FDA 483 Observations in 503B Outsourcing Facilities

In this issue, we will continue our review of FDA 483 observations in 503B outsourcing facilities; specifically, we will look at the "Administrative and Regulatory" observations.

ADMINISTRATIVE AND REGULATORY

• The labels of your facility's drug products are deficient.
• The required statements, "This is a compounded drug" and "Not for resale," are not included on some labels.
• Storage and handling instructions are not included on some labels.
• The responsibilities and procedures applicable to the quality-control unit are not in writing or fully followed.
• Your firm changed the contract testing laboratory performing your finished product sterility testing. No change control was created to review and evaluate this change to ensure that all tasks are needed to be completed, such as method suitability, were performed and that the change to the sample preparation method was appropriate.
• Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established (no smoke study after installing a new ISO-5 BSC, inadequate contact time for the sporicidal agent used, failing to document the lot number of the biological indicator used, the incubation temperature, the duration of the incubation and who reported the results).
• Your firm has no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.
• Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel.
• Sterility testing data is supposed to be backed up according to your firm's procedures; however, data file backup did not occur for a number of months.
• There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.
• Your firm does not conduct investigations when finished product rapid sterility samples are deemed "background too high." This has occurred in over 25% of the tests.
• You compound drugs that are essentially a copy of one or more approved drugs within the meaning of sections 503B(a)(5) and 503B(d)(2).
• Your firm's smoke studies do not adequately mimic each critical step of our most challenging conditions of sterile drug processing.
• Your firm has not conducted validation of the procedures used to sterilize equipment used in the production and monitoring of your sterile drug products, including goggles and air sampling equipment.
• Your firm has not conducted validation of the procedures used to depyrogenate your glassware used in sterile drug production.
• Your firm conducted recertification of your HEPA LAF Workbench and discovered seven leaks within the filter, some indicated as unrepairable. Your firm did not conduct an investigation into the potential impact on production of sterile drug products since last passing the certification and did not conduct an investigation into the potential production days with deficient air supply.
• Your firm has not conducted sterility hold-time studies to confirm the indefinite hold times for in-house sterilized goggles and air-sampling equipment, in-house depyrogenated glassware, which are cleaned/sanitized in an unclassified environment and stored uncovered in the ISO-7 area prior to sterile drug production.
• Your master batch production records and your batch records for sterile drug production do not include procedures on the required minimum mixing time for your xxx injection and do not include instructions on extended holding and storage of intermediate steps.
• The firm has failed to collect/retain samples for any of the finished drug products that have been manufactured.
• All stability data for sterile products was requested for support of extended BUDs used at your firm. You provided "Technical Reports" with the following issues...
• Data provided supports sterility testing; no potency testing was conducted.
• Accelerated studies were either not conducted or data not provided that demonstrates there are no degradant products formed or potency altered under such conditions.
• Not all product has data to support the use of extended BUDs.
• Investigations into out-of-trend (OOT) and out-of-specification environmental monitoring (OOS EM) data are not always conducted per the firm's written procedures.
• There is a 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 already been distributed.
• Your firm has incomplete methods and method validations for many products.
• Your firm lacked valid analytical and stability data to support the 60, 90, and 180-day BUDs assigned to all of your products.
• You failed to respond timely to the aberrant test results which later tested as OOS test results for xxx for injection.
• During a review of retained test samples of an injection, your firm failed to identify the particulates formed in the retained samples following a complaint.
• Your firm currently states on the label "sterile solution for injection" or "solution for injection" but does not include the type of injection (epidural, retrobulbar, intraocular, IV, etc,).
• The responsibilities and procedures applicable to the quality-control unit are not fully followed.
• There is a 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 already been distributed.
• Packaged and labeled products are not examined during finishing operations to provide assurance that container and packages in the lot have the correct label.
• Your firm does not collect a representative number of finished drug products for an evaluation and documentation of correct labeling.
• Your firm compounded drugs that are essentially a copy of one or more approved drugs within the meaning of sections of 503B(a)(5) and 503B(d)(2). Specifically, you compound drug products that are identical or nearly identical to an approved dug that is not on the drug-shortage list in effect under section 506E at the time of compounding, distribution, and dispensing.
• The labels of your outsourcing facility's drug products do not include information required by section 503B(a)(10)(A). Specifically, your product labels do not include a list of active and inactive ingredients identified by established name and the quantity or proportion of each ingredient. If there is no space on the product label, such information should be included on the container per section 503B(a)(10)(B)(i).
• Your firm did not conduct any dynamic smoke studies from dates xx through xx.
• Your firm's smoke studies are inadequate as they do not demonstrate that your hood and/or line is designed to prevent microbiological contamination, or to provide high assurance of product sterility.
• In the cleanroom, HEPA filter air was being blocked by the equipment (repeater pump) within the hood, and the video failed to demonstrate laminar airflow around the equipment when open syringes are connected to the filling tubing.V
• Cracks and chips were observed on the acrylic view screens of the ISO-5 laminar flow hoods. The crack appeared to be 5 inches in length. A thick and uneven bead of silicone caulk was used to repair the crack on an unknown date - there were no maintenance records for the repair. The crack and uneven caulk surface is not smooth or hard and therefore may be difficult to disinfect and sanitize.
• The smoke study is deficient, as it does not continuously show that the air is moving unidirectionally, as the smoke is either too faint and/or the smoke source is depleted and there is no smoke present. Also, the smoke study was not conducted while simulating the current manufacturing and operating process.
• You do not evaluate the air velocity at the work surface of your ISO-5 LAF hoods.
• You do not have a system in place to track the repairs made to your HEPA filters.
• The bottom of carts appeared to be rusty.
• Your standard operating procedures (SOPs) do not include information on all the equipment located in the sterile compounding area to assure appropriate monitoring is performed.
• On a walkthrough of your firm's aseptic processing areas, a brown/black residue was observed on the inside of the LFH bottom left panel between the panel and the metal bench table lip edge.
• On a walkthrough of your firm's aseptic processing areas, cracked side panels from the overtightening of two connecting screws in a LAF were observed. In the cracking area around the screws, a brown residue was observed.

More next week.

IJPC is extending an invitation to pharmacists/pharmacy technicians to submit their experiences about how COVID-19 has affected their business, their patients, their staff, their personal lives, etc. With your permission, these submissions will be considered for publication in our journal (at no charge). They will be accepted in any format, and the editorial staff will assist in the writing of the submissions. If interested, please send your submissions as quickly as possible to Submissions@ijpc.com with a copy to lwilliams@ijpc.com