Without effective quality management (consisting of quality assurance and quality control), the innovative medicines developed by drug manufacturers to save lives and improve quality of life have the potential to cause harm instead. As bio/pharmaceutical companies increasingly rely on contract service providers to access specialized technologies and accelerate time-to-market, the quality performance of contract research and contract development and manufacturing organizations (CROs and CDMOs, respectively) has become an important differentiator. Outsourcing partners that have a consistent quality record seek to exceed minimum quality compliance requirements and are early adopters of new quality initiatives have the greatest likelihood of attracting and retaining pharma customers.
Current global economic trends and pharmaceutical industry dynamics are driving growth in the pharmaceutical outsourcing market. An ageing global population, increasing numbers of patients with chronic diseases and expanding middle classes in emerging economies are all leading to greater demand for advanced medicines. Increased cash flows have, in turn, allowed significant investment in innovation, leading to robust pipelines filled with drug candidates that exhibit novel mechanisms of action. The implementation of accelerated approval pathways has meant that greater numbers of these candidates are receiving approvals and being commercialized. Many of these novel drug substances are highly complex and/or require specialized equipment and skills for their production and handling. As a result of these various factors, many large, small and emerging bio/pharmaceutical companies are turning to CROs and CDMOs to provide the expertise and capacities needed to develop and produce these state-of-the- art therapies.
Results of the 2016 Nice Insight CRO and CDMO Outsourcing Surveys of professionals in the pharmaceutical and biopharmaceutical industries reflect the impact of these influential market forces [1,2]. For the fourth year in a row, respondents indicated that their companies dramatically increased year- on-year spending.
In the contract manufacturing space, the biggest change is occurring at the highest spending level. From 2012–2015, the percentage of respondents whose companies spent more than $50m annually on outsourcing remained fairly stable at 24–23%. That number nearly tripled to 71% for CMOs and CDMOs in 2016. Meanwhile, the percentages of respondents whose companies spent less than $10m and $10–$50m on outsourcing both decreased from 2015 to 2016 from 62% and 16% to 23% and 3%, respectively. As importantly, 75% of respondents to the 2016 CDMO survey expect their companies to increase expenditures on contract development and manufacturing services during the next five years, and 69% of participants in the CDMO survey expert to increase the number of CDMOs and CMOs they use going forward.
When it comes to outsourcing contract research services, respondents indicated that their companies dramatically increased year-on-year spending on outsourcing from 2013 to 2015. In 2013, 47% spent $10–$50m annually; in 2015, this number increased to 62%. Most notably, the percentage of respondents whose companies spent more than $50m annually on outsourcing more than doubled to 56% in 2016 from 24 to 23% during 2012–2015. In addition, 71% of respondents to the CRO survey expect their companies to increase expenditures on contract research services, and 64% of respondents to the CRO survey expect to increase the number of service partners they hire going forward.
However, not all service providers will benefit from the increasing level of pharmaceutical outsourcing. Bio/pharmaceutical companies are looking for CROs and CDMOs that have a strong track record of quality performance. The number one goal survey respondents hope to achieve when outsourcing to CROs and CDMOs is improved quality. Quality compliance is also the top performance attribute that sponsor companies evaluate post- engagement and when making decisions on whether to continue doing business with a CRO or CDMO. Survey participants identified poor product and service quality as the greatest source of dissatisfaction, and poor quality performance is the top driver for switching from one service provider to another.
Since the introduction of its 21st Century Initiative in 2002, which was intended to modernise the FDA’s regulation of the pharmaceutical quality of drugs, the agency has increasingly focused on improving its ability to ensure that consumers have access to quality medicines, regardless of their type or where they are produced.3 Despite these efforts, quality issues continue to occur and, in some cases, have led to numerous recalls, shortages of critical medications and, in some cases, harm to patients [4]. Clearly, the agency’s focus on post-market surveillance of deviations from current good manufacturing practices are insufficient to encourage improvement in quality management systems and pharmaceutical manufacturing facilities [4].
The Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 further enhanced CDER’s Quality Initiative by requiring that inspections of manufacturing facilities are risk-based [5]. The FDA must consider the compliance history, past recalls and prior inspection frequency at facilities when determining inspection schedules. The agency is developing performance metrics (with input from industry) that will be used to evaluate the quality systems at facilities, allowing not only the earlier identification of potential quality issues at production sites and their more timely resolution, but, particularly for CDMOs, comparison of quality performance [6]. In the latter case, the public availability of performance data should reward high performers with preferential selection by sponsor companies and place significant market pressure on providers with poor quality records to change their behaviors [7].
To streamline its drug quality monitoring processes, the FDA created the Office of Pharmaceutical Quality (OPQ) in January 2015 with the goal of creating ‘one quality voice’ for all non- enforcement-related drug quality activities (drug application reviews, post- approval improvements and surveillance and inspections of global manufacturing facilities) [8]. This approach allows the agency to proactively prevent quality issues from occurring and mitigate those that do.
Within the OPQ, the Office of Program and Regulatory Operations (OPRO) is responsible for managing all processes associated with drug product quality reviews and facility inspections.6 The Office of Policy for Pharmaceutical Quality (OPPQ) develops, implements, and updates science- and risk-based policies, standards and guidance documents, including chemistry, manufacturing and controls (CMC) review policy and CGMP/inspection policy and standards. The Office of Biotechnology Products (OBP), Office of New Drug Products (ONDP) and Office of Lifecycle Products (OLDP) are responsible for quality reviews of drug substances, drug products and biopharmaceuticals. The Office of Process and Facilities is responsible for the evaluation of pharmaceutical manufacturing process design and controls for their ability to be implemented at commercial scale.
OPQ will use the new quality metrics data and new data management/ informatics tools to identify product areas and manufacturing facilities with potential quality risks [9]. In addition, because lack of compliance with cGMP, process deviations and system failures have been shown not to be reliable indicators of product quality, the FDA is working to develop a new inspection and reporting paradigm [6]. The first step in this process is the New Inspection Protocol Project (NIPP), which the agency expects will provide a more quality focused, semiquantitative approach with streamlined and structured inspection reports [6]. It is based on expert investigator questions and assessment approaches and, notably, should allow the recognition of facilities and behaviours that exceed basic compliance, something that has not been a component of FDA inspections in the past.
OPQ is also working closely with the Office of Regulatory Affairs (ORA) to streamline processes related to inspection and enforcement [6]. The new office will also integrate the review of drug applications with the evaluation of manufacturing facilities to achieve more informed quality assessments, and work with the Office of Compliance and ORA to establish consistent quality standards and clear expectations for industry. The overall goal is to anticipate and mitigate quality problems before they can lead to recalls and drug shortages. OPQ is also focused on encouraging the adoption of emerging pharmaceutical technology to enhance pharmaceutical quality.
Since its inception, OPQ has published numerous guidance documents covering very specific technical issues to very broad topics that may impact the entire industry. Table I lists the documents that are available on the FDA’s website.
Although many CDMOs and CROs simply aim to operate in a compliant manner, leading firms recognise the many benefits of striving to exceed the minimum quality requirements established by regulations. At these companies, the value of quality is stressed to all employees through top- down communication from the highest levels. The worth of highly skilled employees who embrace such a quality philosophy is also highly prized by high- performing CDMOs/CROs.
When quality is assured rather than controlled, compliance with regulatory requirements follows naturally. In addition, there are fewer manufacturing issues and thus reduced downtime and product losses [10]. The overall result is often lower operating costs, which, along with an excellent quality reputation is a key driver for selection by pharmaceutical customers [1,2].
A culture of excellence also generally leads to the early adoption of state-of-the- art technologies in all areas of company activities, including quality [11]. Innovative CROs/CDMOs that are willing to explore and implement the advanced techniques being pushed by the FDA — such as QbD and PAT — are positioning themselves to be responsive to new regulatory regimes and achieve significant competitive advantage. These companies recognise that the traditional ways of doing business in the pharmaceutical industry are no longer effective. They are pursuing approaches focused on risk minimisation and management that enable designing of quality into processes and products from the start.
1. The 2016 Nice Insight Contract Research – Preclinical and Clinical Survey. http://www.niceinsight.com/
2. The 2016 Nice Insight Contract Development & Manufacturing Survey. http://www.niceinsight.com/
3. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/2004/ucm108359.htm.
4. www.brookings.edu/~/media/research/files/ papers/2014/05/01-quality-metrics-fda/quality- metrics--meeting-summary.pdf.
5.www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm20027187.htm
6. www.fda.gov/downloads/AboutFDA/Centers Offices/OfficeofMedicalProductsandTobacco/ CDER/UCM442666.pdf.
7. http://pharmas-almanac.niceinsight.com/books/szyj/#p=12
8. www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDER/ ucm418347.htm.
9. www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDER/ ucm417014.htm.
10. www.wellspringcmo.com/blog/good- manufacturing-practice-its-pharmaceutical- qualitys-dna.
11. www.tefen.com/insights/industries/Life_Sciences/responding_to_the_emerging_trends_and_challenges_of_the_life_sciences_industry.
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