Robert Michalik is advisor (Quality and Corporate Compliance) at Shabas Solutions LLC.

Robert Michalik

Disclaimer: This article was not written by the FDA, and it does not necessarily reflect the views of the agency.

The pharmaceutical industry’s investments in the latest manufacturing technologies and quality practices have contributed greatly to assuring the reliable supply of safe and effective drugs.And yet, lingering manufacturing process and product quality problems continue, which can result in drug shortages and jeopardized the health of patients.

As outlined in the first article (1) of a multi-series publications relating to 

FDA’s Quality Management Maturity (QMM) initiative

, FDA and other public health experts point to how well senior management implement quality processes and inculcate quality into the manufacturer’s corporate culture.

In this article, the authors examine how QMM principles and practices can positively influence a sustainable drug supply and bolster the bottom-line of drug manufacturers, API suppliers, and contract development and manufacturing organizations (CMO/CDMOs).

FDA’s Center for Drug Evaluation and Research’s (CDER)’s Office of Pharmaceutical Quality (OPQ), in collaboration with other stakeholders, is currently engaged in operationalizing a voluntary QMM rating program for domestic and foreign pharmaceutical manufacturers (2). Since first formally proposed in 2020, the QMM initiative has steadily gained momentum.FDA selected Shabas Solutions as one of two contractors to design and test draft QMM assessment tool with volunteer drug manufacturers. Lessons learned from the several pilot assessments conducted by Shabas for foreign API manufacturers have been used to further refine its approach toward QMM assessment.

The QMM model focuses on four key pillars that help inform senior management at a site achieve quality maturity and minimize quality problems, prevent drug recalls leading to shortages, and enhance profitability. The animating ideas behind four key QMM pillars include:

Sustainability of a mature quality management system (QMS)

Managing operational risks including integration of quality risk management

Meeting and exceeding regulatory compliance

Over the course of a multi-day assessment, Shabas led API manufacturer senior management through an in-depth exchange of questions using its QMM assessment tool as a guide to gauge how well the manufacturer has built mature quality practices based on International Council for Harmonisation (ICH) Q9, ICH Q10, and other industry standards into its organization. In the process, both FDA observers and participating manufacturers gained insights into this innovative assessment method.

Once the QMM assessment methodology is finalized, FDA expects that QMM ratings may improve global regulatory oversight, empower manufacturers to improve their quality system effectiveness, realize regulatory inspection flexibilities described in 

, result in fewer quality issues (i.e., defects, reworks, complaints, and recalls) and obtain efficiency gains (e.g., speed, throughput, supply timeliness) from investing in quality culminating in a high-quality and reliable drug supply.

Scope and root causes of the drug product shortages

Public health experts concur that while the underlying factors contributing to drug shortages are myriad, the dominant factor relates to “quality problems during the manufacturing process, which give rise to a halt in production in order to address the problem” (3).

From a ‘bird’s eye’ level, the scope of the drug shortage problems is reported by the American Society of Hospital Pharmacists (ASHP) in conjunction with University of Utah Health Science Center’s Drug Information Service and FDA CDER Drug Shortage Staff (

Figure 1: National Drug Shortages: New Shortages by Year (January 2001 to December 31, 2022) Source : 

https ://www.ashp.org/drug-shortages/shortage-resources/drug-shortages-statistics

 [Figure courtesy of authors. Fair Use waiver to copyright image granted by University of Utah Drug Information Service]

Experts presenting at Duke University’s Margolis Center conference in 2018 reported that an alarming 91% of all drug shortages were related to product and manufacturing quality (manufacturing issues (64%) and raw material supplier shortages (27%).These findings were comparable to data reported by FDA in a 2019 inter-agency report, entitled 

Drug Shortages: Root Causes and Potential Solutions - A Report by the Drug Shortages Task Force

 in which the authors concluded “Of 163 drugs that went into shortage between 2013 and 2017, 62 percent went into shortage after supply disruptions occurred that were associated with manufacturing or product quality problems” (4).

The majority of these drugs are considered life-sustaining, and therefore, their unavailability underscores the gravity and urgency of the problem and need to address the root causes.Pharmaceutical business trends can also significantly impact drug supply, including global consolidation (mergers and acquisitions), low profit margins for generic drugs, and ineffective contracting practices.In addition, heavy reliance on foreign-sourced materials (e.g., API, other key components) coupled with logistical and supply chain risks (global pandemics, natural disasters, etc.) contribute to unpredictable shortages in the US drug market (5). 

Several potential solutions to address drug shortage have been proposed, and many of these have already been implemented, in part, with some degree of success (6). The categories amenable to faster implementation include regulatory mandates and public policy incentives to boost contingent supplies of critical drugs. Even so, with quality as the leading root cause, FDA’s QMM initiative remains the most promising solution in the long run (7). 

Manufacturers, API suppliers, and CMO/CDMOs–industry dynamics

Drug manufacturers (abbreviated new drug application [ANDA] holders) may delegate authority to manufacture API components and finished drugs to CMO/CDMOs, but they cannot assign overall responsibility for those drug products’ quality.Drug manufacturers remain legally responsible for approving or rejecting drug products manufactured by the contract facility and are ultimately liable for any harm caused (8).

Regulators (including FDA) generally lack the legal authority to mandate data from API suppliers and CMO/CDMO contractors, relating to production issues (9), which creates a lack of transparency within the industry.For these reasons, finished drug manufacturers must be vigilant which contractors and key suppliers they engage to use to manufacture their products.API and CMO/CDMO degree of culpability in the drug shortage problem is directly related to their quality management maturity. NDA and ANDA holders must know the extent to which its contractors meet critical parameters associated with the four QMM pillars.

Virtual QMM assessment–a cost-effective method for screening API suppliers

A supply of reliable and high quality API drug components is a key to finished drug product availability. Very often there is only one API supplier for a particular drug and the supplier may be outside the US. Therefore, selection of an API supplier is of such critical importance to the finished drug product manufacturer, where QMM can play a role to assess their quality management maturity to assure the suppliers reliability. By using a tailored QMM assessment tool for API manufacturers, a virtual screening can be expeditiously performed to efficiently down select API vendors who may have a well-established QMS or quality culture at the site. Specifically, a QMM assessment could reveal strengths and weakness related to critical API site business processes of interest to finished drug product manufacturers such as an effective corrective and preventive action (CAPA) program, proactive change control management embracing emerging technology, predictive equipment monitoring supporting facility operations, optimized processes leveraging identification and trending off key metrics, and quality risk management (QRM) integration, to name a few.

Using a QMM assessment tool, prerequisite surveys of API or CMO/CDMO manufacturer site operations could reveal weaknesses in a site’s practices that evade detection during routine GMP compliance audit and aid finished drug manufacturers during vendor selection.Moreover, this new quality screening approach can provide the assurance needed to verify the partner has the maturity to meet its commitments.Cost of an independent QMM assessment can off-set the costs (time and money) associated with vendor selection allowing the finished drug product maker to concentrate on more viable API suppliers.

Adoption of QMM principles and practices can lower costs and benefit API (10) or CMO/CDMO manufacturer in several other ways. QMM assessments offer keen insights into service areas needing attention, focused improvements, and ultimately a higher QMM rating which would attract more clients and greater profitability.In addition, the reputation of more mature component and service providers tend to attract employee candidates who are drawn to quality organizations, and thereby elevating the performance level across the organization.

Adopting a QMM-based strategy to use customer service and satisfaction as a differentiator can lead to savings from greater emphasis on root cause analysis of issues. Incorporating QRM into a site’s QMS and the manufacturer’s Enterprise Risk Management framework (e.g., supply risk, cyber risk, human resource risk, etc.) would offer reduced volatility, avoidance of surprises, enable detection of potential issues before any disaster happens, and fewer interventions from regulatory health authorities. FDA is also considering incentives for manufacturers who adopt the QMM approach to operational practices.Incentives suggested included reduced inspection frequency, and regulatory flexibility for pre-inspection and post-approval changes. Combined, these could save considerable staff time for API and CMO/CDMO manufacturers.

Embracing QMM principles and practices can reduce manufacturing quality problems at the root cause level, reduce time and expenses associated with API supplier and CMO/CDMO selection, and substantially elevate the reliability and quality of the manufacturing chain, overall.Furthermore, achieving a mature state of corporate quality culture makes a drug manufacturer, API supplier and CMO/CDMO more attractive to both regulatory authorities and the general public.

,R. Introduction to Pharmaceutical QMM Model: QMM Assessment to Promote Pharmaceutical Operational Excellence. 

2. FDA. CDER Quality Management Maturity. FDA.gov (accessed April 19, 2023). (

https://www.fda.gov/drugs/pharmaceutical-quality-resources/cder-quality-management-maturity

3. Drug Shortages Roundtable: Minimizing the Impact on Patient Care. Am J Health Syst Pharm. 2018 Jun; 75(11): 816–820. doi: 10.2146/ajhp180048

4. FDA Drug Shortages: Root Causes and Potential Solutions - A Report by the Drug Shortages Task Force (p.33) 

2019 Drug Shortages Report, Updated February 21, 2020 (fda.gov)

 - Search List of Extended Use Dates to Assist with Drug Shortages; FDA.gov (accessed on Feb. 25, 2023).

5.Shukar, S, Z, et al., Drug Shortage: Causes

2:693426. 2021 doi: 10.3389/fphar.2021.693426

6. Throckmorton, D., Dep. Dir. Reg Programs, FDA CDER, Federal Efforts to Prevent Drug Shortages An FDA Perspective, presented at Duke Univ. Margolis Center for Health Policy, Nov 27, 2018 [Identifying the Root Causes of Drug Shortages and Finding Enduring Solutions], 

https://www.fda.gov/media/119514/download

7. Office of Pharmaceutical Quality (OPQ), CDER, FDA “White Paper: Quality Management Maturity: Essential for Stable U.S. Supply Chains of Quality Pharmaceuticals”, (2022) 

https://www.fda.gov/media/157432/download

Quality Management Maturity Workshop - 05/24/2022 | FDA

Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients

. (for clarification on scope of CMO and API responsibilities) (ICH, 2018).

9. Congressional testimony by Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration, “Safeguarding Pharmaceutical Supply Chains in a Global Economy”, October 29, 2019, 

https://www.fda.gov/news-events/congressional-testimony/safeguarding-pharmaceutical-supply-chains-global-economy-10302019

10. Pharmaceutical Tech. An Overview–Active Pharmaceutical Ingredient. Pharmaceutical-tech.com (accessed April 19, 2023) 

https://www.pharmaceutical-tech.com/articles/an-overview-active-pharmaceutical-ingredient

Mr. Somnath Mishra (Project Director), Mr. William Hauck, Dr. Clyde Schultz, and Mr. Zachary Royal all participated in the FDA QMM Pilot for Foreign API Manufacturers. Mr. Robert Michalik, JD, RAC is a regulatory attorney and quality compliance professional with expertise in drug and biologics development and management.

Shabas Solutions LLC sincerely acknowledges the FDA CDER QMM team for their support and guidance during the QMM Pilot and for reviewing this article. Also wish to thank Dr. Erin Fox, PharmD, BCPS, FASHP, Sr Director, Drug Information and Support Services University of Utah Drug Information Service.


Vol. 47, No. 5
May 2023
Pages: 48–49, 52

When referring to this article, please cite it as Mishra, S.; Hauck, W.; Schultz, C.; Royal, Z.; Michalik, R. QMM for Pharmaceutical Manufacturers–Implications for Drug Manufacturers, API Suppliers and Contract Manufacturers. 

Articles

QMM principles and practices can positively influence a sustainable drug supply and bolster the bottom-line of drug manufacturers, API suppliers, and CMO/CDMOs.

QMM for Pharmaceutical Manufacturers– Implications for Drug Manufacturers, API Suppliers and Contract Manufacturers

In recent months, FDA has begun championing Quality Management Maturity (QMM), a new quality surveillance initiative intended to raise awareness at all levels of management in the pharmaceutical industry as to how to best achieve quality objectives and improve manufacturing site quality and supply chain reliability in drug manufacturing processes. QMM follows a maturity modeling paradigm first developed and adopted by other high technology industries. The nexus between a clearly articulated mature quality culture, technical processes, and corporate-wide business practices that are integrated with quality objectives has crystallized into a viable roadmap for enhancing a drug manufacturer’s operations, while satisfying patient needs and corporate goals.

Since first introducing the proposed initiative, FDA has conducted two QMM pilots to measure quality management maturity levels at an establishment—one for domestic finished-product manufacturing sites and another aimed at overseas API manufacturing sites. Shabas Solutions LLC (Shabas) was selected to run the QMM pilot for overseas API manufacturers in which eight sites—of various sizes, location, age, and product focus—participated voluntarily (1). The Shabas team (including the authors of this article) collaborated with FDA to develop a comprehensive QMM assessment tool to inform FDA’s vision for the QMM program. The tool is characterized by four pillars and 15 practice areas, more than 60 QMM questions with accompanying interview guides, a 5-level rating system, and a scoring and reporting process.

The pilot program yielded findings that helped FDA and industry participants better understand what impact the QMM initiative might have to enhance quality management for a drug manufacturer, both at its corporate level and specific manufacturing site, and how adoption of QMM could eventually benefit the industry.

In this article (first of a multi-part series), the authors leverage insights gained from the FDA QMM pilot to explain what QMM means in practice to a firm’s management, trace its evolution, and explain the benefits of adopting it.

According to FDA, QMM is the state attained when drug manufacturers have consistent, reliable, and robust business processes to achieve quality objectives and promote continual improvement (2). FDA mentioned QMM in its 2019 report, Drug Shortages: Root Causes and Potential Solutions, which pointed to a lack of manufacturer incentives to improve their quality management beyond the minimum required for current good manufacturing practice (CGMP) compliance (3).

In an earlier article, FDA officials noted: “A drug manufacturer is responsible for implementing dependable daily operations that assure consistent drug quality. Management’s daily decisions on myriad issues involving equipment, materials, maintenance, staff qualifications, supervision, process control, and investigations will ultimately determine the quality of the drugs that are shipped from a given facility” (4).

In other words, site management’s proficiency in governing a site’s business processes as well as their level of integration with quality objectives, influence the performance of the quality management system and technical processes involved in developing a product and, therefore, impacts product quality and availability.

In a competitive market, reliable delivery of high-quality product and reduced quality-related shortages sustainably over the long-term—the essence of QMM as identified by FDA—is a management concern in all industries, in which their lessons learned are also applicable to pharma. Shabas researched the pharma and other industries to identify key foundational competencies (“four pillars”) that undergird QMM for an organization aspiring to be “quality management mature”:

Compliance management: ability to consistently meet and/or
exceed compliance with applicable laws, regulations, and industry best practices

Risk management: ability to identify and manage organizational risks and build resilience

Quality culture: ability to develop and maintain an organizational mindset and behaviors that value continuous learning and improvement, and customer satisfaction

Sustainability: ability to successfully secure and manage appropriate technology, infrastructure, human capital, suppliers, customers, institutional knowledge, and other resources to
sustain the operations.

Achieving site QMM starts with understanding where an organization is in terms of QMM—thus the need for an assessment. Increased site maturity would be evident through improved quality metrics and other relevant, but carefully, chosen indicators. But a prerequisite to achieving an optimized site maturity is for site management to invest in establishing systematic business processes that are well integrated with quality objectives and committing to developing the culture—the two key facets of an “operations excellence” program. Such a demonstrated intent of management’s willingness could serve as useful evidence to a QMM assessor.

By integrating continuous improvement in the business processes as the focus of the organization as QMM seeks to do, management may successfully realize the potential of achieving long-term growth in line with corporate strategy.

A QMM assessment is not an FDA quality audit of an organization’s quality management system or products but should rather be viewed as an alignment check between an organization’s planned strategy and its actual execution. An independent pharmaceutical site QMM assessment would therefore inform site management with a “snapshot in time” as to its institutional capacity, culture, and knowledge related to manufacturing medicines, how well the organization is able to leverage them to guide the design and governance of the site business processes to produce high quality medicines reliably, and how committed the site management is to institutionalize a quality culture.

Brief history of quality management and its maturity

The fundamentals of modern quality management practices can be traced to innovative principles developed by Joseph Juran and Edward Deming. Juran’s model of quality, referred to as Total Quality Management (TQM), focused on prospective quality practices employed throughout a manufacturing process, rather than reactively weeding out non-conforming products during finished product quality control (QC) inspection (5).

By the 1960s and 1970s, manufacturers and regulators in various industries began to take notice of the impact that TQM practices were having on product quality and productivity in Japan (6). In 1978, FDA embedded TQM principles into GMP regulations (e.g., prospectively defined product and process specifications driven by written standard operating procedures [SOPs]). Globally, TQM practices were adopted by International Organization for Standardization (ISO 9000 series) and International Council for Harmonisation (ICH) in their pharmaceutical best practices related to technical and quality standards (Q, S, E, and M series). By 2000s, ICH became a leading standards organization for the development and manufacture of pharmaceuticals globally (e.g., Q7 through Q12 guidance) (7,8).

Beginning in the late 1980s and into 1990s, the US Department of Defense and military contractors engaged with the Carnegie Mellon Software Engineering Institute to propose a Capability Maturity Model assessment tool (now, CMM-Integration [CMMI] with 5-level maturity scale) to illuminate subtle issues at the senior management level which stymied TQM effectiveness (9). CMM assessments enabled management at companies in high-tech industries to discern whether its quality mission statement was effectively being communicated throughout the organization (10). In 2017, FDA’s Center for Devices and Radiological Health endorsed CMMI for their Voluntary Manufacturing and Product Quality Pilot Program aimed at medical device manufacturers (11,12).

Given the success of quality maturity modeling assessments seen in other high-tech industries—and driven by FDA’s Congressional enabling legislation (13) and its own policy initiative to address drug supply chain problems—in 2016 (3), FDA sponsored researchers at the University of Gallen’s Institute of Technology Management to conduct a study of Operational Excellence (OPEX) metrics to identify root causes of quality system problems that could lead to drug shortages for vulnerable patient populations.

A series of three reports issued by St Gallen Pharma OPEX Study demonstrated a remarkable correlation between the “assessed” level of quality management maturity and quality system effectiveness, or “operational excellence” (14). It addressed an important question: “To what extent does a pharmaceutical manufacturer’s quality management maturity affect its ability to convey a culture of quality throughout its organization?”

Not surprisingly during the QMM pilot assessment, sites that received higher QMM scores generally performed well in similar key performance areas as noted by Juran in 1946 (corporate culture, quality messaging, and communication throughout the organization).

Today, with the advent of the digital revolution and artificial intelligence (AI) machine learning capabilities, the quality landscape is once again being transformed. Conducting a QMM assessment becomes more critical than ever as a means to inform site management of their organization’s current maturity level and its ability to integrate changes.

Site management decisions related to various business processes often create a de facto quality culture that impacts product quality and availability. While FDA provides oversight of the site quality management processes and product quality via CGMP inspections and other surveillance methods, there are currently no comparable regulatory tools that examine a site’s business processes and how well they are integrated with quality objectives. QMM fills that much needed gap, as illustrated by 

Figure 1. Quality Management Maturity and Shabas Assessment Approach. Figure courtesy of the authors.

In a future article, the authors will cover typical symptoms of low and high QMM that were encountered while conducting the FDA QMM pilots.

Based on the authors’ experience from administering the FDA QMM foreign pilot, industry participants of any company size would benefit from adopting QMM by moving toward greater systemization and optimization of their business processes and their integration with quality objectives. This will result in improved investment decisions, risk-based redundancies, and enhanced operations in terms of resiliency, workforce efficiency and collaboration, customer and supplier relationships, management oversight of quality, and ultimately a robust quality culture at the site thereby paving the way to achieve targeted strategic objectives. As an example, the QMM assessment tool developed by Shabas demonstrated to the pilot participants how systemization can provide greater visibility of business processes and remove barriers to collaboration between different functional areas, ways to improve supplier and customer collaboration processes, and how to progressively fit quality into a site’s strategic plan.

The QMM initiative is squarely aimed at operationalizing the vision laid out in the FDA’s report on Pharmaceutical Quality for the 21st Century: “a maximally efficient, agile, flexible manufacturing sector that reliably produced high-quality drug products without extensive regulatory oversight” (7). It is a logical evolution in the history of pharma quality management to adopt principles of operations excellence to systematically link management proficiency, business process maturity including digitalization, corporate culture, and continuous improvement ethos to achieving long-term growth, quality goals and strategic corporate objectives.

Shabas Solutions LLC sincerely acknowledges the FDA CDER QMM team for their support and guidance during the QMM Pilot and for reviewing this article. We also wish to acknowledge and thank Major General (retired) John Handy, Mr. Joseph Delukey, and Dr. Clyde Schultz for their invaluable contribution to the FDA QMM Pilot project.

Shabas Solutions LLC (www.shabas.net), based in Fairfax, Virginia, USAis a small business provider of scientific and management consulting services to multiple US federal government agencies. Our experts and staff members bring decades of experience in Defense and Health Supply Chain Management, Pharmaceutical Quality Management, Pharmaceutical Research and Development, Federal Policy and Regulatory Operations, and Technology Integration.

 “Quality Management Maturity for Active Pharmaceutical Ingredients Pilot Program for Foreign Facilities; Program Announcement

“Quality Management Maturity: Essential for Stable U.S. Supply Chains of Quality Pharmaceuticals

Drug Shortages: Root Causes and Potential Solutions A Report by the Drug Shortages Task Force 2019

J. Woodcock and M. Wosinska, “Economic and Technological Drivers of Generic Sterile Injectable Drug Shortages,” 

American Society for Quality, The History of Quality available from asq.org [accessed Nov. 14, 2022].

INC Magazine, “Total Quality Management,” Article, Jan. 5, 2021.

Pharmaceutical Quality for the 21st Century: A Risk-Based

ICH, Quality Guidelines available from ich

Software Engineering Institute, CMMI: A Short History, Brochure, 

M.C. Paulk, et al., Capability Maturity Model for Software, Version 1.1, Technical Report, 

FDA, “Fostering Medical Innovation: Case for Quality Voluntary Medical Device Manufacturing and Product Quality Pilot Program,” Notice, 

FDA, Fostering Medical Device Improvement: FDA Activities and Engagement with the Voluntary Improvement Program, Guidance Document, 

FD&C Act, sec. 301(a); 21 U.S.C. 331(a);see also 

FDA Quality Metrics Research Final Report Year 1

,
University of St. Gallen (Switzerland), November 2017.

Somnath Mishra, Somnath.mishra@shabas.net, is president, William Hauck is senior associate, Zachary Royal, is senior consultant, and Robert Michalik is advisor (Quality and Corporate Compliance), all at Shabas Solutions LLC.


Vol. 46, No. 12
December 2022
Pages: 30–33

When referring to this article, please cite it as S. Mishra, W. Hauck, Z. Royal, and R. Michalik, “Introduction to Pharmaceutical QMM Model: QMM Assessment to Promote Pharmaceutical Operational Excellence,” 

QMM is an evolutionary advancement in FDA’s quality management maturity initiative that provides industry with a viable methodology to assess and improve manufacturing quality and supply chain reliability. 