Assessing and Mitigating Risk in a Consent Decree Environment.
Ben Venue Laboratories is a healthcare pioneer, one of the first companies in the world to use freeze-drying technology to make medicines affordable, transportable and storable, and was a leader in the large-scale production of life-saving blood plasma during World War II. Established in 1938, Ben Venue Laboratories is the sterile injectables manufacturing arm of Bedford Laboratories, a Boehringer Ingelheim company. Bedford Laboratories is one of the largest generic injectable pharmaceutical companies in the United States, offering a broad range of multisource injectables across multiple therapeutic classes. Ben Venue began an assessment of their regulatory compliance with FDA guidelines across all aspects of their organization. Controlled-environment logistics was included in their internal assessment. Modality Solutions reviewed the process and identified some key objectives.
The focus of the engagement was to:
- Create a process map the current controlled-environment logistics network to better understand risks from point of manufacture to point of use.
- Assess risk to patient safety, product quality, and regulatory compliance based on current practices as compared to FDA regulations and guidance documents published by various trade organizations (e.g. PDA).
- Document risks in a technical assessment.
- Recommend risk mitigation strategies to controlled-logistics network for identified high risks.
The approach recommended by Modality Solutions was our methodology developed from dozens of risk assessment conducted in the lifesciences industry. The approach taken for Ben Venue for the risk assessment follow:
- Map logistics network. A map of the current controlled-environment logistics network was developed. The map identified process steps, transport lanes, packaging, and product handling characteristics that drove the risk assessment.
- Conduct risk assessment of controlled-environment logistics network. The current product handling characteristics, logistics network, and packaging were assessed to identify opportunities to mitigate any patient safety, product quality, or regulatory compliance exposure. Modality Solutions incorporated their proprietary Hazard and Operability ('HAZOP') risk assessment tool developed specifically for the lifesciences industy. Using pre-selected guide words and parameters to focus the risk assessment, the high, medium, and low risks were identified and categorized in a single day.
- Document risks and mitigation strategies in a technical report. The identified risks and their likelihood, severity, and chance of detection for each risk were documented. A phased approach strategy to mitigate any high risks was designed.
After review and mitigation of the risks identified in their cold chain, eleven (11) major gaps in cGDP compliance to regulations and requirements in existing GDP procedures at Ben Venue’s distribution facility:
DELIVERABLES FOR IMPLEMENTATION
- Comprehensive risk-based assessment for CRT distribution process, including identification of any gaps in stability data, has not been completed.
- Controlled ambient (i.e. CRT) product shipping temperature ranges and any allowable exposures outside defined range have not been defined.
- Non-conformance procedures for trending and documentation of CRT temperature excursions have not been updated to comply with latest regulatory requirements.
- A process for translating package insert requirements for temperature control and a process for managing these requirements have not been established.
- Thermal packaging solutions to meet CRT temperature requirements need to be selected and qualified.
- Specifications for all critical thermal packaging components need to be created.
- Thermal packaging system for CRT products needs to be verified in the field.
- Upgrade standard operating procedures for handling CRT products.
- Pack out instructions for thermal packaging systems needs to be generated.
- Training for GDP awareness for CRT shipping needs to be conducted and tracked.
- Performance management review of critical-to-quality metrics for CRT product logistics processes needs to be implemented.
Ben Venue engaged Modality Solutions to close these gaps. The focus of the follow on engagement was to:
MEASURES OF SUCCESS
- Close all eleven (11) major gaps with appropriate assessment, qualification, procedural controls, and management review practices
- Reduce compliance risk to controlled-logistics network by improving and updating current quality management system for CRT logistics and distribution operations
- Qualify thermal packaging solutions to current Good Distribution Practices (GDP) and industry benchmarks
Progress toward the objectives were measured by:
VALUE TO BEN VENUE LABORATORIES
- Comprehensive risk-based assessment completed and all appropriate steps documented in a corrective and preventative action (CAPA) record in the Ben Venue quality management system
- Updated documents in the quality management system including discussion on acceptable shipping temperatures of CRT products and non-conformance process for documentation and trending for CRT product logistics
- Thermal packaging qualified to all current GDP and industry best-demonstrated practices
- Improved monitoring and controls for CRT distribution operations
The value of this project identified by the Ben Venue management included:
- Access to experience in preparing operations in highly-regulated distribution environments for audits from multiple jurisdictions (e.g. FDA, EMEA, etc.)
- Learning opportunity across organization to better understand current best practices in controlled-environment logistics process improvements for controlled-room temperature (CRT) products
- Mitigate identified high risks to controlled ambient (i.e. CRT) logistics network
- Ensure thermal packaging qualification and distribution operations for controlled ambient logistics has best opportunity to complete internal or external audits with no findings of observations
The detailed approach on the assistance that Modality Solutions provided to Ben Venue for the regulatory compliance risk mitigation follow:
After the approval of the PQ protocols, Ben Venue executed the protocols at their facility, with their personnel, using the pack out instructions (Step #7 in Methodology section) to complete verification.
- Conduct comprehensive risk-based assessment for CRT distribution process (Gap #1). Risk assessment is an integral part of the quality risk management process. Once risks were identified and evaluated, mitigation plans were put in place to address significant risk events. The current product handling characteristics, logistics network, and packaging were assessed to identify opportunities to mitigate any patient safety, product quality, or regulatory compliance exposure.
- Assist in defining controlled ambient product shipping temperature range and any allowable exposures outside defined range (Gap #2). Review revised US Pharmacopeia chapter <1079>, published industry and regulatory guidance, and current product stability data to define a universal shipping temperature range for controlled ambient products. Determine if any exposures outside of shipping ranges are allowable. Justify the definition allow excursions in a technical document approved by the Quality Unit.
- Update non-conformance procedures for trending and documentation of CRT temperature excursions (Gap #3).Update procedures created to ensure proper documentation, root cause analysis, and trending of issues are completed for the CRT logistics process. The documentation, root causes, and trends for CRT temperature excursions must be added to management review process to review data, approve corrective and preventative actions undertaken, and verify effectiveness of process improvements implemented.
- Establish process for translating package insert requirements for temperature control into CRT logistics processes (Gap #4). The current package insert requirements for temperature control will be reviewed and documented for incorporation into the requirements for thermal packaging qualification and distribution operations improvements. A process to translate these requirements for new products will be documented in the quality management system.
- Select and qualify up to ten (10) thermal packaging solutions based on package dimensions (Gap #5).Package insert instructions and available stability data is translated into a ‘global’ thermal control requirement (step #2), ‘off the shelf’ packaging that substantially meets requirements will be identified. The selected packaging will be qualified to regulatory requirements and industry best-demonstrated practices.
- Create specifications for all critical-to-quality thermal packaging components (Gap #6).Specifications for manufacturers on thermal packaging components will be created. These specifications are an explicit set of requirements for the components are fit for intended use.
- Create pack out instructions for thermal packaging (Gap #9). The pack out instructions will be included in the document management system to improve revision control and training. The pack out instructions will conform to requirements demonstrated in thermal packaging qualification.
- Verification of thermal packaging system (Gap #7). The qualified thermal packaging system will be subjected to three (3) verification shipments in actual transport lanes. This performance qualification (PQ) will confirm the package design performs as expected and is robust and results are reproducible.
- Upgrade standard operating procedures for handling controlled-room temperature products (Gap #8). A review of handling procedures will improve operations for minimizing, monitoring, and documenting all out-of-storage temperature events for CRT products.
- Create and conduct controlled-environment (refrigerated and CRT) awareness training (Gap #10). Written training to improve understanding and develop knowledge base for employees involved in controlled-environment logistics. Introductory and ‘refresher’ training for employees focused on the critical-to-quality attributes to maintaining compliance, product quality, and patient safety in the distribution environment.
- Implement a management review process of critical-to-quality metrics (Gap #11). Implement a review process for managers with executive responsibility to review the suitability and effectiveness of the newly defined CRT logistics quality system at defined intervals and with sufficient frequency. The review shall ensure that the quality system satisfies the requirements of the established quality policy and objectives for temperature control of CRT product in the logistics network. A method to document the dates and results of management reviews were created.