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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Cody Laboratories, Inc 07-Apr-06

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

Public Health Service
Food and Drug Administration

 

Southwest Region
Food and Drug Administration
Denver District Office
Bldg. 20-Denver Federal Center
P.O. Box 25087
6th Avenue & Kipling Street
Denver, CO 80225-0087
Telephone: 303-236-3000
FAX: 303-236-3100



April 7, 2006

Sent via FAX
(301587-7597

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Ref. # DEN- 06-14

Mr. Richard Edward Asherman, CEO
Cody Laboratories, Inc.
601 Yellowstone Avenue
Cody, WY 82414

Dear Mr. Asherman:

The Food and Drug Administration (FDA) inspected your firm, Cody Laboratories, 'Inc. (Cody Labs), located at 601 Yellowstone Avenue, Cody, Wyoming, on March 7-17, 2005. The inspection found deviations from the current good manufacturing practice (CGMP) requirements within the meaning of 21 U.S.C. §351(a)(2)(B) [Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act ("the Act")] . See Title 21, Code of Federal Regulations (C.F.R.), Parts 210 and 211 (21 CFR §§ 210 - 211). The CGMP deviations cause your Active Pharmaceutical Ingredient (API) product Hydromorphone HCI and finished drug product Morphine Sulfate Concentrate Oral Solution to be adulterated within the meaning of 21 U.S.C. §351 (a)(2)(B) [Section 501(a)(2)(B) of the Act] in that the methods used in, or the facilities or controls used for, the manufacturing, processing, packing, storage or holding of these products are not operated or administered in conformity with CGMP.

Since the close of the inspection, we have received a copy of the Drug Master File Amendment No. [redacted] Cody Laboratories, Inc., [redacted], filed [redacted]. We have also received four written responses - first from Patrick Cole, Quality Assurance Manager and E. Dawn Brumbaugh, Quality Control Manager, dated May 26, 2005; second from Patrick Cole, Quality Assurance Manager, E. Dawn Brumbaugh, Quality Control Manager, and Heidi Sanderson, Sr. Vice President, dated October 4, 2005; third, from Heidi Sanderson, Sr. Vice President, dated January 6, 2006; and fourth, a facsimile from Heidi Sanderson, Sr. Vice President, dated January 17, 2006. We apologize for the delay in completing our evaluation of the inspectional observations, which resulted from the need to thoroughly review your firm's above-noted substantive responses and complete laboratory analyses of samples. We have completed our review of the corrective actions in these responses and concluded that they do not adequately address the deficiencies indicated by the observations listed on the Form FDA 483 issued to you at the close of the inspection. A copy of that FDA-483 is enclosed for your reference.

The following are examples of the deviations from CGMP noted during the current inspection. We address your applicable responses below each deviation summary:

1. There is a failure to ensure that automatic, mechanical, or electrical equipment or other types of equipment will perform a function satisfactorily. [21 CFR § 211.68(a)]

For example, the reverse osmosis (RO) water system used in the manufacture of finished dosage forms does not have complete Installation Qualification. The Operational Qualification did not include backflow prevention, nor flush times or maximum hold time in the storage tank. The RO Water System Validation Protocol does not list specific acceptance standards for Volatile Organic Compounds, Nitrogen, Sulfates, and Metals in Phase I testing, and Heterotrophic Plate Count in Phase 1, II, or III testing.

This issue is not addressed in your May 26 response. Your October 4 response indicates that the RO "water system has backflow preventors," however, it is noteworthy that during the inspection, personnel at the firm did not know whether the RO system was equipped with backflow prevention. This response also indicates that the initial validation which included testing for volatile organic compounds (VOC), metals, sulfide, chlorine and nitrates, was to determine the needs of your pre-filter system and that you have determined that this testing is no longer required. However, no data was provided to justify this conclusion. Your response also indicates that the old validation protocol was not "up to the standards needed for an effective validation of the system" and that the system was "retrospectively validated" using a "new validation system, master validation plan and documentation system . . ." that " . . . are more robust and supply additional data to more effectively test and challenge the water system." However, it appears that this new protocol requires less testing and data collection than the previous protocol. You did not provide an explanation regarding why less testing and data collection, as compared to the old validation protocol, was deemed appropriate. The Summary Report does not include any additional data other than data collected in a six-month period from February 2005 to July 2005, prior to issuance of the new validation protocol. In addition, there is no data to justify the timetrames indicated in the summary report. For example, Section 5 of the summary report indicates that the Purified Water System [redacted], will be under continuous monitoring by testing sample points at least [redacted] per month. There is no indication in this report, though, on how [redacted] testing was deemed adequate.

2. There is a failure to follow procedures. [21 CFR § 211.100(b)]

For example, you are not following your standard operating procedure (SOP) [redacted] Reverse Osmosis (RO) Water System [redacted] in that Purge Ports, [redacted] Backflush, [redacted] UItraViolet Lamp Check, and Pressure Readings have not been maintained since April 2004. In addition, the Daily RO Water Purging Log kept prior to this time indicates that the elapsed time between purges ranged from [redacted] Water produced by the RO Water System is used in the manufacture of finished dosage forms.

This issue was not addressed in your May 26 response. Your October 4 response indicates that you are still not following procedures. For example, this response includes a Process Validation Protocol [redacted] issued on [redacted] and approved on [redacted] and [redacted]. Section [redacted] of this document states [redacted]. However, the data used for the evaluation was collected between [redacted] (prior to the March 2005 inspection) and [redacted] a period that began and ended before approval of the protocol. As noted in item 1 from above, your response stated that the old validation protocol was not "up to the standards needed for an effective validation of the system." Therefore, data collected from any previous studies is suspect, as you have not provided a rationale regarding the acceptability of data collected using a protocol that you have indicated did not meet standards.

3. The written program designed to assure proper performance of automatic, mechanical, or electronic equipment is not adequate. [21 CFR § 211.68]

For example, [redacted] , Inspection and Testing of Manufacturing Equipment, which applies to all activities for testing and inspection of equipment at Cody Labs, and the Installation Qualification Manufacturing Equipment form do not fully describe the requirements for equipment qualification, including environmental conditions for equipment operation, any necessary ancillary equipment needed for operation, and routine maintenance required. There is no requirement for a Performance Qualification protocol. Further, the Quality Control Unit (QC) is not required to review the Installation, Operation, and Performance Qualifications of equipment upon completion. The Validation Master Plan does not contain an operational qualification for the [redacted] used for Morphine Sulfate Oral Solution.

This issue is not addressed in your May 26 response. Your October 4 response addressing this issue is inadequate. For example, this response includes a Validation Master Plan, issued and approved on [redacted] Section '[redacted] this document states that [redacted]. This statement indicates that you do not fully understand the requirement for validation, which is to demonstrate that the process being proposed for use in manufacturing a drug product can meet predetermined goals or specifications. "Fine tuning" of the protocol, if any, should occur before an attempt is made to validate a process. In addition, the validation protocol should be followed and any deviations or variations from the approved protocol should be investigated.

4. There is a failure to assure that the air filtration system, including prefilters, is working correctly when used on air supplies to the production areas for both finished dosage forms and APIs. [21 CFR § 211.46]

For example, API products sold as dry powders are manufactured in a suite[redacted] solution drug product is manufactured. There have been no studies showing whether contamination of the solution drug product by the dry powders cannot occur when doors to the manufacturing suites are opened at the same time. The air handling system, including the air filters and filter combinations, have not been qualified to demonstrate that the drug product does not become contaminated with the dry powders. There are no diagrams showing the flow of air through the rooftop vents, fans, and air return units.

This issue is not addressed in your May 26 response. Your October 4 response on this issue is inadequate. For example, the air flow diagrams provided in this response indicate that the API production rooms have [redacted] airflow and the oral solution rooms have [redacted] airflow. However, [redacted] issued and approved on [redacted] requires that these conditions are measured and certified at least [redacted] a year, but makes no provision for installation of a manometer to provide an indication of the proper air pressure differential when the manufacturing rooms are in use. In addition, no mention is made of a schedule to change or replace the filters for air entry points into themanufacturing rooms.

5. Written procedures for cleaning and maintaining equipment used in the manufacture, processing, packing, or holding of a drug product, are inadequate. [21 CFR § 211.67(b)]

For example, The Validation Master Plan for Morphine Sulfate Concentrate Oral Solution does not address the use of [redacted] as a cleaning solution, and the Process Validation/Equipment Performance report does not address removal of [redacted] from the equipment.

This issue is not addressed in your May 26 response. Your October 4 response on this issue is inadequate. For example, [redacted] Used Equipment Cleaning Form, does not address what agents are used to clean the equipment. This SOP must address, among other things, what will be manufactured in the equipment, the reactivity of the equipment with the cleaning solutions, and the residues that may exist after cleaning. Obviously, previous product residues may be transferred to current product being manufactured, and depending on the product being manufactured, cleaning compound residue may transfer to the drug product. Also, there is no indication if the final rinse verification by QC is still visual, or if there is a rinse analysis to ensure that the equipment is clean.

6. There is a failure to investigate a batch that did not meet specifications. [21 CFR § 211.192]

Lot 801-05055-009 of Morphine Sulfate Oral Solution failed to meet the acceptable range listed on the batch production record. An investigation into this discrepancy was not conducted.

7. There is a failure to date and sign the Master Production and Control records. [21 CFR § 211.186 (a)]

Your response included a revised Master Production and Control Record for Morphine Sulfate Concentrate Oral Solution; however, it was not dated, signed or independently checked.

8. Failure of the Master Production and Control Records for each batch of Morphine Sulfate Concentrate Oral Solution to include: a statement of the theoretical yield and a specimen of a copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling, as required by 21 CFR 211.186(b)(7) and (8).

For example, at the time of the inspection, the space in the Master Production and Control Record specified for the theoretical yield was blank In your response of May 4, you have established new theoretical yield ranges; however, there was no discussion regarding how the theoretical yield range was derived . In addition, there is no indication that you have considered temperature, humidity, and loss of product in transfer lines and filters. Finally, there is no indication that the theoretical yield figure has been validated to determine that the calculation is accurate.

9. Adequate washing facilities, including hot and cold water, soap or detergent and clean toilet facilities easily accessible to all working areas are not provided. [21 CFR §211.52]

For example, for employees to wash their hands prior to entering the manufacturing areas for finished and API dosages, they must go through uncontrolled environments [redacted]. Your response of May 4 indicates that you have corrected this by providing a station with a bottle of hand sanitizer and towels. This is not an adequate washing facility.

10. Failure to have written procedures for complaints to include review to determine whether the complaint represents a serious and unexpected adverse drug experience which is required to be reported to the Food and Drug Administration in accordance with 21 CFR §310.305 and §514.80. [21 CFR § 211.198(a)]

For example, your May 4 response contains Corrective and Preventative Action procedure [redacted] and Adverse Drug Event (ADE) procedure [redacted]. However, the corrective action procedure does not cross-reference the ADE procedure to ensure that complaints, which represent a potential ADE, would be adequately handled. It also does not state that all complaints will be reviewed and evaluated to determine if a complaint represents a potential ADE.

In addition to the above violations, we note the following regarding manufacture of the APIs:

1. Failure to follow written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or. are represented to possess. For example, you have not completely validated the new manufacturing process for [redacted] described in the Drug Master File Amendment, in that you have completed one batch without predetermined acceptance goals, and have not performed an adequate qualification on your RO water system.

2. Failure to test each batch of API to determine conformance to specifications. For example, the result of a sample of Hydromorphone HCI, lot 300-05047-161, (FDA sample #299555) collected during the inspection and tested by FDA was, [redacted]. This result exceeds the limit [redacted] for this USP Class 3 residual solvent.[Redacted] which is also known as [redacted] is used by your firm in the manufacture of Hydrornorphone HCI. Residual solvent testing of Hydromorphone HCI lot 3000-05047-161 performed by your laboratory in February 2005, did not include testing for [redacted], even though your DMF [redacted] Residual Solvent Method [redacted] required residual solvent testing for [redacted]. In addition, your amended [redacted] dated [redacted] also references [redacted] Organic Volatile Impurities, which indicates that it is necessary to perform residual solvent tests for solvents that are used or produced in the manufacturing process. Your January 17, 2006 response indicates that you will verify all residual solvent testing on all products manufactured. However, it is noteworthy that the procedures in place during the inspection (as indicated above) required residual solvent testing, yet it was not performed.

3. Failure to establish complete written procedures for cleaning of equipment used in the manufacture, processing, packing, or holding of APIs. Your response of May 4 contains new validation formats that have not been reviewed and approved by the [redacted] unit, and procedures that have not been validated. For example, the Cleaning Validation Protocol (tab 6 of the May 4 response) has not been reviewed and approved. The following procedures for cleaning equipment dedicated to manufacture of Hydromorphone HCI API contain requirements, parameters, or limits that have not been validated: [redacted]. For example, it is unclear how Cody Labs determined that [redacted] testing is appropriate, how alarm and alert limits were established for microbiological testing, or what effect [redacted] testing failures will have on batches manufactured in the period before testing.

4. Failure to have an adequate written program for manufacturing equipment performance and failure to assure that manufacturing equipment is performing properly. For example, [redacted], Manufacturing Equipment: Qualification intended for equipment used to manufacture APIs is inadequate. The forms contained in the SOP are not designed to allow recording of the information that they are required to contain under the SOP. For example, there are no provisions in the form to record or check the specifications against which the Installation Qualification (IQ) is to be performed. The SOP also does not require the review and approval of the Operation Qualification (OQ) and Performance Qualification (PQ), by [redacted].

The use of the [redacted] dryer in the manufacture of APIs has not been adequately validated, and product has had to be reworked because shavings from the [redacted] dryer were found in the product. Your October 4 response indicates Cody Labs investigated the shavings from the dryer and reworked the product according to section [redacted] of [redacted] - Control of Nonconforming Product, effective [redacted]. The investigation report, dated August 9, 2005, still does not address the root cause of the shavings in the product. In fact, the IQ and OQ were not performed on the [redacted] Dryer. In addition, it was not inspected prior to use in production. There was noPreventative Maintenance (PM) on this equipment. A complete investigation would have noted that the IQ/OQ and PM were not conducted, and should have determined the root cause of the shavings in the product. This response also indicates that the [redacted] dryer has been removed from service and a new [redacted] Dryer has been installed. However, because only blank IQ forms were included and not the actual IQ data for this new dryer, we could not evaluate how your firm currently performs an IQ.

In addition, in the Equipment CI assification/Qualification section of the DMF, complete equipment qualification (IQ, OQ and PQ) are only performed for what is termed [redacted] Equipment. "Only IQ and OQ are performed for what is termed [redacted] Equipment," which includes the [redacted] unit of the [redacted], and only IQ is performed for what is termed [redacted] Equipment," including [redacted] Complete equipment qualification must be performed for all of this equipment.

During a previous inspection of your firm in March 2002, even though no FDA 483 was issued, several discussion items were brought to your attention. These included the need to establish procedures to prevent cross-contamination and the necessity for process validation. Based on the findings of the current inspection, the violations indicated above, and the response you have provided, this advice was not heeded. While your response to the observation that the roles and responsibilities of the Quality Control Unit are not fully outlined in writing [FDA 483 Observation #10] appears to be adequate, the deviations cited above indicate the failure of your firm's Quality Control Unit to assure overall compliance with the CGMP regulations and indicate an incomplete understanding of the importance of the quality system in your manufacturing processes.

The above identification of violations is not intended to be an all-inclusive list of deficiencies at your facility . As President of Cody Laboratories Inc., it is your responsibility to assure adherence with all requirements of the Act and Good Manufacturing Practice Regulations for all the drugs produced at your manufacturing facilities. Other Federal agencies are advised of the issuance of all Warning Letters about drugs so that they may take this information into account when considering the award of contracts. Additionally, pending NDA, ANDA, or export approval requests may not be approved until the above violations are corrected.

We request that you take prompt action to correct these violations, to establish procedures whereby such violations do not recur, and to review your operations and your product labels to ensure compliance with all applicable laws and regulations. Failure to do so may result in regulatory action without further notice. These actions include, but are not limited to, seizure and/or injunction.

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 stated violations, including an explanation of each step being taken to identify violations and make corrections to ensure that similar violations will not recur. If the corrective action cannot be completed within 15 working days, state the reason for the delay and the time frame within which the corrections will be implemented.

Any reply should be sent to the attention of Howard E. Manresa, Director, Compliance Branch, at the above address.

Sincerely,

/S/

B. Belinda Collins
District Director