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*This article is an opinion piece and does not necessarily represent the views of BioPharm International.
On July 28, 2015, FDA published Draft Guidance for Industry: Request for Quality Metrics in the Federal Register with a 60-day comment period. The intention of this long-anticipated document is to establish a risk-based frequency of regulatory inspection for pharmaceutical companies through review of quality metrics data on lot rejection rates, frequency of invalidated out-of-specification (OOS) results, product complaints, and on-time rates for annual product and quality review reporting. Quality metrics reporting would justify reduced general, pre-approval, and post-approval manufacturing change inspections and improve overall quality in the pharmaceutical industry. Taking up the theme introduced by Jill Wechsler in her July 29, 2015 “Regulatory Beat” column, the “carrots” for the pharmaceutical industry are the promise of a reduced frequency of regulatory inspections, whereas the “stick” if quality metrics are not reported is the possibility of having products designated as adulterate in terms of the Federal Food, Drug, and Cosmetic Act (FD&C Act).
FDA intends to request quality metrics from establishments registered with the agency under section 510 of the FD&C Act that are engaged in the manufacture of drug substances and drug products. What type of healthcare product providers would be exempt from the reporting requirements? These would include Section 503B sterile compounders; regional blood banks; vaccine manufacturers and manufacturers of cell- and gene-therapy products; makers of allergenic extracts; and plasma-derived products. Requests would extend to contract manufacturers, sterilizers, and packagers of the drugs covered by the guidance. Excipient and packaging component manufacturers are out of the scope of this guidance document.
Impact on contract manufacturers
Are contract testing laboratories conducting release and stability testing for drug manufacturers required to maintain and report quality metrics? The short answer is, probably no. Of the seven major quality metrics FDA plans to monitor-number of lots attempted, number of lots rejected, number of tests conducted, number of OOS results, number of invalidated OOS results, number of lots released, and number of product complaints for each drug product-only the quality metrics related to OOS results directly impact contract testing laboratories.
Laboratory testing, which is required by cGMP regulations (i.e., 21 Code of Federal Regulations 211.160 and 211.165), is conducted as necessary to confirm that drug products conform with established specifications, including stability or shelf-life specifications. These testing activities should be consistent with FDA guidance on cGMPs, which includes OOS investigations. A contract-testing laboratory has the same responsibility of meeting cGMP requirements as a manufacturer. The FDA Guidance for Industry, Investigating Out-of-Specification Test Results for Pharmaceutical Production states that contract testing laboratories should report their data, findings, and supporting documentation to the quality control unit of the drug manufacturer, who should then initiate an OOS investigation. The guidance document describes the responsibility of the analyst and laboratory supervisor in conducting the laboratory investigation and emphasizes that laboratory error should be relatively rare, but when clear evidence of laboratory error exists, the results should be invalidated. Whenever laboratory error is identified, the source of the error would be determined and corrective action taken. Conversely, when no evidence of laboratory error is clear, the customer should conduct an investigation of their manufacturing operation, which is outside the scope of the contract testing laboratory. All these activities would be fully documented. Furthermore, the draft quality metrics guidance clearly states that manufacturers can expect that reported quality metrics data might be verified during on-site inspections. If inconsistences in these data are detected, the integrity of the quality metrics report may be questioned; inconsistencies may be used to justify additional risk-based or for-cause regulatory inspections.
How will these regulatory changes impact contract testing laboratories? With OOS results being a key quality metric, more attention must be given to this crucial area. As an observer of the state of contract testing, I see many challenges resulting from these upcoming regulatory changes. Samples may be submitted by manufacturers to contract testing laboratories via purchase orders with one or more of the following issues: no identification as to dosage form and product name; test procedures requested that are not fully described; sample size may not comply with compendial test requirements; testing laboratories may not be fully aware of product specifications; and test methods may not be adequately qualified. These potential issues all make it difficult for the contract laboratory to test, evaluate, and identify an OOS result. Although a manufacturer may reject a lot based on the reported results from the contract laboratory, this does not negate the need to perform an OOS investigation. In a few isolated cases, misguided manufacturers may resubmit additional samples from the same batch for testing-without the knowledge of the contract laboratory-in an attempt to test the product into compliance with the specification.
Because many manufacturers are increasingly outsourcing release and stability testing as a cost-savings strategy, they may be tempted to skimp on ordering OOS investigations. Annually reporting lots attempted, OOS results, OOS results invalidated, and lots rejected will open a manufacturer up to additional regulatory scrutiny. There is always the question whether OOS investigation costs can be billed directly to the customer or amortized across all customers, and whether OOS investigations would only be conducted per explicit request by the manufacturer. In addition, an invalidated OOS result rate is a laboratory performance measurement that would be tracked and trended, and would potentially be used to drive corrective actions and improvements in the contract testing laboratory.
During general regulatory inspections, to maintain the FDA laboratory registration, contract testing laboratories would be expected to log all their OOS investigations in terms of opening date, product, OOS result, investigation finding, close-out date, and corrective or preventative actions. Even though pre-approval and for-cause inspections could be related to a single, specific customer, the FDA investigator would still be have the right to request a full review of testing records and OOS investigations across all of the projects within the contract testing lab.
How can these regulatory risks be mitigated? Both manufacturers and contract testing laboratories must be aware of the changing regulatory requirements and comply when they become official. They should take advantage of the 60-day comment period to influence the revision to the guidance. Purchase orders should identify the product, testing required, and test specifications. The details of how OOS results and their subsequent laboratory investigations should be handled should be defined in a quality agreement between the manufacturer and the contract testing laboratory.
About the Author
Tony Cundell is a consultant at Microbiological Consulting, LLC, in Scarsdale, NY, USA.