Issue link: https://www.e-digitaleditions.com/i/1302985
Pharmaceutical Technology Regulatory Sourcebook October 2020 27 The expectations for the extensiveness of the in- formation provided will of course be dependent on the stage of the product(s) being evaluated. For early-stage products, not all items will be avail- able. The individual performing the due diligence should leverage FDA and European Medicines Agency guidance documents that list regulatory expectations at various stages of development listed in Table II. For items that have not been com- pleted at the time of the due diligence activity, it should be reasonable to ask what plans are in place to address these items. It is important for the various disciplines carry- ing out the due diligence exercise to communicate with each other as CMC-related items are often not located in typical CMC data room files. For example, a tablet dissolution question may come from a pharmacokinetic reviewer. In this case, it is critical that the non-clinical, clinical, regu- latory, and CMC representatives work together. For years, FDA has urged biopharmaceutical manufacturing firms to adopt advanced manufacturing processes and proposed the use of quality metrics to document quality practices to improve quality and reduce regulatory oversight. To date, pharma companies have resisted quality metrics and quality ranking programs, citing the need to protect proprietary information. The COVID-19 pandemic and subsequent travel restrictions prompted FDA to rely on past inspection reports, product recall information, customer complaints, sample testing, and social media to assess compliance. The pandemic has also opened discussion about increasing domestic production of medical products and reducing the regulatory burden on companies through real-time assessments of drug quality. An article, "Will COVID-19 Pandemic Finally Establish Drug Quality Metrics?" examines recent strategy proposals by FDA to promote modern manufacturing systems with a focus on data demonstrating quality achievements. It also examines FDA efforts to advance quality metrics initiatives, soliciting industry input, and visiting manufacturing facilities to see how quality metrics are used within the companies to measure quality. Read the article on www.PharmTech.com. —The editors of Pharmaceutical Technology Pandemic-driven quality metrics? Table I. List of critical items to be included in the chemistry, manufacturing, and controls (CMC) due diligence assessment. DS is drug substance. DP is drug product. Area Item Comments CMC regulatory Module 3 section of all filings Include amendments Correspondence relating to CMC issues May not be limited to the chemistry reviewer Drug product (formulation) Preformulation and physicochemical characterization reports Include salt, solvate/hydrate, and polymorph forms Items specific to the intended route of delivery Oral: Biopharmaceutical classification system classification, particle sizes of batches used, bioavailability in various species, Caco-2 permeability, food and alcohol effects, etc. Parenterals: Aseptic process validation, terminal sterilization feasibility, endotoxin control, filter validation, leachable and extractable studies, etc. DP development reports Including process validation Excipients assessment Compatibility, precedence, any novel excipients, drug master file available, transmissible spongiform encephalopathy information, etc. Device (Combination products) Design control information for any devices Human factors studies Drug substance (API) DS development reports Include structure elucidation and process validation Analytical Method development reports Include forced degradation studies, stress testing, validation, etc. DS and DP specifications and rationale Include intermediate specs DS and DP stability data Impurity and degradation product assessment Include levels seen to date, evaluation of potential mutagenic impurities, qualification levels, etc. Manufacture Details for DS, DP, and device manufacture Include all raw materials, their quality standard and source, in process specifications, details of any process analytical technologies, and possibly a typical batch record at an onsite visit Scalability assessment and plans for the DS, DP, and device processes Include any capital needs Capacity/availability at manufacturing sites Include future sites Inspection history over past five years for manufacturing sites Include future sites Cost of goods estimates for DS, DP, and packaging/ device Overall Development timelines Development cost and cost of goods estimates Intellectual property related to the DS, DP and packaging/device Include composition of matter and process patents/ applications and know how