stages of manufacture listed on the DHR that are initialed or signed without being dated.

13. Your firm failed to establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit as required by 21 CFR 820.198(a). For example, your firm has no formally designated unit for handling complaints.

Due to the FDA-483 Observations that include lack of documented investigations (6, 8-2, 10-f) and missing quality control records (10-d-ii, 10-f, 14), we are concerned that your firm does not have sufficient personnel with the necessary education, background, training, and experience to assure that all activities required by the Quality System Regulation are correctly performed as required by 21 CFR 820.25(a).

Additionally, the above stated inspection revealed that your devices are misbranded within the meaning of Section 502(t)(2) of the Act, in that your establishment failed to develop, maintain, and implement written Medical Device Reporting (MDR) procedures for the following as required in 21 CFR Part 803.17:

(a) Internal systems that provide for:
(1) Timely and effective identification, communication, and evaluation of events that may be subject to medical device reporting requirements;
(2) A standardized review process/procedure for determining when an event meets the criteria for reporting under this part; and
(3) Timely transmission of complete medical device reports to FDA and/or manufacturers;

(b) Documentation and recordkeeping requirements for:
(1) Information that was evaluated to determine if an event was reportable;
(2) All medical device reports and information submitted to FDA and manufacturers;
(3) Any information that was evaluated for the purpose of preparing the submission of annual reports;
(4) Systems that ensure access to information that facilitates timely follow-up and inspection by FDA.

This letter is not intended to bean all-inclusive list of deficiencies at your facility. It is your responsibility to ensure adherence to each requirement of the Act and regulations. The specific violations noted in this letter and in the Form FDA-483, Inspectional Observations, issued at the conclusion of the inspection maybe symptomatic of serious underlying problems in your establishment's quality system. You are responsible for investigating and determining the causes of the violations identified by the FDA. You should promptly initiate permanent corrective and preventive action on your quality system.

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. No premarket submissions for Class III devices, to which the QSR deficiencies are reasonably related, will be cleared or approved until the violations have been corrected. Also, no requests for Certificates to Foreign Governments will be approved until the violations related to the subject devices have been corrected and verified.

In order to facilitate FDA in making the determination that such corrections have been made and thereby enabling FDA to withdraw its advisory to other federal agencies concerning the award of government contracts, and to resume marketing clearance for Class III devices for which a 510(k) premarket notification or Premarket Approval application (PMA) has been submitted, and Certificates to Foreign Governments for products manufactured at your facility, we are requesting that you submit to this office on the schedule below, certification by an outside expert consultant that he/she has conducted an audit of your establishment's manufacturing and quality assurance systems relative to the requirements of the device Quality System Regulation (21CFR, Part 820). You should also submit a copy of the consultant's report, and certification by your establishment's Chief Executive Officer (if other than yourself) that he or she has reviewed the consultant's report and that your establishment has initiated or completed all corrections called for in the report. The attached guidance maybe helpful in selecting an appropriate consultant.

The certifications of the audit and corrections should be submitted to this office by the following dates:

  • Initial certifications by consultant and establishment:       June 1, 2005

  • Second certification:                                                                  June 1, 2006

You should take prompt action to correct these deviations and to establish procedures to prevent their recurrence. Failure to promptly correct these deviations may result in regulatory action being initiated by FDA without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil penalties.

We completed our review of your response, dated October 26, 2004, to the Form FDA 483. We determined your response to be inadequate for the following reasons:

  • In your response to Observation 5 your statement regarding USP 27 Chapter<71>Sterility Tests is incorrect. In USP 27 Chapter <71>Sterility Tests, the "GROWTH PROMOTION TEST" part of "Suitability Tests" for "MEDIA" states, "Separately inoculate, in duplicate, containers of each medium. . .” Your response failed to include a commitment to perform growth promotion tests on sterility media by separately inoculating, in duplicate, containers of each medium.

  • Your response to Observation 6-a failed to include an explanation of each step being taken to identify and make corrections to the problem necessary to assure the same or similar violations will not recur.

  • Your responses to Observation 7, 9, and 19 stated procedures will be created or changed; however, your responses failed to include any training that would ensure that employees are notified of the change and learn how to implement the procedures correctly.

  • Your responses to Observations 8 and I0-f failed to include an investigation to determine why the initial training was not adequate to prevent the violation and an explanation as to how the retraining will be adequate to prevent the same or similar violations from recurring.

  • Your response to Observation 10-b failed to address the lack of a written procedure or mapping plan.

  • Your response to Observation 10-c tacked a commitment to correct the orientation of the existing installed probes for non-viable counts at the ceiling level in the Class 10,000, 100,000, and controlled areas. These probes were specifically referred to in the FDA-483 observation.

  • Your response to Observation 11 lacked a commitment to correct the observation and a corrective action time frame.

  • Your response to Observation 12 failed to include a standard operating procedure change and employee training.

  • Your response to Observation 17 failed to address training other employees who may receive a complaint besides your Quality Control Manager. This includes employees who answer the telephone, sales and marketing employees, employees that receive returned product, etc.  We believe it is important that employees be trained on how to handle a complaint should they receive one. Please keep in mind that a complaint is defined by the Quality System Regulation, in 21 CFR 820.3(b), as "any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device after it is released for distribution."

  • Your response to Observation 18 lacked a corrective action time frame and failed to address employee training.

Please notify this office, in writing, within 15 working days of receipt of this letter of the specific steps you have taken to correct the noted violations, including (1) the time frames within which the corrections will be completed, (2) any documentation indicating that the corrections have been achieved, and (3) an explanation of each step being taken to identify and make corrections to any underlying systems problems necessary to assure that similar violations will not recur.

Your response should be sent to Michael Lang, Compliance Officer, Food and Drug Administration, 550 West Jackson Blvd., 15th Floor, Chicago, IL, 60661-5716. If you have any questions regarding this letter, please contact Mr. Lang at (312) 596-4225.



Scott J. MacIntire
District Director