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PharmTech.com Regulating Innovation, Quality, and Risk eBook January 2024 Pharmaceutical Technology ® 31 Qualit y summarizing the many tangible gains accrued from highly capable operations from a broad array of indus- tries, including some recent pharmaceutical data, and indicates that improved return-on-investment (ROI) calculations can be pivotal in supporting needed up- grades to manufacturing operations and timely reso- lution of medicinal quality risks. Although the business benefits of improving pro- duction capabilities have been demonstrated in a wide array of industries, there is a lack of research regarding quality-business synergies in the pharma- ceutical industry. Highly capable manufacturing is particularly important for pharmaceuticals, as robust quality performance is essential to ensure the contin- ued availability of safe and effective medicines for patients (1,2). This paper explores the state of phar- maceutical manufacturing and provides key insights from an extensive literature analysis that establish the clear business case made by non-pharmaceutical industries for avoiding unreliable operations due to the risks they pose to both quality and business out- comes. This existing knowledge on the quantitative relationship between reliable manufacturing and positive business outcomes for non-pharmaceutical industries may help to support adoption of similar models by the pharmaceutical industry. This paper is intended to promote increased efforts to understand how synergies between quality investment and busi- ness goals can be more comprehensively rationalized in the pharmaceutical industry, and better meet the needs of all of its stakeholders. Manufacturing determines quality Real-world examples throughout the manufacturing industries broadly demonstrate how poor quality prod- ucts produced by deficient manufacturing operations can have various degrees of adverse consequences (3,4). Poor quality can lead to adverse consumer experiences ranging from momentar y dissatisfaction to grave health hazards. Regarding the latter, there are exam- ples in many industries (e.g., automotive, aerospace, food, software, chemical, nuclear, electronic, toy) in which failures have led to severe harm. The capability of a factory to consistently produce a high quality product is determined by several factors in the manufacturing operation, including the facili- ties, equipment, materials, environment, people, and measurement systems chosen by a company to con- duct their manufacturing operations (5–10). These factors are often collectively assessed using an Ishi- kawa fishbone at the hazard identification stage that is the first step of quality risk management (11). Unreliable manufacturing processes permit exces- sive variation in the quality of finished products. A low reliability process may yield acceptable products on some days. But when that operation experiences its inherent capacity for excessive variation on any given day, the quality of finished units will suffer. In contrast, highly reliable processes use robust manu- facturing operations that are capable of high-quality output, each day, throughout processing. The quality of nonpharmaceutical finished products is normally readily visible to customers. For example, when a computer crashes, a car stalls, a toy breaks, or the sole of a new shoe comes off, the consumer can im- mediately see the defect and report a complaint to the manufacturer. In addition, the modern consumer can even create or access product ratings and reviews (e.g., Consumer Reports) (12) in many cases. Importantly, this quality feedback on consumer outcomes normally incentivizes producers to pursue higher quality and thus increase customer satisfaction. In contrast, the pharmaceutical industr y makes products that act on our body's biochemistr y, and the safety and efficacy performance of a drug taken on a typical day is not readily accessible to the pa- tient with few exceptions (e.g., infrequently, a physi- cian may closely monitor blood levels or other clin- ical response after patient use of the medicine). The consumer is rarely directly aware of pharmaceutical quality or its impact, and is particularly reliant on the manufacturer to maintain high reliability operations. Regulatory agency interactions and healthcare pro- fessional feedback also play major roles in promoting supply of quality medicines. However, these entities are not present at the point of production each day to observe the conduct of operations and there are also other risk detectability limitations. Further, due to the low probability that a consumer will readily de- tect an intrinsic drug quality problem, exposure to an ineffective or unsafe drug is not easily traced back to a failure in the manufacturing operation (13). Conse- quently, even when a quality defect was the source of an adverse event, linking the etiology to a substandard product may be confounded by inherent limitations in the healthcare system, unique patient circumstances, or other elements that compromise detectability. This complex quality feedback is notable, as the visibility of a drug quality issue contrasts in a very basic way with many other commodities for which a defect is far more apparent to the consumer (enabling customer feedback). This reality underscores the importance of building quality into the drug manufacturing infrastructure and the systems that govern daily performance. Clearly, no ethical manufacturer in any industry wants to iden- tify a quality problem only once the defective product is distributed and associated with consumer harm. When defects are difficult to detect, even more onus shifts to, and trust is placed in, the producer of goods. Preventing such quality hazards requires a commitment to invest in highly capable manufacturing operations.