Quality initiatives are imperative in the pharmaceutical industry, but not all quality systems are equal. The new, proactive approach to quality adopted in 2016 by client-focused UPM Pharmaceuticals includes implementation of manufacturing quality assurance (MQA), the use of metrics to evaluate performance, and realignment of its laboratory functions to increase both efficiency and responsiveness. Together, these changes add up to accelerated delivery of high-quality products.
FDA Focus on Quality
The U.S. Food and Drug Administration Safety and Innovation Act (FDASIA), which was passed in 2012, requires FDA to use a risk-based approach to the inspection of pharmaceutical manufacturing sites and authorizes the agency to collect manufacturing quality data and other records in advance of, or in some cases instead of, conducting inspections. In response, FDA formed the Office of Pharmaceutical Quality and issued a draft guidance on its intended use of quality metrics to determine site risk rankings, redesign inspection protocols, predict possible drug shortages and encourage the implementation of advanced quality management programs. The proposed metrics included lot acceptance rate (LAR), product quality complaint rate (PQCR), invalidated out-of-specification rate (IOOSR) and annual product review on time rate (APROTR).1
FDA was, however, finding it difficult to compare quality performance between different companies because the definitions of terms such as batch, lot and rejection vary among manufacturers and even sometimes within different sites of the same firm. The agency thus issued a technical reference document providing recommendations on the submission of data to be used for the calculation of quality metrics as part of the process validation life cycle and pharmaceutical quality system (PQS) assessment.2
In response to industry concerns, FDA released a revised version of the Draft Quality Metrics Guidance in November 2016.3 The program was changed to include an initial voluntary phase through 2018, the number of data types to be collected was reduced and the data definitions were revised and supported with examples. Pharmaceutical manufacturers were also given more flexibility in how they report the data (site and product reports will be allowed). The agency is now focusing on LAR, PQCR and IOOSR and will use the data to prevent drug shortages, prepare for site inspections and use the calculated metrics in its post-approval manufacturing change reporting program.
Also in 2016, FDA announced that it will be focusing not just on metrics, but also on quality culture.4 Part of this effort includes introduction of the New Inspection Protocol Project (NIPP), which requires inspectors to consider quality practices that go beyond the minimum requirements and the state of quality at a manufacturing site, including the quality culture, design and effectiveness of the quality programs — not just specific deficiencies. Sites will be ranked according to six performance levels, including two that recognize performance that exceeds basic compliance. The agency will initially target sterile drug manufacturing but expects to ultimately apply the approach to all inspections.5
Moving Quality to the Forefront
In light of the changing focus on quality metrics and quality culture at FDA, in 2016 UPM Pharmaceuticals elected to adopt a new approach to quality management and implemented a manufacturing quality assurance (MQA) initiative. In essence, MQA removes quality from the backend of the manufacturing process and incorporates it into the entire process from start to finish. Rather than checking final dosage forms after they have been produced, with MQA, quality is evaluated during the entire manufacturing process in real time, so that any potential issues can be quickly addressed. The result: accelerated batch release and product review processes, leading to more rapid delivery of high-quality products to our customers. Once a sufficient dataset is generated (after at least one full year), statistical evaluations will provide further information on areas that can benefit from further improvements.
More Efficient Organization
The second initiative at UPM, undertaken in 2016 with the goal of improving our quality performance, was the realignment of our laboratories along specific capabilities. Today we have labs focusing on raw material testing, release testing, stability testing and microbiological testing. This reorganization has not only boosted the quality of our output, it has increased our efficiency and responsiveness.
A third change in 2016 involved the institution of a team approach for client support. Each UPM customer is now supported by an R&D manager, who is teamed with a quality project manager. These individuals are involved with a project from the time the client first brings it to the company through to completion, from proof of concept to commercialization.
Using Metrics to Identify Opportunities for Improvement
Our fourth new quality program implemented in 2016 was the implementation of quality metrics. We have begun using metrics to evaluate the quality performance at both the department and individual level. Error rates in manufacturing and at our laboratories are closely monitored to identify any areas where repeated errors occur. An investigation into the root cause is then conducted to try to understand the reason for the errors, such as a lack of training or need to redefine poorly written standard operating procedures (SOPs). We also look for non-human sources of error, such as problems with maintenance SOPs, equipment breakdowns, etc. During 2017, we plan on continuing to monitor and refine our metrics and align them with FDA’s quality metrics initiative.
The overall goal of this program and all other quality initiatives at UPM is to implement all activities and processes correctly the first time, every time, in all that we do. We are also committed to continuous improvement; there are always some performance areas that can be further improved upon. We take quality very seriously and are focused on looking to uncover potential issues very early on before they become problems, identify the root causes and take the necessary actions to fix or eliminate the issues.
As with the MQA initiative, no analyses have been performed to date. It is important to have a sufficient dataset that will provide valid statistics. Once we have gathered at least one full year of data, we will be conducting in-depth analyses to identify any overarching trends and issues and to determine if the new quality programs we implemented in 2016 are leading to reductions in error rates.
Quality by design (QbD), another FDA quality initiative, is based on risk assessment and proactive risk control.
Importance of QbD
Quality by design (QbD), another FDA quality initiative, is based on risk assessment and proactive risk control. It involves designing quality into processes and products from the concept stage through commercialization and requires in-depth knowledge of both product and process properties to ensure consistent quality.
At UPM, we recognize the value of the QbD approach. The key to the successful definition of optimum process conditions that provide a consistent quality product with the highest yields is having an in-depth understanding of the process so that scale-up to commercial manufacturing does not impact product quality. Small batches are run in our R&D laboratory to evaluate processes and identify critical process parameters (CPPs). Once we have established the acceptable limits for each CPP, we then move to GMP operations to confirm performance on a large scale.
Proactive Rather than Reactive
We have always had a right-first-time philosophy, and are now following a natural extension of that approach with the measurement of performance, which will lead to further improvements. With MQA we are considering quality during all stages of the manufacturing process, from production to filling to packaging. Although this approach requires more human capital, leaving quality evaluations to the final product release stage actually costs more. We find it is much more effective to address any issues as they arise.
Indeed, we are committed to being proactive rather than reactive. It is much more effective to fix things before they become major problems than to undo something that has already been done. Both our adoption of a QbD approach with the design of quality into processes and systems upfront, and our recent implementation of manufacturing quality assurance, reflect this commitment.
Compliance Comes with a Price
The various initiatives outlined above have required investment by UPM. To be effective, quality programs require the installation of proper systems and personnel to man them and ensure they are properly maintained. MQA, for instance, requires a minimum of skilled, quality professionals to ensure full implementation. UPM has hired additional quality experts to ensure that this new approach is successful. We have also expanded our quality assurance and quality control staff to ensure that each laboratory runs as efficiently and effectively as possible and that the right R&D/quality teams can be formed for each client. Overall, in 2016 we added about 24 new quality experts.
The results of this new quality journey at UPM have been noticeable and highly rewarding. Being proactive clearly bears results. The cost to react exceeds the cost to address issues as they occur in real time. We are not only experiencing more efficient production, but more consistent operations, and we are able to deliver products to our customers more quickly.
Our quality culture at UPM, which underlies all aspects of the company’s activities, has facilitated the implementation of MQA and our other new quality initiatives. The systems we now have in place not only ensure quality performance with continuous improvement but also help accelerate the product development and commercialization process. With reduced time to market an essential factor for success in the pharmaceutical industry today, we believe we are well positioned to meet crucial customer needs.
- Draft Guidance for Industry: Request For Quality Metrics. U.S. Food and Drug Administration. July 2015. Web.
- Quality Metrics Technical Conformance Guide: Technical Reference Document. U.S. Food and Drug Administration. 28 July 2015. Web.
- Submission Of Quality Metrics Data Guidance For Industry. U.S. Food and Drug Administration. Nov. 2016. Web.
- Quality Forum. U.S. Food and Drug Administration. 4 Mar. 2015. Web.
- Villax, Guy. “Quality Culture Wins over Compliance.” Pharma’s Almanac. Q2 2016. Web.