US FDA has made significant strides in designing and implementing programmes to manage the quality of pharmaceuticals with a more systematic approach. The Quality Systems Working Group, formed at the launch of the initiative, was dedicated to enhancing the consistency and predictability of FDA's approach to production quality and safety assurance among centers and field components.
Quality Systems Framework
The Quality Systems Framework WG has developed a standard quality systems framework that integrates and enhances the Agency's existing and planned internal quality programmes. This quality systems framework was created to ensure quality and consistency of reviews, inspections, and other regulatory activities. The framework provides common vocabulary and required system elements. Elements include typical quality systems requirements, such as ensuring that there are process plans with written procedures; well-trained staff; record keeping and review; knowledge sharing and coordination; and continuous process and product evaluation and improvement.
The Quality Systems Framework for Internal Activities was approved by the FDA Management Council and incorporated into the FDA Staff Manual Guides to demonstrate executive commitment and to ensure Agency-wide implementation of quality systems approaches. To provide Agency-wide advice regarding the implementation of quality systems, the Management Council chartered a new subcommittee on July 1, 2004, the Quality Resource and Guidance Team (QRGT). The Quality Systems Framework emphasizes customer identification as a critical step in developing quality awareness and quality system effectiveness.
In addition to the FDA quality systems work that is already underway discussed earlier, other important projects are being undertaken using the new FDA Quality Systems Framework:
" Warning Letters for CGMP-related issues
" Recalls
" Pharmaceutical Inspectorate
" PAT initiative
Quality Systems Guidance Development
The draft guidance Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations is intended to provide recommendations on how to meet the requirements of the CGMP regulations while using a comprehensive quality systems approach to the manufacturing of human and veterinary drugs, including biological drug products.
This draft guidance provides a contemporary framework for implementing quality by design, continuous improvement and risk management in the drug manufacturing process. The guidance, along with the flexibility of the CGMP regulations, allows manufacturers to implement modern quality systems in their manufacturing operations in a manner that is tailored to their specific manufacturing environment. The resulting robust quality system may serve to lower the need for regulatory oversight, allowing for more efficient, focused inspections and less review oversight.
Quality principles are inherent in the CGMP regulations. However, the regulations do not fully delineate the means by which quality is achieved during the manufacture of pharmaceuticals. The elements that make up this approach intertwine with the basic principles of CGMP and are instrumental to successful pharmaceutical development and manufacture.
GMP Harmonization Analysis
As part of the initial announcement in 2002, FDA indicated that the CGMP regulations for pharmaceutical products (21 CFR parts 210, 211) "appear to provide a degree of flexibility to allow the Agency to shift the emphasis to a science-based, risk management approach." However, the evaluation of comments from the May 1996 proposed drug CGMP amendments will continue, and consideration will be given to revising these regulations and others (e.g., 21 CFR 11) in the future.
The GMP Harmonization Analysis Working Group was charged with the challenging task to, "Perform a formal analysis of 21 CFR 210 and 211 against: EU GMPs, PIC/S and other CGMP regulations across the Agency," the goal being "to call out the differences and benchmark against those to determine the value of adding to or changing the current 210 and 211 regulations."
The working group, comprising members from CBER, CDER, CDRH, CFSAN, CVM, ORA and the Office of Combination Products, assigned the comparisons accordingly:
" CBER, CDRH, and ORA members compared 210/211 with 820
" CDER members compared 210/211 with the EU GMPs
" CVM members compared 210/211 with 226 and compared it looking the opposite way, from 226 to 210/211
" CFSAN members compared 210/211 with Juice HACCP while an ORA member compared Juice HACCP with 210/211.
" A CFSAN member also compared 210/211 with 110/111.
The working group determined that the EU GMPs and the PIC/S GMPs were virtually identical, in base requirements, although the EU GMPs are more comprehensive. The group concluded that there are many more similarities than differences among the various regulations, and, where differences do exist, they are often related to the commodity in question. Although a number of differences were identified between Parts 210/211 and the main EU GMPs, most were not considered substantive.
To reinforce the Agency's decision stated earlier in this report, based on the analysis of this working group, FDA will take an incremental approach to modifying parts 210/211, while pursuing international harmonization through ICH and PIC/S. The ultimate goals of the modifications will be to encourage timely detection and response to emerging defects or indications that product quality has been compromised; to provide further clarity and modernize the regulations; and to harmonize various aspects of parts 210/211 with other Agency regulations, and regulations of our international counterparts.
This working group will carefully consider comments on the draft Quality Systems guidance as well. The Agency will review those concepts in light of the many comments submitted to the proposed rule, more recent scientific and technical advances, and quality systems principles in going forward with rulemaking to incrementally modify parts 210/211.
Process Validation
FDA has begun updating our current thinking on validation under a Cross-Agency Process Validation workgroup led by CDER's Office of Compliance Coordinating Committee with participation from CDER, CBER, ORA and CVM. The CPG stresses the importance of rational experimental design and ongoing evaluation of data. The document also notes that achieving and maintaining a state of control for a process begins at the process development phase and continues throughout the commercial phase of a product's life-cycle. The CPG incorporates risk-based approaches with respect to inspectional scrutiny; use of advanced technologies, and by articulating more clearly the role of conformance batches in the product life-cycle. The document clearly signals that a focus on three full-scale production batches would fail to recognize the complete story on validation.
GMP/Good Guidance Practices
On August 4, 2004, FDA implemented a new approach to providing timely guidance on cGMP-related questions on human, animal, and biological drug products. This approach enables more widespread dissemination of cGMP information and provides more transparency of FDA policy concerning cGMPs. Guidance will be provided in a question and answer format.
Agency guidance represents the FDA's current thinking on a specific topic (21 CFR 10.115). It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach can be used if the approach satisfies the requirements of the applicable statutes and regulations. Inquiries for information concerning a specific guidance document, should be directed to the originating office.
Related Activities
In conjunction with all of the CGMP activities, FDA hosted an internal seminar series for all FDA units involved in the regulation of pharmaceuticals. This series was entitled Quality Systems and Risk-Based Approaches and their Application to
FDA Pharmaceutical Product Quality Regulation.
(Extracted from Pharmaceu-tical cGMPs for the 21st Century - A Risk-Based Approach; Final Report - Fall 2004 by Department of Health and Human Services US Food and Drug Administration)