Team personnel have qualified production equipment and validated production processes for FDA approval. Their engineering experience often gives them an intuitive feel for the equipment that facilitates the validation work. They have performed both retrospective and prospective validation on various systems, and have written and prepared the final packages for a number of validation protocols. Their experience includes the following:
1.1 Abbott Bioresearch Facility Validation
CALCET Company team members were involved in the validation of a biotechnology research facility. CALCET Company wrote and executed protocols for the equipment qualification and for controlled-environment shipping studies. CALCET Company personnel coordinated activities with individuals in the United States and in Europe to complete testing execution. In addition, CALCET Company personnel prepared change control documentation for validated systems, coordinated the implementation of the changes, executed change control testing, and closed out the change control packages.
1.2 Abgenix Production Facility Validation
CALCET Company personnel provided support for the validation of a new biotechnology production facility. CALCET Company personnel generated protocols for the installation, operational, and performance qualifications for utility systems and support equipment, including:
1.3 Aradigm Laboratory Equipment Qualification
CALCET Company personnel qualified equipment used in Quality Control laboratories. CALCET Company wrote and executed protocols for heat blocks and analytical instruments. CALCET Company also reviewed the protocols and provided execution support and laboratory environmental monitoring systems. CALCET Company also reviewed a laboratory information management system for compliance with 21 CFR Part 11 and provided execution support for the management system validation protocols.
1.4 Baxter Healthcare Hayward Compressor Qualification
CALCET Company has qualified a new compressed air generation system to replace the generation system on an existing Compressed Dry Air Utility. CALCET Company generated, executed, and prepared the final package for a qualification protocol to qualify an interim compressor used to supply air while the new, permanent compressor system was being installed. CALCET has also determined the testing required tu guarantee ai quality, while the interim compressor provided air to the system. CALCET Company has also generated, executed, and prepared the final package for the IOQ and PQ protocols required to validate the new, permanent compressor system.
1.5 Baxter Healthcare Hayward Thermal Mapping Studies
CALCET Company generated, executed, and prepared final reports for equipment qualification protocols for incubetors, ovens, refrigerators, freezers, and autoclaves. CALCET Company executed thermal mapping studies and calibrated thermocouples on Kaye-Digi monitoring devices. CALCET Company executed sterilizer cycles using biological indicators and summarized the results for final package preparation. CALCET Company also trained and supervised production people on the calibration and use of the Kaye-Digi thermal mapping devices.
1.6 Baxter Healthcare Hayward HVAC Validation
CALCET Company performed testing, take measurements, and analyzed data for the HVAC systems Class 100,000 and Class 10,000 manufacturing areas. CALCET Company analyzed the airflow patterns in the Test Balance Reports, reviewed the data from QC monitoring procedures, and prepared final reports for the performance of the HVAC system in the manufacturing areas for over one year period.
1.7 Baxter Healthcare Hayward Gap Analyses and Cleaning Studies
CALCET Company reviewed existing validation documents, prepared reports detailing the gaps in the validation protocols, and developed and proposed corrective action plans to resolve the gaps. CALCET Company executed and prepared final reports for Performance Qualification protocols for fermentation and purification processes. CALCET Company executed and prepared final reports for cleaning studies that tested the efficacy of various cleaning solutions. CALCET Company supervised manual cleaning per the appropriate SOPs, took samples for QC testing, summarized test results, and prepared the final cleaning packages. CALCET Company prepared reports detailing the results of quality testing for WFI systems and prepared quarterly reports in support of the master validation plan.
1.8 Bayer Pharmaceutical Discrepancy Investigations
CALCET Company performed discrepancy management and investigation work for a fermentation facility. CALCET identified the most probable cause for failure, the impacted product lots, and the corrective actions for the discrepancies. CALCET Company also evaluated the effect of discrepancies, determined any trend(s) present due to discrepancies in the facility, and developed and implemented the corrective actions as part of the discrepancy management procedures.
1.9 Baxter Healthcare Hayward Database Qualification
CALCET Company reviewed and trained on database software used to track metrology data and discovered a bug that violated 21CFR Part 11 (Electronic Records/Electronic Signatures). CALCET Company analyzed the software for compliance to 21CFR Part 11 and reported the findings to the software manufacturer and to the validation department. CALCET Company reviewed and executed the manufacture’s validation protocol and prepared the package for approval.
1.10 Bayer Pharmaceutical Qualification of Fermentation and Purification Equipment for KG-3 Clinical Trial
CALCET Company generated and executed validation protocols (IQ, OQ, PD, and PQ) for the fermentation, purification, filling, and freeze drying processes of the KG-3 project. This large-size, fast track project required a daily schedule update and a continuous interaction with QA, Validation, Process Science, and Project Engineering personnel. The equipment qualified included:
1.11 Baxter Healthcare Hayward Revalidation/Requalification Support
CALCET Company is involved in the ongoing process of revalidation/requalification effort of process equipment at Baxter Hayward. CALCET Company is performing gap analyses on existing process equipment validation protocols in order to determine potential deficiencies, develop validation strategies, and prepare revalidation documents to address those deficiencies. CALCET Company generated and executed requalification protocols for autoclaves, freezers, and incubators. CALCET Company performed thermal mapping testsas part of protocol execution and reviewed the final packages prior to routing for approval.
1.12 Baxter Healthcare Thousand Oaks Facility Validation
CALCET Company was involved in the CV/IQ/OQ/PQ of process equipment for an rAHF expansion facility. CALCET Company executed protocols, reviewed protocol execution, and prepared the final packages for equipment located in the Cell Culture and Purification areas. The equipment included but was not limited to:
1.13 Bayer Pharmaceutical Albumin-Free rFVIII Process Development
CALCET Company developed process development protocols for the cell culture and filling/freeze drying of albumin-free rFVIII. CALCET Company has prepared protocols to evaluate the effect of process input parameter changes on the quality of the final output streams. CALCET Company has also prepared Batch Production Records and SOPs for the production of albumin-free rFVIII under the direction of the Process Sciences department.
1.14 Bayer Pharmaceutical Albumin-Free rFVIII Equipment Qualification
CALCET Company has generated and executed equipment IOQ protocols for the qualification of equipment to be used in the preparation of clinical lots of albumin-free rFVIII. The IOQ protocols cover equipment including autoclaves, fermenters, and chromatography skids.
1.15 Bayer Pharmaceutical B49 Plasma Facility Retrospective Validation
CALCET Company performed retrospective validation for the existing plasma production facility in Building 49. CALCET Company successfully executed
1.16 Bayer Pharmaceutical B60 Licensing Support for Purification Process
CALCET provided licensing support for Building 60 Purification Process Validation of rFVIII-SF. CALCET Company was responsible for the preparation of the Technical Registration Dossiers (TRDs) for the purification equipment and process. These documents summarized and described the equipment and the validation protocols (IQs, OQs, PDs, and PQs) for the process including the cleaning protocols. The equipment described in the TRDs included:
1.17 Bayer Pharmaceutical B60 Process Performance Qualification of the KG-2 Purification Process (30 MMU Scale)
CALCET Company’s personnel have executed the process performance qualification for a total of five test lots from UF-TCF through the KG-2 purification process to UF/DF, bagging, blast freezing, bulking, final filling, and freeze drying. Consistency of process parameters such as flow rate, linear velocity, column volumes and rFVIII IU/mL of gel was verified based on process validation for each run. Test results were verified against the QA acceptance criteria and comparability to 7-11 MMU clinical lots was demonstrated on key parameters such as purity, yield, integrity, potency, and elution profiles. Fold-clearance was used as an alternate means to evaluate results for the purposes of 30 MMU scale comparability testing. The Analysis and Conclusion Section of the report included the Analysis section, List of Validated Parameters, the Summary of Relevant Acceptance Criteria and Actual Results from the Validation Testing and the Conclusion for the test lots addressed in the PPQ. The support test data/documentation included the QA Test Results Comparison to 7-11 MMU Scale, QA Trends Data, DCS Trends, Elution Profiles, Process Parameters for Each Purification Step, Columns Scale Summary, and Chromatography Skid Reports.
1.18 Bayer Pharmaceutical B60 Facility Validation
CALCET Company’s personnel has provided expert consultation for the generation of the IQ/OQ/PD protocols for critical process systems and were responsible for:
Equipment IQ execution on all validated utility systems and on the automated chromatography skids
System OQ execution on the chemical dilution and CIP skids
Process Development of buffer-to-purification transfer lines, and purification tanks
CALCET Company has also reviewed and provided input on the generation of production SOPs/BPRs and preventive maintenance SOPs.
1.19 Bayer Pharmaceutical B60 PLC Software OQ Execution
CALCET Company has led the execution of all CIP system software OQs using the Allen-Bradley PLC. This effort included:
Review and revision of the CIP System Design Description (SDD)
1.20 Bayer Pharmaceutical B60 Control System OQ Execution
CALCET Company has been responsible for the chromatography control system software OQ execution. Methods were developed and tested to ensure compliance with the Software Design Description. A signal generator was used to simulate the various instrumentation alarm conditions. Password protection, event logs, data archival and retrieval, and historical and realtime trending were verified.
1.21 Bayer Pharmaceutical B60 CIP Process Development
CALCET Company’s personnel were responsible for the automated CIP Process Development Validation. The scope included PD/PQ protocol generation and execution. Cycle setpoints were established for chemical once-through and WFI once-through cleaning cycles for transfer lines, and fixed and portable tanks. CALCET Company executed all phases of this effort including soiling, cleaning, and aseptic sampling.
1.22 Bayer Pharmaceutical KG-2 Purification Buffer Preparation and Transfer PQ
CALCET Company’s personnel have developed large-scale buffer preparations Process Performance Qualification (PPQ) protocols for the KG-2 purification process. CALCET Company personnel participated in the execution of the buffer preparation PPQ and provided input to batch production record development. CALCET Company’s personnel have also prepared and participated in the execution of the buffer storage and transfer PPQ.
1.23 Biogen Inc. Control Systems Qualification
CALCET Company personnel documented and validated the installation and implementation of a Eurotherm PLC for the CIP system of a biotechnology pilot plant and the subsequent scaled-up manufacturing plant.
1.24 Biogen Inc. Installation Qualification
CALCET Company personnel executed the IQ protocols for a biotechnology production plant. Team members field verified the plant P&IDs and confirmed the correct installation of plant equipment, including fermenters, fixed tanks, and CIP systems.
1.25 Biomarin Pharmaceutical Inc. QC Laboratory Equipment Qualification
CALCET Companyqualified the Quality Control Department laboratory equipment, which included:
Sample Analysis: HPLC systems, Gas Chromatography systems, and Spectrophotometry systems
Sample Storage: Refrigerators, Freezers, Incubators, and Water Baths
1.26 Biomarin Pharmaceutical Inc. Purification Equipment Qualification
CALCET Company performed the qualification of the purification process equipment for the Clinical Trial Production Pilot Plant for the MPS-I, which included:
1.27 Cell Genesys Inc. Production Facility Validation
CALCET Company provided support for the validation of a new biotechnology production facility. CALCET Company personnel provided support for commissioning activities supervised by the project engineers. CALCET Company personnel generated and executed protocols for various systems, including:
1.28 Genentech, Inc., C2B8 Process Validation
CALCET Company’s personnel have prepared validation protocols for Tangential Flow Filtration (TFF) harvest system and anion and protein-A chromatography systems involved in the initial purification of the chimeric monoclonal antibody C2B8, marketed as Rituxan/RituxiMab. This product is targeted for patients with low-grade non-Hodgkin’s lymphomas. Protocols included developing checklists for Installation Qualification (IQ), Control System Qualification (CQ), and Operational Qualification (OQ) including cleaning validation for the harvest system in accordance with approved Genentech Standard Operating Procedures. CALCET Company reviewed IQ documentation, test procedures, and test forms associated with CQ testing, to ensure completeness and accuracy, remove redundancy, maintain consistency within framework of cGMP requirements. The OQ testing included a process operational test performed during a mock as well as additional cleaning validation. Together with Process Science, CALCET Company was able to correct a concentration factor calculation in the TFF system that effectively used skid automation without operator having to induce diafiltration. CALCET Company has prepared the validation summary reports for regulatory review on a multi-product basis.