Inspections, Compliance, Enforcement, and Criminal Investigations
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Silver Spring MD 20993|
VIA UPS MAIL
September 30, 2010
Mr. Karl Verlinden
Dear Mr. Verlinden:
During our May 3 – 7, 2010 inspection of your pharmaceutical manufacturing facility, Qualiphar n.v., located at Rijksweg 9, B-2880 Bornem, Belgium, an investigator from the Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations 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)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We have reviewed your firm’s response of May 28, 2010, and note that it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
1. Your firm does not have adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)]. Specifically, you fail to have written procedures for the manufacturing process of both the (b)(4) powder (b)(4) tablet drug products. For example:
a. Your 2002 process validation for the manufacturing of (b)(4) powder (b)(4) is deficient in that the batch production records failed to identify the specific type and sizes of equipment used and the manufacturing steps listed were minimal (i.e., (b)(4)). In addition, a comparison of the batch records for the powder (b)(4) instructions used for the 2002 validation batches with the recent 2008-2009 campaign batches showed changes in types of sugars, changes in (b)(4) time, changes in equipment and changes in order of addition of ingredients. In addition, there was no records showing these procedures had been drafted, reviewed and approved by the appropriate organizational unit. Although your quality manager informed our investigator that the changes mentioned were intended to improve content uniformity, there was no documentation to justify these changes as required by 21 CFR 211.100 (b). In addition, your firm could not provide documentation showing that any validation or testing of the powder filling operation had ever been done to ensure that the product remained homogeneous over the entire filling process. Also, a new filling machine was used (single head automatic powder filling machine, serial # 15200). However, there was no documentation of equipment qualification such as: IQ, OQ, PQ, nor documentation of machine operating parameters (i.e., agitator settings, speed, and vibration settings).
b. The only process validation study records available for the manufacture of (b)(4) tablets (b)(4) was summarized in a three page document identifying (b)(4) batches manufactured in 1997. This summary report did not include batch size, identification of equipment used, a detailed description of the manufacturing process (batch production records were not available), equipment parameters, and a description of the sampling plan used. The three-page validation record was undated, unsigned, and references (b)(4) batch numbers ((b)(4)) that are inconsistent with the coding format used in your facility.
Your firm acts as a contract manufacturer for powder (b)(4) and solid dosage drug products. It is essential that you understand your responsibility to operate in full compliance with CGMPs and to inform all of your customers of significant problems encountered during the manufacturing and testing of these products.
Your response acknowledges that the manufacturing process validation could be improved for both powder and tablets. Therefore, in collaboration with your customer, (b)(4) (the (b)(4) holder of (b)(4)), you stopped the production of your (b)(4) products in (b)(4) and dismantled the manufacturing area with the objective of (b)(4). At that time you indicated you would re-validate the entire manufacturing process for both (b)(4) tablets and powder.
The above observations are repeat observations, also cited during two previous FDA inspections of February 25-27, 1998 and November 4-8, 2002, and for which you had also promised corrections in your written responses to the FDA-483s. The February 25-27, 1998 inspection covered (b)(4) tablets and revealed that the (b)(4) process of the (b)(4) had not been validated. The November 4-8, 2002 inspection revealed several CGMP violations, including that the (b)(4) process for had not been validated. Additionally, the batch manufacturing record for (b)(4) tablets lacked detailed instructions regarding the amount of (b)(4) to be placed on the individual (b)(4) during the (b)(4) process.
This is the third occasion in which our investigators found that your facility stopped manufacturing (b)(4) the (b)(4) prior to our visit. For example, prior to our inspection of 1998, your facility last manufactured commercial (b)(4) tablets in (b)(4). Also, prior to the 2002 inspection, your facility had last manufactured (b)(4) powder (b)(4) in (b)(4). Likewise, the May 2010 inspection revealed that you stopped manufacturing both powder and tablet (b)(4) in . Therefore, the manufacture of (b)(4) was difficult to evaluate during these inspections. Your previous and current responses are similar in that your firm plans to (b)(4)
Electronic correspondence between your firm and (b)(4) obtained during the inspection reveals that you are aware of difficulties related to the manufacture of this product. Specifically, you are aware that (b)(4) is very insoluble and that the assay and dissolution results can be affected by slight variations in the manufacturing procedures.
We are concerned that you have not completed, or adequately validated the (b)(4) manufacturing process to current standards and expectations. Additionally, new equipment has not been qualified, and there is no assurance that the manufacturing process will result in a product that can consistently meet specifications. Your validation studies demonstrate yourfailure to consistently manufacture (b)(4) powder (b)(4) and tablets, as reported in this letter under item numbers two and three.
2. Failure to follow written procedures that describe the in-process controls established to be conducted on appropriate samples of in-process materials of each batch, to 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 C.F.R. § 211.110(a)]. For example,
The only sample collected for (b)(4) determination after the (b)(4) of the (b)(4) used for (b)(4) tablet (b)(4) lot #(b)(4), resulted in an out-of-specification (OOS) result of (b)(4)% (batch record specification for (b)(4) is less than (b)(4)%). However, production continued and your firm released the batch without conducting an investigation as required by 21 C.F.R. § 211.192.
Your response states that there is no indication from your release and stability data that higher in-process (b)(4) content in (b)(4) had any effect on the identity, strength, quality, or purity of the finished tablets. We disagree with this conclusion in that quality must be built into the product throughout the manufacturing process. Finished product testing alone is not sufficient to demonstrate that the process is validated, particularly when discrepancies such as (b)(4) control limits are not observed during manufacturing.
Your response is inadequate in that it lacks information regarding any investigation conducted, even after the lot was released, that would explain the root cause of the problem. Your response also fails to state your rationale for releasing this batch without an investigation and the corrective actions implemented to prevent recurrence. We are concerned that other batches not meeting your in-process control procedures may have been released for distribution.
In your response, please include a list of all the products and lots manufactured by your firm within expiration that were released for distribution without meeting the established in-process specification. Also include a complete investigation of the root cause, the corrective and preventive action plan implemented, and any voluntary action necessary to address affected products in distribution.
3. Established laboratory control mechanisms are not followed [21 C.F.R. § 211.160(a)]. For example,
In 2009, various batches ((b)(4)) of (b)(4) powder (b)(4) failed either the assay or dissolution tests prior to release. Your OOS investigation reported that there were no errors related to calculations, analyst, analytical methods, or production process equipment, and that the OOS results were confirmed. However, instead of reporting the OOS as the final result, as required by your OOS investigation procedure, you invalidated the failing results, re-sampled and tested the batches. These batches were released for distribution.
Electronic correspondence collected during the inspection, related to the assay results for the 2009 powder campaign, showed (b)(4) instructed your firm to re-weigh and reject bottles found with excess fill weights because failing assay results were obtained. This practice is unacceptable regardless if requested by your customers, and is an indication of a lack of adequate controls in place to assure that (b)(4) powder (b)(4) products are manufactured in compliance with CGMP.
Your response for batches (b)(4), reports that the assay and dissolution OOS results were due to high bottle fill weights that occurred at the end-of-fill for these batches. This response is inadequate in that it does not provide any investigative report to support your conclusion and rationale. Review of production records for your in-process fill weights show no evidence of excess fill weight of bottles. The only overweight average was obtained on the (b)(4) day of a (b)(4)-day filling operation for batch (b)(4). Additionally, there were no overweight averages obtained for batch (b)(4). Therefore, your conclusion that fill weights were the problem is not supported by your batch records. Furthermore, your batch records are also not clear on how the bottles for the re-test of the “new end-of-filling” testing were selected.
Your response for batch (b)(4) indicates that you were aware of the potential problem at end of filling, and made adjustments to the filling machine to prevent overfilling. Also, overfilling and OOS results were not observed in the subsequent seven batches filled (b)(4)). This response is inadequate in that the batch record for (b)(4) contains an OOS investigation report that confirms failing results for the assay and dissolution tests. Electronic correspondence obtained during the inspection shows that following an instruction from (b)(4) you segregated, re-tested, and released the batch. The retest resulted in values within specifications, but on the lower limit for both the assay and dissolution test. (b)(4) attributed the OOS failure to a technical error in carrying out the method.
Your OOS procedure contains no provision for conducting a re-test of new samples based on a customer (b)(4) request. We are concerned that original release testing of multiple batches of powder (b)(4) yielded failing dissolution or assay results. Yet your firm released these batches for distribution based on passing repeat test results without conducting a thorough investigation as required under 21 C.F.R. § 211.192 to support your conclusion and rationale to release the affected lots. Retesting new samples without conducting a thorough investigation, after obtaining initial OOS results is an unacceptable practice.
In your response, please provide information regarding any voluntary corrective actions you intend for marketed the batches of (b)(4) that obtained an initial assay or dissolution OOS result. Also provide the root cause analysis into the actual or probable cause of the failures, investigation of the manufacturing process that may have caused the problem, and the corrective actions implemented to prevent recurrence of the problem.
Also include a list of all lots of (b)(4) powder (b)(4) manufactured by your firm, intended for shipment to the United States, that remain within expiration and for which an initial assay or dissolution OOS was obtained.
4. Failure to have adequate laboratory controls that includes sampling plans and test procedures designed to assure that your drug products conform to appropriate strength, quality and purity specifications. [21 C.F.R. § 211.160(b)].
For example, in 2009 portions of batches (b)(4) of (b)(4) powder were rejected due to fill weight OOS results. Your firm segregated only the end-of-fill portion of the batch, re-weighted the filled bottles and rejected those bottles that resulted with OOS fill weights. You re-assayed the samples found with high fill weights and reported that the excess weight caused both the assay and dissolution OOS results. However, our review found that this sampling plan and test procedure process lacked controls such as: appropriate documentation to justify your decision to re-weigh these batches, records failed to show when these batches were re-weighed, who conducted the re-weighing process, how many of the (b)(4) plus bottles from each batch were to be re-weighed, what value was to be used as a bottle tare weight, and the acceptance criteria used to release the batches.
For example, the sampling plan record for batch (b)(4) consisted of a one-page document that listed 244 handwritten bottle net weights. Some of these net weight recordings were circled, with a handwritten note at the bottom of the page reading in part, 29 pieces out-of-specification. There was a lack of consistency in identifying OOS units in that similar or higher bottle net weights were not circled and counted as OOS. Also, this record was only identified with the batch number ((b)(4) but not dated or signed by a production or quality unit representative. Furthermore there was no documentary evidence of the sampling plan for batch (b)(4)
Your response acknowledges that this process should be more clearly documented and prior to future production, procedures will be written, and personnel training documented. However, your response lacked documentation to ensure that all (b)(4) plus bottles of each batch met the fill weight specifications. We are concerned that other units from these two batches may have OOS for fill weights, which you have already reported to be associated with failing assay or dissolution results. We are also concerned with the lack of documentation, procedural controls and your determination that these batches of (b)(4) powder comply with CGMP based on your decision to reject only bottles found with excess fill weight at the end-of-fill run.
5. Records do not include the disposition of rejected filled drug product containers [21 C.F.R. § 211.184(e)].
For example, there are no records showing the final disposition of bottles containing (b)(4) powder (b)(4) from batches (b)(4) that were reportedly rejected due to excess (OOS) fill weight. Batch production records for batch (b)(4) indicate that 29 bottles were rejected on an unknown date in either February or March 2009. Batch production records for batch (b)(4) report that 144 bottles from end-of-filling were rejected prior to labeling. However, no records to confirm the final disposition of these units were available for review.
Your response acknowledges that the master record will be amended to document disposition of any rejected units and to incorporate a filling accountability record at the end of filling. You also indicate that product bottles with fill weights outside of the established specifications were rejected and destroyed. However, your response does not provide any documentation of the disposition of these rejected bottles to ensure that these defective units were not released for distribution.
6. Written procedures are not established for evaluations to be done at least annually and including provisions for a review of complaints, recalls, returned or salvaged drug products, and investigations conducted for each drug product [21 C.F.R. § 211.180(e)(2)].
For example, although your firm prepares annual product reviews for the products shipped to the United States, there were no written procedures describing who will prepare the reports, what information will be contained in the reports, or what the distribution of the reports should be. Our review of the two most recent annual reports for (b)(4) powder (b)(4) found the following discrepancies:
a. The 2008 report states that no batches were manufactured, but then lists the OOS results for batches (b)(4). Both the 2008 and 2009 reports state that there were no changes in manufacturing equipment or manufacturing process, but do not mention the new bottle filling equipment used for the batches produced in 2008 and 2009.
The 2009 report states that (b)(4) batches were released, and that none were reprocessed. It states on the next page that two batches were OOS because of the excess fill weight of bottles selected from the end of the batches had filling weight problems. The report does not mention that these two batches were reweighed and bottles found OOS were rejected.
Your failure to have written procedures as indicated in item number 6 of this letter is a repeat observation previously cited by FDA during the previous 2002 inspection for which you promised corrections in your response.
Your May 28, 2010 response acknowledges that written procedures are required for the annual review process, and that you will implement written procedures prior to any future batch production. We are concerned with the continuing failure to have written procedures for the preparation of annual review of your products.
In addition to the items listed above, the inspection brought additional matters to our attention that increase our concerns regarding the quality of drug products manufactured at your facility. These issues include, but are not limited to: lack of cleaning validation on equipment not dedicated to (b)(4) production, the use of dedicated equipment is not clear in the batch records, powder (b)(4) bottle filling records do not show the number of bottles filled or rejected for being out of weight limits, and batch records do not include a record of any sampling performed for each batch of drug product produced.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. If you wish to ship your products to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.
Additionally, your firm is neither registered nor has it listed every product in commercial distribution in the United States with FDA, as required by 21 C.F.R. § 207.40 and section 510(i) of the Act [21 U.S.C. § 360(i)]. Information on how to register and list is available at the following internet website: http://www.fda.gov/cder/drls/registration_listing.htm. You must complete the required registration and listing and provide evidence that you have fulfilled these requirements in your response to this letter.
Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, FDA will be refusing admission of articles manufactured at Qualiphar n.v., Rijksweg 9, B-2880 Bornem, Belgium into the United States. The articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)], in that, the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. Also include distribution records to your U.S. customer and the current and future manufacturing status of (b)(4) products, as well as existing inventories of remaining (b)(4) products at your facility. If you cannot provide the requested information and complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have complied with our requests. Please identify your response with FEI # 1000627334.
If you have questions or concerns regarding this letter, contact Edwin Melendez, Compliance Officer, at the below address and telephone number.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Branch
White Oak, Building 51
10903 New Hampshire Ave.
Silver Spring, MD 20993
Tel: (301) 796-3284
Fax: (301) 847-8741
Richard L. Friedman
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research