Inspections, Compliance, Enforcement, and Criminal Investigations
Contract Pharmaceutical Services of Australia Pty Ltd 5/17/13
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Silver Spring, MD 20993|
RETURN RECEIPT REQUESTED
May 17, 2013
Mr. Colin Stibbs,
Chief Executive Officer
Contract Pharmaceutical Services of Australia Pty. Ltd.
5 Eden Park Drive
North Ryde, NSW 2113
During our October 30, 2012 through November 1, 2012 inspection of your pharmaceutical packaging facility, Contract Pharmaceutical Services of Australia Pty. Ltd., located at 5 Eden Park Drive, North Ryde, NSW 2113, Australia, investigators from the U.S. 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.
Our inspection also revealed that your firm failed to fulfill its registration obligations under Section 510(i)(1) of the Act and its listing obligations under Sections 510(i)(2) and 510(j), which is prohibited under Section 301(p). 21 U.S.C. 360(i)(1) and (2), 360(j), and 331(p).
We have conducted a detailed review of your firm’s response and note that it lacks sufficient corrective actions.
Our investigators observed specific violations during the inspection, including, but not limited to, the following:
1. Your firm failed to provide equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product (21 CFR 211.46(b)).
For example, blister rooms (b)(4), where (b)(4) capsules are packaged, had no mechanism to maintain and control the relative humidity (RH) at (b)(4)% - (b)(4)%, as specified in your master packaging batch record (MPBR). Process design studies on this product found that the capsules are sensitive to humidity and that after (b)(4), approximately 50% of the capsules exhibited brittleness. Significantly, the lack of humidity controls and storage conditions observed at your firm can lead to performance problems with this (b)(4) product due to the capsule brittleness. Dose performance problems as a result of changes in capsule brittleness and (b)(4) ((b)(4)) could potentially lead to a higher risk of severe (b)(4) in patients. Your response indicated that you have now installed a humidification unit for one of the (b)(4) blister lines and you expect to complete qualification some time in 2013.
Your response was inadequate because you did not adequately investigate and address the impact on the drug product already distributed to the U.S. market. Your response also does not indicate whether your contract packaging facility plans to use the blister line that still lacks adequate humidity controls to repack products for the U.S. market. Additionally, for the blister line that your firm commits to improve, the response did not explain how the RH will be controlled during packaging until qualification of the new humidification unit is completed.
In your response to this letter, provide a detailed action plan for ensuring adequate monitoring and control of the humidity in the packaging areas for the products. Also, include a qualification study that evaluates the effectiveness of the humidification equipment. We will verify the acceptability of packaging conditions during our next inspection.
2. Your firm failed to establish time limits for the completion of each phase of production to assure the quality of the drug product(21 CFR 211.111).
Specifically, the MPBR did not include a time limit for the (b)(4) capsule packaging process. (b)(4) (and (b)(4), a similar product which is subject to (b)(4)) capsules have been shown to be adversely affected by exposure to <(b)(4)% RH for periods longer than justified in the product owner’s studies. However, you did not specify a time limit in the MPBR, and batch records for commercial lots #(b)(4), #(b)(4) and #(b)(4) of (b)(4) capsules to ensure packaging times do not fall outside the justified times.
Additionally, there were no written procedures to assure adequate protection for humidity-sensitive products, including (b)(4) and (b)(4), and defining actions (e.g., investigation, quarantine, rejection) to take if humidity or time limitation deviations occur during the blister packaging operation. Furthermore, you did not provide a scientific rationale for the current placement of the humidity probe during routine in-process humidity monitoring during packaging.
You committed to revising procedure 02-04-08 to ensure that the bulk product will be returned to closed containers in the event of a humidity excursion, and that this will be documented. However, this may not adequately protect the capsules from the humidity impact.
In your response to this letter, provide a detailed corrective action plan to address holding times of (b)(4) and (b)(4) capsules during the packaging process. Include copies of the revised master batch records for (b)(4) and (b)(4). Additionally, provide procedures to ensure that sufficient corrective actions are taken if humidity excursions occur, as well as scientific rationale for the placement of the humidity probes on the packaging lines.
3. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
Specifically, your firm did not initiate an investigation to determine the root cause of a humidity excursion during the packaging of (b)(4) lots # (b)(4) (Master No. (b)(4)), # (b)(4) (Master No. (b)(4)), and # (b)(4) (Master No. (b)(4)). The humidity conditions in blister rooms (b)(4) fell below the lower RH limit ((b)(4)-(b)(4)% RH) specified in your master packaging record.
You indicated in your response that your investigation procedure was adequate and that personnel did not follow it. Your response is inadequate because you did not address the fact that your investigation documentation form lacks sufficient details of steps taken during the investigations. Additionally, you failed to identify the root cause of the humidity excursion and provide the appropriate corrective and preventive actions.
In your response to this letter, please provide a detailed description of the changes and improvements you have made to your investigation system, including improved procedures, provisions for root cause determination, and better staff training and qualifications.
As part of the pre-approval inspection for (b)(4), the investigator observed that your firm stores the bulk (b)(4) mg capsules in a warehouse that does not provide humidity control. However, your bulk standard specification for (b)(4) mg capsules, # SP-432, calls for humidity-controlled storage conditions, specifically, storage at (b)(4)%-(b)(4)% RH. In your response, your firm committed to completing a temperature and humidity mapping study of the warehouse by the end of Q1 2013. Provide a copy of the mapping study report and your plan to monitor and control the RH in the warehouse. Also, provide a copy of the bulk standard specification for the (b)(4) capsules.
The violations cited in this letter are not intended to be an all-inclusive list 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.
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, your failure to correct these violations may result in FDA continuing to refuse admission of (b)(4) packaged at Contract Pharmaceutical Services of Australia Pty. Ltd., into the United States under Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). The articles may be 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 and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer package the drug product, provide the date and reasons you ceased production. Please identify your response with FEI # 3006368299.
Please send your reply to:
Allison A. Aldridge, Ph.D.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing and Product Quality
Division of International Drug Quality
White Oak, Building 51, Room 4254
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-0483
Fax: (301) 847-8741
Michael D. Smedley
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research
Mr. John F. Crapper
Unit 2, 10 Rodborough Road
Frenchs Forest, NSW 2086