Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Silver Spring MD 20993|
VIA UPS MAIL
March 9, 2012
Mr. Mario Merino
Pax-All Manufacturing Inc.
7115 Tomken Road
Mississauga, Ontario L5S1R7
Dear Mr. Mario Merino:
During our September 19-23, 2011 inspection of your pharmaceutical manufacturing facility, Pax-All Manufacturing Inc. located at 7115 Tomken Road, Mississauga, Ontario, Canada, investigator(s) from the U.S. Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP), Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug product(s) 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.
Specific violations observed during the inspection include, but are not limited, to the following:
1. Your firm does not have, for each batch of drug product manufactured, appropriate laboratory determination of satisfactory conformance to final specifications for drug products, including the identity and strength of each active ingredient, prior to release [21 C.F.R. § 211.165(a)].
Specifically, you failed to perform in-process and finished product testing for your drug products. Between September 2009 and September 2011, you distributed approximately (b)(4) batches of drug products manufactured at your facility to the U.S., (b)(4) of which were not tested according to finished product specifications.
Your firm should include in its response to this letter your commitment to test all products according to in-process specifications after formulation and during filling operations, as well as full finished product testing according to finished product specifications. Additionally, you should include a list of all products distributed to the U.S. without adequate determination of conformance to final specifications. Include in your response a detailed corrective and preventive action plan. Such plan should include at minimum, an evaluation and testing of your reserve samples, and the action you intend to initiate regarding those lots that fail to meet the final drug product testing specifications.
2. Your firm does not have a written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates [21 C.F.R. § 211.166(a)].
For example, you have no stability program for (b)(4) or (b)(4). In addition, you were unable to provide raw data to support the stability summary chart you presented for (b)(4), Lot (b)(4), and the stability data you received from a contract laboratory for (b)(4) did not contain a lot number.
Please include in the response to this letter documentation to support the current expiration dates assigned to the products currently on the market, as well as a commitment to ensure that all products are tested according to an approved stability program. For any ongoing stability studies, provide detailed information about the program and a copy of your stability protocol. Please include the following: products, lot numbers, date stability study started, stability interval, tests performed, storage conditions (temperature/humidity), testing site and assurance that your analytical methods are stability indicating, and validated (if not USP).
3. Your firm fails to follow written procedures designed to assure that correct labels, labeling and packaging materials are used for drug products. These procedures shall incorporate the identification of the drug product with a lot or control number that permits the determination of the history of the manufacture and control of the batch [21 C.F.R. § 211.130].
For example, you fail to ensure the traceability of formulation lots and packaging materials used in the production of drug products. Your firm failed to identify the lot numbers of the packaging materials in batch records for (b)(4), lot (b)(4); and (b)(4), lots (b)(4), (b)(4) and (b)(4). Your firm also failed to include the lot number of the bulk product (formulation lot) in the batch record for (b)(4), packaged on June 10, 2011. In addition, some finished product batches were identified with incorrect lot numbers after packaging. The inspection also reported that you fail to include specimen labels within your packaging records.
It is your responsibility to document the examination of components, as well as packaging and labeling materials for suitability and correctness before the packaging operation is initiated. It is also your responsibility to document the inspection of the packaging line prior to use in order to assure that all previous drug products, packaging, and labeling materials have been removed from the packaging line.
Please include in your response the corrective actions for maintaining traceability of all materials used in production. Additionally, include in your response a detailed review of your records and retain samples, to demonstrate that drug products lots released to the market were not incorrectly labeled.
4. Your firm failed to ensure that equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size and suitably located to facilitate operations for its intended use and for its cleaning and maintenance [21 C.F.R. § 211.63].
Specifically, the (b)(4) section of Filling Line (b)(4), was repaired and redesigned using clear and duct tape, and torn corrugate cardboard box. The tape was used to connect the (b)(4) of the (b)(4) and the pieces of cardboard box were used as (b)(4) at the (b)(4) and (b)(4) of the (b)(4). These materials are not suitable materials of construction or easily cleanable, and are not adequate for the manufacture of drug products.
Your firm should include in its response proposed corrective actions to ensure that all equipment used to manufacture drug products is adequate for its intended use and an evaluation of products currently on the market manufactured on Line (b)(4).
5. Your firm has not cleaned and maintained equipment at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality, or purity of the drug product [21 C.F.R. § 211.67(a)].
Specifically, your SOPs do not outline cleaning procedures. You do not document when cleaning is performed and you failed to perform cleaning validation for multi-use equipment.
In your response, you should include your updated cleaning procedures and evidence that these procedures are effective. Please also include an evaluation of the impact to all products currently on the market.
In addition to the items listed above, the investigators uncovered other deficiencies that lead us to question the effectiveness of your current quality system to achieve overall compliance with CGMP at your facility. We recommend that you seek the advice of a third-party consultant regarding your current non-compliant CGMP status and to assist you in determining the improvements needed to meet the CGMP requirements during the manufacture of your drug products.
We remind you that you are responsible for ensuring that you firm’s drug manufacturing operations comply with applicable requirements, including the CGMP regulations. FDA expects Pax-All Manufacturing Inc. to undertake a comprehensive and global assessment of your manufacturing operations to ensure that your processes, and ultimately, the drug products you manufacture, conform to FDA requirements.
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)]. The FDA investigators discussed this issue with you during the inspection. Your response did not address this issue. 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.
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 continue 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.
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, until such time as your manufacturing practices are verified to comply with CGMPs, your firm will remain under FDA Import Alert and FDA will continue to refuse admission of all articles manufactured at Pax-All Manufacturing Inc., 7115 Tomken Road, Mississauga, Ontario, Canada, into the United States. Because your firm is currently under Import Alert, 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 Current Good Manufacturing Practice within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].
If, as a result of receiving this Warning Letter or in general, you are considering making a decision that will result in a decreased number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER’s Drug Shortages Program immediately, as you begin your internal discussions, at firstname.lastname@example.org in order to ensure that your action(s) does not adversely affect the public health.
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. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute the drug products manufactured at this facility, and provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3003986222.
If you have questions or concerns regarding this letter, contact Maan Abduldayem, Compliance Officer, at the below address and telephone number.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-3916
Fax: (301) 847-8741
Director, Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research