Is Senior Management Responsible for GMP Compliance?

The Europharma Case: A Turning Point in Regulatory Enforcement

On December 13, 2016, a whistleblower-initiated inspection by the Danish Medicines Agency (DKMA) uncovered serious GMP compliance violations at Europharma, a pharmaceutical repackaging company operating in Denmark. The investigation revealed that the company had been falsifying expiry dates on repackaged medicinal products—a grave breach of fundamental pharmaceutical quality principles. In addition to these falsifications, inspectors discovered deliberately concealed information, use of contract acceptors without proper audits, and multiple systematic failures in the company’s quality management system.

The DKMA’s response was decisive and multifaceted. The authority immediately prohibited the company from manufacturing and importing pharmaceutical products, and withdrew its Good Manufacturing Practice (GMP) certification (No. DK H 00073116). However, what made this case particularly significant was an unprecedented regulatory action: the DKMA explicitly demanded the replacement of the Chief Executive Officer (CEO). This dramatic step represented a clear statement from the regulatory authority that corporate wrongdoing was ultimately the responsibility of top management.

It is important to note that the DKMA emphasized that while the GMP violations were severe, there was no immediate safety concern for patients using products already on the market. Following the appointment of a new managing director and implementation of comprehensive corrective actions with external GMP consultants, Europharma’s manufacturing authorization was reinstated on March 13, 2017. However, subsequent inspections in September 2017 revealed continued non-compliance issues, leading to another suspension. This pattern demonstrated what the DKMA described as “a general lack of will and ability to adhere to the principles of good manufacturing and good distribution practices.”

The Evolution of Quality Responsibility: From QPs to Senior Management

Historical Approach: Focus on Qualified Persons

As the Europharma case illustrates, EU regulatory authorities have traditionally focused on Qualified Persons (QPs) as the primary individuals accountable for quality failures. Under EU pharmaceutical regulations, QPs play a critical gatekeeping role by certifying that each batch of medicinal product has been manufactured and tested in accordance with Good Manufacturing Practice and the requirements of the Marketing Authorisation.

However, this approach presented a fundamental challenge: in many pharmaceutical companies, QPs occupy middle management positions rather than senior executive roles. While QPs possess the technical expertise and legal authority to release or reject batches, they often lack the organizational power to drive systemic changes in quality culture, allocate substantial resources, or influence strategic decisions that affect the pharmaceutical quality system as a whole.

The ICH Q10 Paradigm Shift

The publication of ICH Q10 “Pharmaceutical Quality System” guideline in 2008 marked a fundamental shift in regulatory thinking. This internationally harmonized guidance introduced a comprehensive model for pharmaceutical quality systems that explicitly recognizes senior management’s ultimate responsibility for ensuring an effective pharmaceutical quality system throughout the product lifecycle.

ICH Q10 complements regional GMP requirements by describing a quality system that spans all stages of a product’s lifecycle: pharmaceutical development, technology transfer, commercial manufacturing, and product discontinuation. Critically, the guideline emphasizes that management commitment and leadership are essential enablers of an effective pharmaceutical quality system. Senior management must establish the quality policy, ensure adequate resource allocation, define clear roles and responsibilities, conduct regular management reviews, and foster a quality culture throughout the organization.

The ICH Q10 model is built upon several key elements:

Management Responsibility: Senior management must demonstrate active leadership in quality matters, not merely delegate quality functions to middle management.

Process Performance and Product Quality Monitoring System: Systematic monitoring of manufacturing processes and product quality to ensure the state of control is maintained.

Corrective Action and Preventive Action (CAPA) System: Robust systems for investigating and addressing quality problems, with management oversight of effectiveness.

Change Management System: Formal evaluation and approval of changes that may affect product quality, with appropriate management involvement in risk-based decision making.

Management Review: Regular review of the pharmaceutical quality system by senior management to ensure its continuing suitability, adequacy, and effectiveness.

Codification in EU GMP Guidelines

The principles established in ICH Q10 have been progressively incorporated into EU GMP requirements. Most notably, EU GMP Annex 16 “Certification by a Qualified Person and Batch Release” (revised in 2016 and entering into force on April 15, 2016) explicitly states in its General Principles section:

“The ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy, lies with the marketing authorisation holder (MAH).”

This statement represents a clear regulatory position that while QPs retain specific technical and legal responsibilities for batch certification, the overarching accountability for pharmaceutical quality rests with the organization’s leadership—the MAH and, by extension, its senior management.

Annex 16 clarifies that the QP’s primary task is the certification of each batch for release. The QP must personally ensure that specified responsibilities are fulfilled, including verification that starting materials comply with specifications, that the supply chain is secure, that deviations and complaints are properly handled, and that the manufacturing and control processes comply with the Marketing Authorisation and GMP requirements. However, the QP operates within a quality system that must be established, resourced, and maintained by senior management.

International Harmonization: PIC/S GMP Annex 16

Important Regulatory Update: The original observation that “PIC/S GMP Annex 16 does not exist as it is specific to the EU region” requires updating based on recent developments. Following the 2016 revision of EU GMP Annex 16, the Pharmaceutical Inspection Co-operation Scheme (PIC/S) recognized the need to harmonize requirements regarding product release on an international level.

In June 2021, PIC/S launched a consultation process to adapt EU GMP Annex 16 for PIC/S member countries. The PIC/S version uses the term “Authorised Person” (which is strictly equivalent to the EU term “Qualified Person”) and focuses on important technical elements of release decisions while maintaining applicability across PIC/S participating authorities worldwide. This adaptation supports better international harmonization of GMP standards and aims to have non-EU/EEA PIC/S members incorporate these principles into their regulatory systems.

The PIC/S adoption of Annex 16 reinforces the global trend toward recognizing that product quality responsibility extends beyond individual technical experts to encompass senior organizational leadership.

Enhanced Requirements in PIC/S GMP Chapter 1 (2022 Revision)

The 2022 revision of PIC/S GMP Chapter 1 (Pharmaceutical Quality System) further strengthened the emphasis on senior management responsibility with explicit language:

“Senior management has the ultimate responsibility to ensure an effective Pharmaceutical Quality System is in place to achieve the quality objectives, and that roles, responsibilities, and authorities are defined, communicated and implemented throughout the organisation.”

Additionally, the revision specifies:

“Senior management should determine and provide adequate and appropriate resources (human, financial, materials, facilities and equipment) to implement and maintain the Pharmaceutical Quality System and continually improve its effectiveness.”

These requirements make it unambiguous that senior management cannot simply delegate quality responsibilities downward. Leadership must actively establish quality policy, provide resources, ensure implementation, and maintain oversight through regular management reviews and participation in quality decision-making.

Contemporary Regulatory Expectations

Quality Culture and Data Integrity

Recent regulatory guidance has expanded the concept of management responsibility to include the establishment of an appropriate quality culture. The US FDA’s “Data Integrity and Compliance with Drug CGMP” guidance explicitly states: “It is the role of management with executive responsibility to create a quality culture where employees understand that data integrity is an organizational core value and employees are encouraged to identify and promptly report data integrity issues.”

This represents a recognition that technical controls alone are insufficient; organizational culture—which is fundamentally shaped by senior leadership—plays a critical role in preventing quality failures. When employees feel pressured to meet production targets at the expense of quality, or fear retaliation for reporting problems, the likelihood of data integrity failures and GMP violations increases significantly.

Risk Management and Continual Improvement

Modern pharmaceutical quality systems are expected to embrace risk-based approaches as described in ICH Q9 “Quality Risk Management.” Senior management must ensure that quality risk management is integrated into decision-making processes, that risks to product quality are proactively identified and controlled, and that a culture of continual improvement is fostered.

This requires management to move beyond a reactive approach (responding only when problems occur) to a proactive stance that anticipates potential quality issues, invests in prevention, and systematically improves processes based on performance monitoring and lessons learned.

Oversight of Outsourced Activities

The increasing complexity of pharmaceutical supply chains, with manufacturing, testing, and distribution activities often outsourced to contract organizations, has heightened the importance of management oversight. Marketing Authorisation Holders retain full responsibility for product quality regardless of whether activities are performed in-house or by contractors.

Senior management must ensure that effective quality agreements are in place, that contractors are appropriately qualified through audits and ongoing monitoring, and that there is adequate oversight of the entire supply chain. The QP certification process described in Annex 16 explicitly requires confidence in the quality systems of all sites involved in manufacturing and testing, which can only be achieved through robust management oversight.

Implications for Pharmaceutical Companies

The Europharma Lesson

The Danish Medicines Agency’s enforcement action in the Europharma case sends an unmistakable message to pharmaceutical companies: when serious, systemic quality failures occur, regulatory authorities may look beyond technical staff to hold senior leadership accountable. The demand for CEO replacement—though unusual—reflects a regulatory philosophy that quality system failures ultimately represent failures of leadership.

This approach aligns with principles long established in other industries where safety is paramount (such as aviation and nuclear power), where accountability for systemic failures extends to the highest levels of organizational leadership.

Practical Implementation

For pharmaceutical companies, this regulatory landscape requires senior management to:

Establish Clear Quality Policy: Develop and communicate a quality policy that reflects the organization’s commitment to product quality and patient safety, ensuring this policy drives decision-making at all levels.

Provide Adequate Resources: Allocate sufficient human, financial, and material resources to quality functions, recognizing that under-resourcing quality operations creates risks that senior management cannot delegate away.

Define Organizational Structure: Clearly delineate responsibilities and authorities related to quality, ensuring quality units have appropriate independence and authority to fulfill their functions.

Conduct Regular Management Reviews: Systematically review the performance of the pharmaceutical quality system, examining quality metrics, audit findings, CAPA effectiveness, and other indicators to identify improvement opportunities and ensure continuing system effectiveness.

Foster Quality Culture: Through visible leadership, appropriate incentives, and accountability systems, create an organizational culture where quality is genuinely valued, problems are openly discussed, and employees at all levels understand their role in maintaining product quality.

Ensure QP Support: While maintaining the QP’s independence in batch release decisions, provide the organizational support, resources, and authority structure that enables QPs to fulfill their responsibilities effectively.

Oversee Supply Chain: Maintain robust oversight of outsourced activities through qualification, auditing, quality agreements, and ongoing monitoring to ensure contracted organizations meet the same quality standards as internal operations.

Moving Forward

The evolution from focusing quality accountability primarily on Qualified Persons to recognizing senior management’s ultimate responsibility represents a maturation of pharmaceutical quality systems. It acknowledges that while technical expertise embodied in QPs and quality units is essential, sustainable quality performance requires leadership commitment, appropriate organizational structures, adequate resources, and a culture that prioritizes patient safety above all other considerations.

The Europharma case, though now several years past, remains instructive. It demonstrated that regulatory authorities possess both the will and the tools to hold senior management accountable when quality systems fail. More importantly, it reinforced the principle articulated in ICH Q10 and codified in GMP regulations worldwide: the ultimate responsibility for the Pharmaceutical Quality System rests with senior management, not with middle management technical experts alone.

For pharmaceutical companies navigating an increasingly complex regulatory and technological landscape, this principle should serve not as a burden but as a foundation for building robust, resilient quality systems. When senior leadership genuinely commits to quality—through policy, resources, culture, and oversight—the entire organization is positioned to meet its fundamental obligation: ensuring that every medicinal product is safe, effective, and of the highest quality for the patients who depend upon it.

Conclusion

Yes, senior management is unequivocally responsible for GMP compliance and the pharmaceutical quality system. While Qualified Persons retain critical technical responsibilities for batch certification and release, the ultimate accountability for establishing, maintaining, and continually improving an effective pharmaceutical quality system lies with senior organizational leadership, specifically the Marketing Authorisation Holder and its executive management team.

This responsibility cannot be delegated. It encompasses quality policy, resource allocation, organizational structure, management review, quality culture, and oversight of all activities that affect product quality—whether performed internally or by contractors. Regulatory authorities worldwide, as demonstrated by cases like Europharma and codified in guidelines like ICH Q10, EU GMP, and PIC/S GMP, are increasingly holding senior management accountable for quality system performance.

For pharmaceutical companies, embracing this responsibility as a core leadership obligation—rather than viewing it merely as a compliance requirement—represents the path to sustainable quality excellence and the fulfillment of the industry’s primary purpose: protecting and improving patient health through the provision of safe, effective, high-quality medicines.