Clyde Schultz works for Shabas Solutions.

Clyde Schultz

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.