- Chromsystems Instruments & Chemicals GmbH
- Issuing Office:
- Center for Devices and Radiological Health
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||10903 New Hampshire Avenue|
Silver Spring, MD 20993
AUG 8, 2014
VIA UNITED PARCEL SERVICE
Mr. Michael J. Meier
Chromsystems Instruments and Chemicals GmbH
AM HAAG 12
Dear Mr. Meier:
During an inspection of your firm located in Grafelfing, Germany on 03/17/2014 through 03/20/2014, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures immunoassay and reagent based products. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body.
This inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Act, 21 U.S.C. § 351(h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.
We received a response from Mr. Michael J. Meier, Owner and General Manager dated April 07, 2014 concerning our investigator’s observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, which was issued to your firm. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
1. Failure to maintain a record of the investigation, when an investigation is made, by the formally designated unit identified in paragraph (a) of 21 CFR 820.198, as required by 21 CFR 820.198(e). For example, the Chromsystems’ procedures for Handling of Complaints (b)(4), Version 2.1 dated 02/28/2014, and (b)(4), Version 2.3, dated 02/28/2014) describe the receipt and handling of complaints for the firm’s Class I and II medical devices. Complaints are recorded on one of 3 forms depending on product type: Form FB-CS-116-EN (Technical Complaints); Form FB-CS-117-EN (Non-Technical); or Form FB-CS-118-EN (Column Complaints). However, at least 3 of 13 of the complaint forms lacked documentation of investigation details. Furthermore, there was no evidence that documented that other complaints had been reviewed in order to identify reports of similar issues for the same product. Specifically:
a. Complaint # CS-1404 regarding product #65100 Vitamin C (columns) did not document on the form that review of other complaint records or production records was conducted in order to identify similar occurrences of this issue. There were 16 complaints recorded for this issue before the firm finally opened a CAPA to investigate. It was documented retroactively (on 06/11/2013) on the complaint form CS-1404 that CAPA #03-2013 had been opened to investigate the issue.
b. Complaint # CS-1596 regarding product #41211 Reference Electrode received on 10/03/2013 did not document on the form a review of other complaint records in order to identify similar occurrences of this issue.
c. Complaint #CS-1609 regarding product #3130 Column for Serotonin in Plasma received on 10/05/2013 did not document on the form a review of other complaint records in order to identify similar occurrences of this issue.
We reviewed your firm’s response and conclude that it is not adequate. Your firm states that it will retrospectively evaluate all related complaint documents and apply corrective actions. Your firm states that it will modify work instructions, complaint report forms and provide training on these revised documents. Your firm proposes to complete the corrective actions by 07/01/2014.
The response is not adequate because your firm did not provide evidence that it conducted a retrospective review of all complaints received, not just related complaints, to ensure that complaint investigations were documented as required. Furthermore, your firm did not provide evidence that it conducted investigations and documented complete investigations for Complaints CS-1404, CS-1596, and CS-1609, as required, as a correction to this deficiency.
2. Failure to establish and maintain procedures for acceptance of incoming product, as required by 21 CFR 820.80(b). For example, the Chromsystems' Incoming and Testing procedure, (b)(4), Version 2.0, dated 03/05/2014, describes receiving and testing of incoming raw materials used in production of the firm's Class I and Class II medical devices, but fails to mention checking temperatures of incoming products if they are delivered at other than ambient temperature to ensure that incoming product is inspected, tested, or verified to conform to specified temperature requirements. Specifically, the firm’s procedure (Storage of Raw Materials Section 5.4) describes the storage conditions for various raw materials, including ambient temperature, refrigerated, freezer and special storage conditions (for highly flammable materials). The matrix raw materials (blood, plasma and serum) are to be stored frozen until used. The following discrepancies were noted during examination of the firm’s procedures and records:
a. In the Incoming and Testing procedure, there was no requirement to check the temperature of products that have specific temperature requirements, such as incoming raw material (whole blood, serum, plasma products) that are transported from the supplier to the firm in a frozen state and held in the firm’s freezer until production, upon receipt as part of the incoming/inspection process. On the documentation for a blood product shipment received by the firm on 02/28/2014, there was a failure to demonstrate that product temperature was checked when received by the firm to ensure that the specified temperature requirement for the blood, serum and plasma was met.
b. The Incoming and Testing procedure, Section 5.3, p. 4, describes only signing the Certificate of Analysis (C of A) from a chemical supplier. There is a failure to mention other inspections required for incoming chemical raw materials, such as checking the C of A to see if the received chemical complies with the specifications as ordered. During review of the firm's records, the incoming inspection documentation for the chemical (b)(4) consisted only of initials and a date on the lower right comer of the supplier's Certificate of Analysis.
We reviewed your firm’s response and conclude that it is not adequate. Your firm has provided a modified work instruction to state that the inspector shall compare the specifications of incoming goods to the received C of A and apply, date and initial the sticker applied to the C of A after performing this activity (b)(4); Exhibit A-1 Modified on 3/20/14, Version 2.1). Your firm indicated it has updated training records for the modified work instruction used for the comparison of incoming product specifications to the received C of A. Your firm states that it will obtain a temperature monitoring device for all blood product shipments so that it can monitor and record the travel conditions of the shipments. Accordingly, your firm also states that it will modify its Incoming Receiving Form for Matrix Blood Products (b)(4) to verify that the proper cold temperature was maintained during shipment.
The response is not adequate because your firm did not provide the modified work instructions regarding testing incoming temperature sensitive blood or chemical materials with the temperature monitoring device. Your firm also did not provide documentation that a systemic corrective action was considered to include a retrospective review of all temperature sensitive items in inventory to ensure that the temperature of these items were being checked and adequately documented as required and that retrospective review of all incoming product would be performed to ensure they were checked for meeting specifications as required. Additionally, your firm did not provide documentation that checking product specifications to the C of A have been implemented for all incoming raw material, including the blood products and the chemical (b)(4) as a correction to this deficiency.
3. Failure to establish and maintain procedures to ensure that sampling methods are adequate for their intended use and to ensure that when changes occur the sampling plans are reviewed, as required by 21 CFR 820.250(b). For example, the same numbers of samples were submitted for final acceptance testing as documented in the Device History Records (DHRs) for Chromsystems' released medical devices, regardless of the lot size. The firm failed to reference a valid statistical sampling plan in the quality testing procedure contained within the DHR. This issue was noted in DHRs for these products:
a. Product #6009 Lot #0714 Urine Calibration Standard for Catecholamines (4 samples are run per analyst-2 person minimum, for the (b)(4) size of 7010 bottles).
b. Product #65005 Lot# 0414 Vitamin C Precipitation Reagent (2 bottles run in duplicate for (b)(4) size of 5200 bottles).
c. Product #65003 Lot #0514 Calibration Standard, Vitamin C (4 samples are run per analyst-2 person minimum, for (b)(4) size of 3969 bottles).
We reviewed your firm’s response and conclude that it is not adequate. Your firm states that it will modify its Statistical Techniques procedure (b)(4) to be based upon a national standard sampling plan (ISO 2859-1:2004-01 or ANSI/ASQ Z1.4:2008). Your firm also states that it will submit the modified work procedure and training records for review.
The response is not adequate because your firm did not provide updated testing records using the revised procedure, (b)(4), for sampling plans used when conducting final acceptance activities for Product #6009 Lot #0714, Product #65005 Lot# 0414, and Product #65003 Lot #0514 as a correction to this deficiency. Furthermore, your firm did not state that it will consider a systemic corrective action to include a retrospective analysis on all product lots to ensure that acceptance activities for all lots (or the same products in different lots) were conducted using a valid sampling plan as required.
Your firm’s responses dated April 29, 2014 and June 27, 2014 to the Form FDA 483 (FDA 483) were not reviewed because they were not received within fifteen business days of issuance of the FDA 483. The responses will be evaluated along with any other written material provided in response to the violations cited in this Warning Letter.
U.S. federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected.
Please notify this office in writing within fifteen business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, including an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again. Include documentation of the corrections and/or corrective action (which must address systemic problems) that your firm has taken. If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities. If corrections and/or corrective actions cannot be completed within fifteen business days, state the reason for the delay and the time within which these activities will be completed. Please provide a translation of documentation not in English to facilitate our review. We will notify you regarding the adequacy of your firm’s response(s) and the need to re-inspect your firm’s facility to verify that the appropriate corrections and/or corrective actions have been made.
Your firm’s response should be sent to: Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Field Inspections Support Branch, White Oak Building 66, Rm 2622, 10903 New Hampshire Ave., Silver Spring, MD 20993.Refer to CMS case # 432126 when replying. If you have any questions about the contents of this letter, please contact: James L. Woods, at 301-796-6225 or fax 301-847-8513.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility. It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems.
Your firm should investigate and determine the causes of the violations, and take prompt actions to correct the violations and bring the products into compliance.
Office of In Vitro Diagnostics
And Radiological Health
Center for Devices and
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