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White Paper - Application of FDA Current Good Manufacturing Practices
- 1. Quality and Regulatory Compliance Solutions Camp Hill, PA miampietro@msn.com 1 Application of FDA Current Good Manufacturing Practices (CGMPs) For Drug/Drug Delivery "Combination Products Quality and Regulatory Compliance Solutions Mark Iampietro 01-15-2017
- 2. Quality and Regulatory Compliance Solutions Camp Hill, PA miampietro@msn.com 2 Application of FDA Current Good Manufacturing Practices (CGMPs) For Drug/Drug Delivery "Combination Products" Definition of "Combination Products" The FDA views drug or biologic products that are intended for use only with a specified device either physically combined as a single entity, e.g. prefilled syringe or auto-injector, or packaged together in a single package, co-packaged, e.g. inhalers, auto-injectors, pumps, as combination products. The drug and device are both constituent parts of the combination product and as the drug provides the primary mode of action; the pharmaceutical manufacturer is responsible for regulatory compliance of the product. Daunting Task of Regulatory Compliance Can Be Simplified for "Combination Products" As such, drug companies with "combination products" must comply with the FDAs Quality Systems Regulations, 21 CFR 820, in addition to the drug CGMPs.21 CFR 210/211. This may seem a daunting task at first, but with the pragmatic approach suggested below, it may be accomplished by simply augmenting the existing drug quality system, thereby significantly minimizing resource allocation and training requirements. Recommended Process to Narrow Potential Regulation Requirements The first recommendation is to create a matrix or list referencing which of the medical device Quality System Regulations are already addressed by the existing quality systems drug based standard operating procedures. If the quality system in place is already fully compliant with the drug CGMPs, this matrix should indicate that only a few incremental requirements exist that must be addressed with new procedures for "combination products". These requirements should be 820.20 Management Review, 820.30 Design Controls, 820.50 Purchasing Controls, 820.100 CAPA (Corrective and Preventive Actions), 820.170 Installation and 820.200 Servicing. "Installation And Servicing" Regulations Compliance Typically Don't Apply. For most companies, Installation and Servicing will not apply as these requirements are only applicable when a device specifically requires installation or where servicing is a specific requirement of the device.
- 3. Quality and Regulatory Compliance Solutions Camp Hill, PA miampietro@msn.com 3 We are then left with the requirements for Management Review, Design Controls, Purchasing and Corrective and Preventive Action (CAPA). As a "combination product" manufacturer these processes must be embedded into your end to end regulatory compliance. Management Review, Purchasing Controls, and Corrective and Preventive Action (CAPA), although not requirements of the drug CGMPs, are typically addressed in some fashion through Good Business Practices (GBPs). The fundamental requirements for "Management Review" are that: 1) Management with executive responsibility must establish a quality policy and ensure that it is understood, implemented and maintained throughout the organization; 2) An appropriate organizational structure to ensure product quality is established; 3) Quality Metrics must be established and monitored at defined intervals by senior management with executive responsibility to review the suitability and effectiveness of the quality system. The fundamental requirements for Purchasing Controls are: 1) Requirements for the product and quality must be established and met by all suppliers; 2) There must be a documented system to evaluate and select suppliers based on their ability to meet the specified requirements; 3) The type and extent of supplier controls based on the above evaluation results shall be defined and documented; In addition there shall be a record of acceptable suppliers usually referred to as an Approved Supplier List (ASL) and where possible supplier agreements shall be established to ensure the manufacturer is notified of any changes to the product or service, Reference 820.40. The fundamental requirements for CAPA (Corrective and Preventive Action) are that there are established procedures for implementing corrective and preventive actions. These procedures shall include the requirements for: 1) Analyzing quality data from such sources as work operations and processes, audit reports, complaints, returned products, and other quality problems utilizing appropriate statistical methods; 2) Investigating the root cause of nonconformities relating to product, processes and the quality system; 3) Identifying the actions needed to correct and prevent recurrence of quality problems;
- 4. Quality and Regulatory Compliance Solutions Camp Hill, PA miampietro@msn.com 4 4) Verifying the corrective and preventive actions to ensure they are effective; 5) Recording and disseminating this information to those responsible for assuring product quality and Management Review. The Major Gap Is "Design Controls". Design Controls typically represent the largest gap in compliance for pharmaceutical companies as they transition to be "combination product" manufacturers. The fundamental requirement of Design Controls is that there are established procedures defining the product development process. These procedures shall include: 1) The development of formal design plans describing the resource allocations and responsibilities for design development; 2) A mechanism for addressing incomplete, ambiguous or conflicting design requirements; 3) Design input requirements shall be documented and approved; 4) Adequate evaluation of design output requirements in terms of conformance to design input requirements; 5) Design output requirements shall be documented and approved. In addition to these requirements, the manufacturer shall establish procedures that ensure: 1) The formal documented review of the design results are planned and conducted at appropriate stages of the designs development - these reviews shall ensure that participants at the review include representatives from all functions concerned with the design stage being reviewed as well as an independent reviewer; 2) Design verification shall confirm that the design outputs meet the design input requirements; 3) The results of design review, design verification and all pertinent development information to demonstrate that the design was developed in accordance with the approved design plan and regulatory requirements were met shall be documented in the design history file (DHF); 4) Design validation shall be performed under defined operating conditions to defined specifications on initial production lots or their equivalents - design validation shall ensure that devices conform to defined user needs and intended uses and may require Human Factors studies in addition to the clinical studies required for drug development; 5) Formal design transfer of the design to the Device Master Record (DMR) and lastly;
- 5. Quality and Regulatory Compliance Solutions Camp Hill, PA miampietro@msn.com 5 6) Design changes are identified and validated or as appropriate verified and approved before their implementation. Summary The potential compliance gaps in a cGMP compliant drug quality system, when transitioning to a cGMP compliant combination product quality system are: Management Review, Design Controls, Purchasing Controls, Corrective and Preventive Action, Installation and Servicing. Of these "combination product (single entity and co-packaged drug delivery devices plus a drug)" requirements, Installation and Servicing will likely not be applicable in most cases and given common Good Business Practices (GBPs) Management Review, Purchasing Controls and Corrective and Preventive Action are typically already addressed in some fashion within the existing quality system for drugs. This leaves Design Controls as the area likely requiring the most work in bridging the gap to fully compliant combination product quality system.