Inspections, Compliance, Enforcement, and Criminal Investigations
First Priority, Inc. 09-Jul-07
Department of Health and Human Services
Public Health Service
July 9, 2007
RETURN RECEIPT REQUESTED
Lawrence F. Schneider, President
First Priority, Inc.
1590 Todd Farm Drive
Elgin, Illinois 60123-1287
Dear Mr. Schneider:
An inspection of your drug manufacturing facilities located at 1585 and 1590 Todd Farm Drive, Elgin, Illinois, conducted by an investigator from the U.S. Food and Drug Administration (FDA) from October 24 through November 9, 2006, confirmed your firm was not operating in compliance with the current Good Manufacturing Practice (cGMP) regulations, Title 21, Code of Federal Regulations, Parts 210 and 211 (21 CFR Parts 210 and 211), for the manufacture of finished pharmaceuticals. Your firm's non-compliance with these cGMP regulations causes your finished pharmaceutical products to be adulterated within the meaning of Section 501(a)(2)(B) [21 U.S.C. 351 (a)(2)(B)] of the Federal Food, Drug, and Cosmetic Act ("the Act"). Section 501(a)(2)(B) [21 U.S.C. 351(a)(2)(B)] of the Act requires that the methods used in, or the facilities or controls used for, the manufacturing, processing, packing, and holding of drugs be in conformity with cGMP regulations. You can find the Act and its associated regulations on the Internet through the links on the FDA web page at www.fda.gov.
In addition, the inspection also revealed that you are manufacturing "Purple Lotion Wound Dressing," which is adulterated within the meaning of Section 501(a)(5) [21 U.S.C. 351(a)(5)] of the Act, in that it is a new animal drug which is unsafe within the meaning of Section 512(a) [21 U.S.C. 360b(a)] of the Act.
We acknowledge receipt of a letter dated February 16, 2007, that was written on your behalf by Mr. Deepak Naik, Director of Regulatory Affairs, in response to the Form FDA-483, Inspectional Observations, ("FDA-483") issued to and discussed with you on November 9, 2006. We have reviewed your written response and concluded that it does not adequately address the inspectional observations. For example, some of your responses do not contain complete information; some were limited to address only the specific examples listed in the FDA-483 versus globally correcting the cGMP violations; and, several of your responses indicate that corrections will take longer than one year from issuance of the FDA-483 to be completed. We feel that they should be completed within a much shorter timeframe.
Our inspection found violations including, but not limited to the following:
Failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has been already distributed [21 CFR 211.192]. For example:
The investigation of a complaint submitted by a customer on 8/11/06 regarding a possible reaction of two dogs to Pyrantel Pamoate Suspension Canine-2X (4.54 mg / mL), Lot [redacted], was not thoroughly and/or completely documented. The assay of the product returned by the customer found 142.7% label claim. The specifications for this product are [redacted] % of label claim. The letter to the customer says the higher assay value indicates that the bottle was not shaken well. However, there is no documentation of the receipt and examination of the returned sample. In addition, the report of the investigation of the complaint does not indicate that the batch record, process validation data or stability information was reviewed as part of the investigation.
There is no documented investigation of the leaking bottles of Povidone Iodine Shampoo, Lot [redacted] which resulted in the reworking of returns and warehouse stock into new bottles in March 2006. There are no records of an investigation to determine the cause of the leaking bottles, to assure the issue did not impact other lots of drug products and to identify actions needed to prevent a recurrence. This lot was released on 9/27/05.
This observation is discussed in your written response to FDA-483 item #1. The response states that your firm has revised its SOP entitled "Complaint Procedure 2-035" to require more detailed investigations and corrective actions. However, the SOP fails to provide guidance on what must be addressed during investigations. An example of this deficiency is the fact that the SOP does not require that investigations be extended to other lots or other drug products that may be associated with the specific failure or reported defect. Additional comments we have regarding your response to this particular FDA-483 item are as follows:
The response does not address the four specific examples listed in the FDA-483 observation. The response fails to indicate whether investigations were done to determine the cause and needed corrective actions for the stability test failure of Pyrantel Painoate Suspension (2.27 mg / mL), Lot [redacted] the use of defective seals that resulted in the removal of Ivermectin Equine Oral Liquid, Lot [redacted] from the market; or the leaking bottles of Povidone Iodine Shampoo, Lot [redacted]
No data or information was provided to support the conclusion that the 142.7 % of the active ingredient found in a returned bottle of Pyrantel Pamoate Suspension (4.54 mg / mL), Lot [redacted] was the result of the failure to shake the bottle.
Please discuss whether your firm has conducted any type of investigations to assure the expiration date for Pyrantel Pamoate is acceptable and that corrective actions to prevent the use of defective seals and wrong caps have been identified and implemented.
Failure to fully establish and follow written procedures describing the handling of all written and oral complaints regarding a drug product [21 CFR 211.198(a)]. For example:
The inspection revealed that returns of drug products because of defects or quality issues are not documented and investigated as complaints. Examples of this practice include:
Your firm's Customer Product Return Form RA#1110 shows that 2 gallon bottles of Iodine Tincture, Product #TP132BT, Lot [redacted] were returned on 1/30/06 because the bottles were leaking from the seams. The customer return was not documented or investigated as a complaint.
Customer Product Return Form RA#1 128 shows that 6 1/2 cases of Cort-Astrin (Hydrocortisone Solution 1%, 1 oz), Product #TPlOOVE, Lot [redacted] were returned on 9/8/06 because the product had a yellow tint and an odor of vinegar. A note says the product was given to the quality control unit; however, the customer return was not documented or investigated as a complaint.
The quarterly reports of product defects received from a distributor are not handled as complaints. For example, Product Defect Reports (Form FDA-1932) were submitted to FDA on 1/12/06, 4/19/06 and 7/27/06 reporting that multiple bottles of multiple lots of Copper Naphthenate Solution were returned because of leaking containers, missing labels or missing caps. These reports of product defects were not recorded and handled as complaints. During the inspection, our investigator was told by representatives of your firm that the lack of an effective seal is a known problem that your firm has not been able to correct. The corrective action implemented was to perform an inspection of every bottle of every lot for leakers. This regulation [21 CFR 211.198(a)] requires that your firm's complaint handling procedures include the review of any complaints involving the possible failure of a drug product to meet any of its specification by the quality control unit (QCU).
This observation is discussed in your written response to FDA-483 item #2. The response states that defects reported in quarterly reports received from distributors will be recorded and handled as complaints, but this is not mentioned in Complaint Procedure SOP #2-035 that was included with the response. The response also states that all returned drug products will be logged on Consumer Complaint Forms and will be investigated as complaints, but, there is no discussion of a procedure that includes this as a written requirement.
Failure to establish and follow written responsibilities and procedures applicable to the quality control unit [21 CFR 211.22(d)]. For example:
Written procedure 2-032, In-House Reference Standards, dated 8/27/04, is not followed. Inhouse reference standards, which are used in testing finished product samples, are not retested annually as required by step 7.3 of the SOP. Examples include:
Phenylbutazone raw material Lot FP6277 was initially qualified as an in-house reference standard in May 2005. The reference standard was never retested. Records show it was used as a reference standard in the finished product assay of Phenylbutazone Tablets, Lot [redacted] on 8/23/06.
Pyrantel Pamoate raw material Lot [redacted] was initially qualified as an in-house reference standard in July 2003. The reference standard has never been retested. Records reviewed during the inspection show that [redacted] was used as the reference standard in assays of Pyrantel Pamoate Suspension process validation samples in 2005, finished product release assays in 2005, and 2006 and stability sample assays in 2006.
Written procedure 1-013, "Validation Policy," dated 12/29/05, was not followed when a change was made to the manufacturing process used for Pyrantel Pamoate Suspension Canine-2X (4.54 mg / mL), Lot [redacted] in April 2006. A planned deviation changed the compounding tank, mixer speeds and mixing times used to make this [redacted] batch of suspension product. The Validation Department did not determine if the modification was major or minor as defined in Section 7.2 of SOP 1-013. In addition the Validation Department did not address the need to do additional testing to assure the product was equivalent to that made by the validated process.
There is no written procedure that describes the visual examination of reserve samples of finished drug products for deterioration. A report titled, "2005 Annual Product Inspection (Visual / Odor)," indicates that all inspected products passed. However, there is no written procedure that describes how the examination is done or that defines the pass/fail criteria. In addition, the lot numbers and number of units examined are not documented in the report.
Of the three examples discussed above, the first two represent failure to follow existing SOPs, while the third example discusses the failure to have a required procedure. We note that during the previous inspection of your firm, which was conducted from August 17 through September 7, 2004, this same deviation was issued and discussed with you as observation #1 of the FDA-483 that was issued on September 7, 2004.
This observation is discussed in your written response to FDA-483 item #4. Our comments on the response to this observation are as follows:
Mr. Naik states that First Priority has revised the procedure for the qualification and testing of inhouse reference standards. A copy of the revision was included with the response. The response says your firm has also designed a new tracking system for all in-house reference standards. The revised SOP includes more testing than previously required. The SOP says two analysts will test the material and the average assay value will be assigned to the standard. However, we believe they should do more than average the results of two assays. The two assay results should agree with each other within a narrow range that approximates the standard deviation allowed in the assay method. The response also says that all in-house reference standards will be qualified using the new procedure, but this will not be completed until December 2007. We do not understand the delay in qualifying reference standards. First Priority should assure that every inhouse reference standard currently in use is within its expiration and retest dates.
The response to the second example does not address the issue of the failure to follow the validation policy SOP when a change was made in the compounding tank, mixer speeds and mixer times for the production of a lot of suspension product (Pyrantel Pamoate Canine (4.54 mg / mL). The response says, in the future, your firm will only make this suspension product in kettles with dual motion sweep agitation. However, your firm made one lot in Tank #8 for the purpose of process validation. We do not understand why, if First Priority determined a new mixing tank should be used for suspension products, was a lot manufactured in Tank #8? The validation consisted of collecting 3 samples, one from the top, one from the middle and one from the bottle of the tank. The three values ranged from [redacted] mg / mL [redacted] %) to [redacted] %). There is no discussion or explanation of the relatively low results provided with the response. If this lot was formulated for 100% as required by cGMPs, we question what happened to almost 5% of the active ingredient in the middle sample and we wonder why this lot was made using Tank #8 when your firm identified the need to change the mixing process using a kettle which has dual motion sweep agitation:
Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product [21 CFR 211.110(a)]. For example:
There is no process validation data available for Levoxine (Levothyroxine Sodium) Powder (a prescription drug product) that demonstrates the current ingredients, formula and manufacturing process consistently produce a powder that meets density requirements to assure that each level teaspoon contains 12 mg of T4, as stated on the label.
The only process validation data available is for one lot (H1R) made in 1999 that was re-worked because it did not meet the density requirement. According to statements made on the "Re-Work Procedure" form, the initial batch was screened through a [redacted] Different grades of Sodium Chloride and Calcium Carbonate and additional amounts of Levothyroxine Sodium were added to the batch and blended as Parts I and II.
The density requirements are not defined in the process validation protocol. Density testing and results are not documented in the process validation data. There is no data to show that the reworked Lot met density requirements. Currently, there are no density specifications for Levoxine Powder.
Levoxine Powder, Lot [redacted], was manufactured in September and approved for release on 9/15/06. The only tests done on the finished product are assay and loss on drying. The assay result is reported as a percentage ([redacted]%). The assay method determines the quantity in mg of Levothyroxine sodium per gram of the sample.
The process validation data for Pyrantel Pamoate Suspension Canine (2.27 mg / mL) manufactured in tank #12 does not demonstrate that the mixing process consistently produces a uniform batch. A process validation batch uniformity study (Protocol [redacted]) was done in 2005 to "verify that the blending procedure as described in the master formula is adequate to provide uniform suspension for [redacted] lots of [redacted] batches." The final report, which is dated 5/27/05, concludes, that based on the evaluation of test data, the validation was successfully completed. However, the raw data for one of the batches [redacted] does not demonstrate batch uniformity. The assay results of the three samples of Lot [redacted] range from [redacted] mg / mL [redacted] % of label claim) to [redacted] mg / mL [redacted] % of label claim). The variability of the results are not discussed in the final report of Protocol [redacted] Tank 12 is currently used to manufacture [redacted] batches of Pyrantel Pamoate Suspension Canine (2.27 mg / mL). For example, Lot [redacted] is a [redacted] batch made in Tank 12 on 5/31/06. This lot was approved for release on 6/7/06 based on the finished product testing of one sample of the bulk suspension collected from the mixing tank.
This observation is discussed in your written response to FDA-483 item #9. Our comment on the response to this observation is as follows:
The response to this observation addresses the three specific products listed on the FDA-483. We note however, that First Priority does not make a commitment to assure that adequate process validation studies are performed for all veterinary drug products. In addition, process validation studies for the products listed on the FDA-483 have not been completed. According to the response, process validation testing was done on one lot of Levoxine Powder and one lot of Chlorhexidine Antiseptic Ointment. Two additional lots of each product will be tested when the batches are manufactured. No estimated completion date for these studies is discussed. The response says the Pyrantel Pamoate Suspension products will no longer be made in compounding tanks, but in kettles with dual motion sweep agitation. A validation study using the kettle for the 2.27 mg / mL product reportedly was completed in 2005. That data is not included with the response.
Our review of the response to this FDA-483 item is, in summary, 1) the validation studies of the three products listed on the FDA-483 are not complete; 2) there is no assurance that acceptable process validation studies have been or will be conducted for all drug products; and 3) the Levoxine Powder study is questionable because samples were mixed before testing.
Samples taken of drug products for a determination of conformance to written specifications are not representative [21 CFR 211.160(b)(3)]. For example:
Finished product release testing of some products is done on samples of the bulk material collected from compounding tanks, kettles and blenders. Samples are not routinely collected and tested after filling operations are completed. There was no documented explanation of how the samples of bulk drug products are representative of the entire manufacturing process, including the hold times between compounding and filling. Such products include:
Pyrantel Pamoate Suspension Canine (2.27 mg Pyrantel base per mL). The sample tested for finished product release is collected from the mixing tank after the addition of the flavor ingredient and homogenization of the batch. The batch record states the bulk material of this suspension product can be held up to [redacted] before filling starts.
Pyrantel Pamoate Suspension Canine-2X (4.54 mg Pyrantel base per mL). The sample tested for finished product release is collected from the mixing tank after the addition of the flavor ingredient and homogenization of the batch. The batch record states the bulk material of this suspension product can be held up to [redacted] before filling starts.
Levoxine Powder (Levothyroxine Sodium, 12 mg T4 / level teaspoon). The samples tested for finished product release are collected from the top, middle and bottom of the ribbon blender after final mixing. The batch record states the bulk powder can be held for [redacted] before filling starts.
During the inspection, the FDA investigator asked how the bulk samples can be considered to be representative of the complete manufacturing process, including the filling operation. Our investigator was told that sampling procedure is used because First Priority has performed process validation testing on all products. However, our inspection revealed that none of the process validation studies reviewed, particularly for suspension and powder products, established a hold time between compounding and filling. We do not believe that testing the top, middle and bottom of the blender for each lot produced, as our investigator was told First Priority does, can account for problems that can occur during the filling operations.
This observation is discussed in your written response to FDA-483 item #13. Our comments on the response to this observation are as follows:
Mr. Naik indicates that First Priority has changed the procedures for the collection of samples for release testing. The collection of samples is described in a new SOP, "Sampling Procedure for Finished Product Release" (1-036). The SOP indicates that dose forms (powder, bolus, tablets and suspensions) samples are collected from the beginning, middle and end of the filling operation. However, only the first unit filled is collected for other liquid based products, including ointments and gels. The first of fill is representative of the packaged product, but we do not understand how it is representative of the entire lot.
The testing and release of drug products for distribution do not include appropriate laboratory determination of satisfactory conformance to the identity and strength of each active ingredient prior to release. Specifically, identity tests are not done on all drug products prior to release [21 CFR 211.165(a)]. For example, batches of the following drugs were released without identity testing:
LevoxineTM Powder (0.22% Levothyroxine Sodium)
Chlorhexidine Antiseptic Ointment (1% Chlorhexidine Acetate)
Chlorhexidine Solution (2% Chlorhexidine Gluconate)
Copper Naphthenate Solution (3.6% Copper Naphthenate)
Povidone Iodine Shampoo (3% Povidone Iodine)
This observation is discussed in your written response to FDA-483 item #16. Our comment on the response to this observation is as follows:
The written response says the global revisions to the drug product batch records will include the addition of an identification test to the finished product test criterion. However, these revisions will not be completed until December 2007. That timeframe is more than one year after the issuance of the FDA-483. There is no explanation of why the corrective action will take so long to implement.
Established test procedures are not followed. The inspection revealed instances in which laboratory testing was not performed using approved analytical methods [21 CFR 211.160(a)]. For example:
The chromatographic system suitability checks specified in Method # FPM020, "Assay for Levothyroxine Sodium," dated 2/22/05, are not performed when testing samples of Levoxine Powder for finished product release. None of the specified system suitability checks, which include replicate injections of the standard preparation and the determination of the tailing factor , were done when testing samples of the following lots of Levoxine Powder: Lot [redacted] tested on 2/13/06 and Lot [redacted] tested on 9/13/06.
Not all of the chromatographic system suitability checks specified in the assay procedures in Methods AAFPM006 and AAFPM007, which are the "ANADA Approved Finished Product Test Methods" for Primex Canine 2.27 mg / mL and Primex Canine - 2X 4.54 mg / mL, are performed when testing samples of Pyrantel Pamoate Suspension for finished product release. One of the system suitability checks specified in the written procedures is the determination of the number of theoretical plates of the column used. This check was not done when testing samples of the following lots of Pyrantel Pamoate Suspension: Lots [redacted] and [redacted] of Primex Canine (2.27 mg / mL) tested on 5/25/05 and 6/1/06, respectively; Lot [redacted] of Primex Canine2X (4.54 mg / mL) tested on 4/21/06.
This observation is discussed in your written response to FDA-483 item #15. Our comment on the response to this observation is as follows:
The written response addresses only the specific examples listed in the FDA-483 observation. It says the test methods will be followed in the future and that all system suitability checks and run times will be performed as written in the test procedures. The response does not provide any explanation of how management will assure this is done. Also, there is no mention of training of employees in these procedures.
In addition to the above violations, the inspection also revealed that you are manufacturing and marketing a product called "Purple Lotion Wound Dressing," which is described in your website (www.prioritycare.com) and in the product's immediate label as "A germicidal, fungicidal, antiseptic, and protective wound dressing for use in the treatment of minor cuts, scratches and superficial abrasions." The labeling for this product indicates that your product contains gentian violet as an ingredient.
Under section 201(g) [21 U.S.C. 321(g)] of the Act, any article "intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals" or "articles (other than food) intended to affect the structure or any function of the body of man or other animals" is defined as a drug. Because you market this product as being intended for use in the treatment of minor cuts, scratches and superficial abrasions of animals described as "livestock," this product is a drug under section 201(g) [21 U.S.C. 321(g)) of the Act.
We also note that according to 21 CFR 500.30, the FDA has determined that gentian violet is not generally recognized as safe and effective for any veterinary drug use in food animals and that it is a new animal drug, under Section 201(v) [21 U.S.C. 321(v)] of the Act, which is subject to Section 512 [21 U.S.C. 360b] of the Act.
Your "Purple Lotion Wound Dressing" product is adulterated within the meaning of Section 501(a)(5) [21 U.S.C. 35 l(a)(5)] of the Act, in that it is a new animal drug which is unsafe within the meaning of Section 512(a) [21 U.S.C. 360b(a)] of the Act. A new animal drug is considered to be unsafe unless there is an approved new animal drug application (NADA) for the product. Your "Purple Lotion Wound Dressing" product is not covered by an approved NADA. This causes the product to be unsafe within the meaning of section 512(a) [21 U.S.C. 360b(a)] of the Act and thus adulterated within the meaning of section 501(a)(5) [21 U.S.C. 351(a)(5)] of the Act.
The above are not intended to be an all-inclusive list of violations that exist at your facility. It is your responsibility to ensure that your overall operation and the products marketed by your firm are in compliance with the Act and its implementing regulations.
Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new animal drug applications and abbreviated new animal drug applications listing your facility as a manufacturer until the above violations are corrected. A reinspection may be necessary.
You should take prompt action to correct these violations and to establish procedures to prevent their recurrence. Failure to promptly correct these violations may result in regulatory action without further notice, such as seizure and/or injunction.
You should notify this office in writing with 15 working days of receipt of this letter of the specific steps you have taken to correct the noted violations, including an explanation of each step being taken to prevent the recurrence of similar violations. If corrections cannot be completed within 15 working days, state the reason for the delay and the timeframe within which the corrections will be completed. Also include copies of any available documentation demonstrating that corrections have been made.
Your response should be directed to the attention of Compliance Officer George F. Bailey at the address listed above. If you have any questions regarding any issue in this letter, please contact Mr. Bailey at (312) 596-4223.
Scott J. MacIntire