1. Your firm failed tothoroughly investigate any unexplained discrepancy or failure of a batch or anyof its components to meet any of its specifications, whether or not the batchhas already been distributed (21 CFR 211.192).
You failed tothoroughly investigate release and stability testing failures concerning twobatches of your (b)(4) drug products. These product failures includedviscosity and appearance. During stability testing, you also identifiedpackaging defects. You did not initiate investigations for each of these drugquality issues. When you did investigate, you failed to adequately evaluate themanufacturing process and associated records, identify root causes, andimplement effective corrective actions and preventive actions (CAPA).
For example, youfound tubes swelling at the 3-month stability time point. You did not investigatethis significant defect, which can be indicative of microbial growth andspoilage. Notably, your packaging stability specification requires “no change inpackaging.”
In response to ourfindings, your customer recalled the remaining in-date batch of this product onNovember 28, 2017.
For more informationabout handling failing, out-of-specification, out-of-trend, or other unexpectedresults and documentation of your investigations, see FDA’s guidance document, InvestigatingOut-of-Specification (OOS) Test Results for Pharmaceutical Production, athttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070287.pdf.
2. Your firm failed toestablish adequate written procedures for production and process controldesigned to assure that the drug products you manufacture have the identity,strength, quality, and purity they purport or are represented to possess (21CFR 211.100(a)).
The processes used tomanufacture your (b)(4) drug products have not been shown to beconsistent and reliable, and consequently batches of your drug products arelikely to significantly vary in strength, quality, and purity.
For example, you lackedadequate process validation studies. Your validation report summarized aretrospective analysis of a single process qualification batch, (b)(4).You manufactured and released this batch in 2015.Notably, testing of this batchfound stability failures of multiple quality attributes, including appearanceand viscosity. Your validation report was approved on March 17, 2017, shortlybefore we inspected your facility. You lack evidence of process validationbecause you have not addressed all potential sources of variation that must becontrolled to consistently yield drugs of uniform character and quality, andhave not demonstrated that the process is reproducible.
Senior managementstated that your firm has struggled with manufacturing this drug product, andthat you were still conducting research to gain better product and processunderstanding. Although you acknowledged a lack of understanding to assureconsistent quality, you still commercially distributed (b)(4) drugproducts to consumers.
Each significantstage of a manufacturing process must be designed to assure that raw materialinputs, in-process materials, and finished drugs meet their quality attributesand specifications. Process validation evaluates the soundness of design andstate of control of a process throughout its lifecycle. Process qualificationstudies provide a determination whether an initial state of control has beenestablished. Successful process qualification studies are required prior tocommercial distribution. Thereafter, ongoing vigilant oversight of processperformance and product quality is essential to ensure you maintain a stablemanufacturing operation throughout the product lifecycle.
See FDA’s guidance document, ProcessValidation: General Principles and Practices, for general principles and approaches that FDA considers appropriate elements of process validation, athttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf.
3. Your firm failed tofollow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR211.166(a)).
You did not haveadequate stability data to demonstrate that the chemical and physicalproperties of your (b)(4) drug products remain acceptable throughout thelabeled (b)(4) expiry period. Two lots reviewed during our inspectionfailed on stability at various tests and time points. You distributed these twolots of (b)(4) drug products to the U.S.
Batch (b)(4)failed for viscosity at multiple time points, and you terminated the stabilitystudy for batch (b)(4) after you identified phase separation in allsamples at the 9-month time point.
At the time of theinspection, you had not taken appropriate action on these batches, such asnotifying your customer or recalling products from the market.
Your April 13, 2017,response to FDA’s inspectional observations wasinadequate. You did not provide sufficient evidence that you are takingcorrective actions to bring your operations into full compliance with CGMP. Inresponse to this letter, provide the following:
A summary of the actions you have taken to comprehensively remediate your investigation process, and an improved procedure.
Your investigations, using your revised procedures, for all drug quality related failures. A detailed summary of your review of all test results, root causes of specification failures, affected batches distributed to the U.S. market, and related CAPA.
A data-driven and scientifically sound process validation program that appropriately identifies sources of variability, and ensures oversight of intra-batch and inter-batch variation on an ongoing basis throughout the product lifecycle.
Timelines for performing prospective process qualification for your drug products.
A procedure describing your stability program.
Data for (b)(4) batches successfully manufactured as part of prospective qualification studies, to demonstrate that these batches are stable over the shelf life.
The disposition of (b)(4) batch (b)(4), including whether you plan to distribute it in the U.S.
Data to demonstrate that your (b)(4)Test–BP method used to test drug products marketed in the U.S.is equivalent to, or better than, the current USP (b)(4)Test.
A thorough assessment of your adherence to CGMP requirements, and a CAPA plan to assure full remediation.
You shouldcomprehensively address each of these items in your written response.
Significant findingsin this letter indicate that your quality unit is not fully exercising itsauthority and/or responsibilities. Your firm must provide the quality unit withappropriate authority, sufficient resources, and staff to carry out itsresponsibilities and consistently ensure drug quality.
Responsibilities as acontractor
Drugs must bemanufactured in conformance with CGMP. FDA is aware that many drugmanufacturers use independent contractors, such as production facilities,testing laboratories, packagers, and labelers. FDA regards contractors asextensions of the manufacturer.
You and yourcustomer, (b)(4), have a quality agreement for the manufacture of (b)(4)drug products. You are responsible for the quality of drugs you produce asa contract facility, regardless of agreements in place with product owners. Youare required to ensure that drugs are made in accordance with section501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, andpurity. See FDA’s guidance document, ContractManufacturing Arrangements for Drugs: Quality Agreements, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM353925.pdf.