US FDA Cleaning validation findings

Failure to clean equipment and utensils to prevent contamination or carry-over of a material that would alter the quality of the intermediates and API.

Employees are not trained in cleaning procedures.

Failure to clean equipment and utensils to prevent contamination or carry-over of a material that would alter the quality of the intermediates and Active Pharmaceutical Ingredient beyond the official or other established specifications.

Use of cleaning and disinfecting agents that may leave residues or not adequately rinsing such agents from containers, closures, or equipment that come into direct contact with drug products.

Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)). You failed to adequately validate your cleaning procedures to ensure the removal of API residue and cleaning agents, as well as control of potential microbial contamination for your non-dedicated manufacturing equipment. In addition, you failed to adequately document the type of cleaning performed or the specific cleaning agent used to clean your equipment that is shared to manufacture both your OTC drug products and cosmetics. In your response, you acknowledge the weakness in your cleaning validation and cleaning documentation practices and commit to revalidating your cleaning process and updating your cleaning procedure. Your response is inadequate. You fail to provide sufficient details on the proposed cleaning revalidation and product impact assessment. In response to this letter, provide: Appropriate improvements to your cleaning validation program with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include, but not be limited to, identification and evaluation of all worst-case: o drugs with higher toxicities o drugs with higher drug potencies o drugs of lower solubility in their cleaning solvents o drugs with characteristics that make them difficult to clean o swabbing locations for areas that are most difficult to clean o maximum hold times before cleaning In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product. A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment. A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices and encompass each piece of manufacturing equipment used to manufacture more than one product including both API and finished products. CGMP Consultant Recommended Based upon the nature of the violations we identified at your firm, we strongly recommend that your firm engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)). Your firm failed to establish an adequate stability program to demonstrate that the chemical and microbiological attributes of your drug products meet established specifications and that they remain acceptable throughout their labeled expiry period. For example, accelerated stability data provided for (b)(4) consisted of three batches tested for (b)(4) at (b)(4) °C with no record of controlled humidity conditions. Multiple timepoints within your accelerated stability study were reported as “Not Available” and you identified failing results at (b)(4) for viscosity, which you did not investigate. Furthermore, your ongoing long term stability studies identified a failing viscosity result at twelve months, which was not investigated. In your response, you acknowledge your failure to perform an appropriate stability study to support labeled expiration dates. You commit to opening a CAPA to conduct a risk assessment for the (b)(4) distributed batches and will determine the appropriate action for the product. Additionally, you will perform a new accelerated stability study with revised viscosity specifications, revise procedures to require real-time stability testing through the assigned expiry, and initiate a new real-time study on at least three validation batches. Your response is inadequate. You fail to provide stability protocols with scientific evidence demonstrating that the test methods used will be stability-indicating for your drug products. In response to this letter, provide a comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to, the following: Stability-indicating methods Stability studies for each drug product in its marketed container-closure system before distribution is permitted An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid Detailed definition of the specific attributes to be tested at each station (timepoint), as part of a program that encompasses each quality attribute that may change over the product shelf-life All procedures that describe these and other elements of your remediated stability program 3. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22). Your quality unit (QU) failed to perform adequate oversight for the manufacture and testing of your drug products. For example, your QU failed to: Validate manufacturing processes for OTC drug products (21 CFR 211.100(a)) Validate cleaning operations for non-dedicated manufacturing equipment (21 CFR 211.67(b)(3)) Investigate and implement appropriate CAPAs to address recurring gasket seal failures on manufacturing equipment (21 CFR 211.67(a)) Establish appropriate content release specification limits for APIs in finished drug products (21 CFR 211.160(b)) Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download. In response to this letter, provide: A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to: o A determination of whether procedures used by your firm are robust and appropriate o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate procedures and practices o A complete and final review of each batch and its related information before the QU disposition decision o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing vigilant monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control. Also, describe your equipment and facility qualification program. A timeline for performing appropriate process performance qualification for each of your marketed drug products. Also provide a risk assessment and any follow up actions to be taken for the distributed drug products produced without performing any process validation studies. Process performance protocol(s), and written procedures for qualification of equipment and facilities. Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case: o Drugs with higher toxicities o Drugs with higher drug potencies o Drugs of lower solubility in their cleaning solvents o Drugs with characteristics that make them difficult to clean o Swabbing locations for areas that are most difficult to clean o Maximum hold times before cleaning In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product. A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.…