The Evolution of GAMP: A Historical Perspective

The Birth and Early Development of GAMP

In 1991, Ron Tetzlaff, an inspector from the U.S. Food and Drug Administration (FDA), conducted an inspection of pharmaceutical companies in the United Kingdom. This inspection resulted in the issuance of a Warning Letter to Glaxo (now GlaxoSmithKline), pointing out deficiencies in pharmaceutical-grade quality control practices.

Glaxo was prohibited from launching new products until corrective actions addressing the issues identified during the inspection were completed. The FDA issued a letter in 1992 demanding completion of these corrective measures.

Many of the FDA’s findings stemmed from the fact that these companies were implementing food-grade manufacturing and quality control practices rather than pharmaceutical-grade standards. Additionally, a significant portion of the observations related to facilities and equipment, making it clear that suppliers needed to be educated on pharmaceutical-level quality control requirements.

This incident became a major turning point in promoting the adoption of computer validation within the pharmaceutical industry.

Note: GLAXO was originally a registered trademark for infant formula powder.

Formation of the GAMP Working Group

In response to this situation, a working group was established in the United Kingdom to develop guidelines for computer validation. In 1993, Arista and Trofsen visited Mentec Corporation to gather information for drafting GAMP, obtaining crucial insights.

Furthermore, the participation of the UK Medicines Control Agency (MCA, now the Medicines and Healthcare products Regulatory Agency, or MHRA) ensured that regulatory perspectives were incorporated into the guidelines.

In February 1994, the first international conference was held in London, where a draft of supplier guidance was presented. GAMP 1 was officially published in 1995.

It is important to note that GAMP was developed as guidance for suppliers, not for pharmaceutical companies. Additionally, GAMP is “guidance,” not a “guideline” in the regulatory sense.

Following this, revisions were made approximately every two years: GAMP 2 (1996), GAMP 3 (1998), and GAMP 4 (2001), with each version substantially expanding the content.

Challenges with GAMP 4

While GAMP 4 offered many advantages, several issues were identified:

1. Insufficient Risk-Based Approach

The same level of documentation and verification was required regardless of system criticality. This resulted in excessive verification work even for low-risk systems, leading to unnecessary compliance costs.

2. Rigidity of Software Categories

The categorization system was fixed from 1 to 5, making it difficult to accommodate new technologies and systems. The criteria for ambiguous classification cases were unclear, causing confusion in practical implementation.

3. Cost Inefficiency

Excessive documentation requirements and uniform verification approaches led to prolonged project timelines, ultimately increasing compliance costs.

4. Difficulty in Application to IT Systems

Process validation terminology centered on facilities and equipment (such as DQ, IQ, OQ, PQ) was used, making application to IT applications challenging. These terms were often unclear in meaning to suppliers, particularly those from the IT industry.

5. Duplication of Work Between Suppliers and Pharmaceutical Companies

Overlapping work occurred between pharmaceutical companies and suppliers, resulting in noted inefficiencies.

These challenges meant that GAMP 4 imposed excessive burdens on pharmaceutical companies. The costs required for regulatory compliance (compliance costs) by pharmaceutical companies tend to be ultimately passed on to drug prices, becoming a contributing factor to increased economic burden on patients.

FDA Modernization Act and Regulatory Environment Transformation

In 1997, the FDA Modernization Act (FDAMA), passed by the U.S. Congress, called for comprehensive reforms in pharmaceutical and medical device regulations. Subsequently, in 2002, the “Pharmaceutical CGMPs for the 21st Century Initiative” was launched, promoting the strengthening of quality management systems and the introduction of risk-based approaches. These efforts supported the establishment of new manufacturing approaches in the pharmaceutical industry.

Influence of PAT and ASTM E55 Committee

Around 2001, the FDA began promoting Process Analytical Technology (PAT), which was commonplace in the chemical industry, but initially saw limited adoption in the pharmaceutical industry. To improve this situation, the ASTM E55 committee was established in 2004, strengthening the framework for standardizing pharmaceutical manufacturing processes.

In 2007, ASTM E2500, “Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment,” was published.

Establishment and Modernization of GAMP 5

Influenced by ASTM E2500 and other factors, GAMP reached a major turning point with the publication of GAMP 5 in 2008. This new version fully introduced a risk-based approach, and the title was changed from GAMP 4’s “GAMP Guide for Validation of Automated Systems” to “A Risk-Based Approach to Compliant GxP Computerized Systems.” It is noteworthy that the term “Validation” disappeared from the title to align with ASTM E2500.

This change also indicated a shift in focus from traditional “Automated Systems” (centered on facilities and equipment) to “Computerized Systems” (centered on IT applications).

GAMP 5 Second Edition and Current State

In June 2022, the second edition of GAMP 5 was published, updated with content addressing the latest technologies and regulatory requirements. The updated version includes enhanced guidance on several critical areas:

Cloud Computing and Software as a Service (SaaS): Recognizing the growing adoption of cloud-based solutions in pharmaceutical operations, the second edition provides comprehensive guidance on validation and compliance strategies for cloud environments, including considerations for data integrity, security, and supplier management.

Agile Development Methodologies: Acknowledging the shift from traditional waterfall development approaches, GAMP 5 Second Edition incorporates guidance on implementing agile and DevOps practices while maintaining GxP compliance, including continuous integration and continuous deployment (CI/CD) considerations.

Data Integrity: With increased regulatory focus on data integrity following the publication of various regulatory guidance documents (including FDA’s 2018 guidance and MHRA’s 2018 guidance on data integrity), the second edition strengthens requirements around ALCOA+ principles (Attributable, Legible, Contemporaneous, Original, Accurate, plus Complete, Consistent, Enduring, and Available).

Artificial Intelligence and Machine Learning: As AI/ML technologies begin to be adopted in pharmaceutical operations, the second edition provides preliminary considerations for validation of systems incorporating these technologies, though this remains an evolving area.

Cybersecurity: Reflecting the increased importance of cybersecurity in computerized systems, enhanced guidance addresses security considerations throughout the system lifecycle, aligning with regulatory expectations and industry standards such as NIST frameworks.

Today’s GAMP has evolved from its initial focus on validation of computerized systems in pharmaceutical manufacturing to a comprehensive guideline for quality assurance and regulatory compliance of computerized systems across the entire pharmaceutical industry. It continues to serve as the de facto international standard for GxP computerized systems, maintained by the International Society for Pharmaceutical Engineering (ISPE) and regularly updated to reflect technological advances and regulatory developments.

Conclusion

The evolution of GAMP reflects the pharmaceutical industry’s journey toward more sophisticated, risk-based approaches to computerized system validation. From its origins addressing fundamental compliance gaps in the early 1990s to its current role as a comprehensive framework addressing cloud computing, AI/ML, and modern software development practices, GAMP has continuously adapted to serve the needs of both industry and regulators. As technology continues to advance, GAMP remains a living document, ensuring that patient safety and product quality remain paramount while enabling innovation in pharmaceutical manufacturing and quality systems.