CALCET  Company

Process Engineering Experience

CALCET Company Team personnel have provided engineering services in support of production for existing manufacturing facilities. They have worked on a variety of facilities, ranging from decades-old plasma production operations to state-of-the-art biotechnology plants.

The Team can help qualify similar facilities after performing process engineering work. Their familiarity with the equipment, which often stretches back to the design phase, allows them to qualify and validate the systems in record time. This familiarity also aids them in training personnel in the operation of the equipment.

The Team has worked in the field to trace the source of production problems, and has engineered novel solutions for these problems. They have provided support for facility startup, reverse engineering of existing facilities, project management, and failure investigation. Their process experience has included the following.

2.1 Baxter Healthcare Plasma Facility P&ID and PFD Development

The Team recently completed the generation of a complete set of Piping and Instrumentation Diagrams (P&IDs) for the plasma fractionation facility in Glendale, CA. This work included:

● Complete walkdown of systems and equipment;

● Development of the Use-Matrix strategy for the representation of non-dedicated process equipment;

● Development of a consistent and accurate equipment numbering system;

● Development of symbology to represent unique process equipment.

The Team has also developed a set of P&IDs for the other production areas in the plasma facility. They have developed the Process Flow Diagrams (PFDs) and Process Flow Summaries (PFS) for the AHF-M purification process, and have put together a database which would allow Baxter personnel to access all specifications of the AHF-M production process online. This database may eventually be expanded to include all products manufactured by the facility.

2.2 Bayer Pharmaceutical -35 ˚C Cold Storage Room Startup and Engineering Checkout

CALCET Company's initial scope of work was to provide startup support for the cold room.  However, since the desinger of refrigeration system had not engineering capabilities to produce the as-built P&IDs  and PFDs, CALCET Company was asked to develop these drawings.  CALCET Company has produced eight size "D" as-built drawings for the entire refrigeration system, air handling units, and make-up air system, including all the air duct system and the disecant wheel de-humidifier.  Then, CALCET Company has provided the required start-up support for the entire cooling system and performed the installation and operation engineering checkout to prepare the system for validation.

2.3 Bayer Pharmaceutical rFVIII-SF Expansion Engineering Checkout

CALCET Company is in the process of commissioning equipment for an expansion of Bayer's rFVIII-SF production plant.  CALCET Company has completed ECOs for equipment including process tanks, chromatography skids and columns, ultrafiltration skids, bench-top instruments, and scales.

2.4 Bayer Pharmaceutical Lyophilizer Startup Support and Engineering Checkout

CALCET Company provided engineering startup support for a lyophilizer used for the preparation of rAHF product.  CALCET Company evaluated the design of the lyophilizer installation, the supporting refrigeration, and the vacuum equipment.  CALCET Company was responsible for change control documentation of the project, and interfaced with QA, Validation, Regulatory Affairs, Production and Engineering to ensure control of the project.  CALCET Company performed field walkdowns to verify vendor documentation matched as-built configuration and revised the P&IDs to match the as-built configuration.  CALCET Company developed the test functions for and executed the Engineering Checkout of the system, and prepared the Turnover Package.  CALCET Company allso authored the preventative maintenance SOP for the lyophilizer and its supporting equipment.

2.5 Bayer Pharmaceutical Plasma Fractionation Facility Reverse Engineering

CALCET Company has completed a value added engineering work for the plasma fractionation facility in Clayton, North Carolina.  This work included:

● Complete walkdown of systems and equipment;

● Development of P&IDs using the Use-Matrix strategy for the representation of nondedicated portable equipment;

● Determination of current equipment specifications through contact with vendors and manufacturers;

● Development of current equipment and instrumentation lists;

● Development of equipment specification sheets;

● Compliance to current Good Manufacturer Practices (cGMP) as detailed by the Code of Federal Regulations, Title 21;

● Evaluation of process equipment;

● Development of a database containing the data from the field Engineering Summary Reports (ESRs);

● Process improvement.

2.6 Bayer Pharmaceutical B60 Engineering Support

The Team has provided a variety of services to Bayer in an effort to fast track design, Startup, and validation of critical facilities and systems.

The Team provided support for the procurement/installation of process equipment, functional testing of critical systems, and construction Startup. They helped develop production and preventive maintenance Standard Operating Procedures and Batch Production Records (SOPs/BPRs) and performed Engineering Checkouts (ECOs) on all utility systems and on a number of critical process systems including:

● Automated Clean-In-Place Skids for Media Preparation, Clarification/Concentration, Buffer Preparation, Purification, and Fermentation systems;

● Fixed and Portable Tanks, including:

● Thaw and Staging Tanks,

● DEAE Chromatography Eluate Collection Tank,

● Viral Inactivation Tank with Associated Heating Station;

● Transfer Equipment, such as Peristaltic Pumps, Filters, and Weigh Stations;

● Ultrafiltration Skids

● Fixed Tanks, Agitators, and Load Cells;

● Purified Water System;

● WFI Stills;

● WFI Storage and Maintenance Loop;

● HWFI and CWFI Distribution Loops;

● Tower Water;

● Plant Steam and Condensate;

● Cold Glycol System;

● Chemical Dilution Storage and Distribution;

● Process Gases (Liquid N2 , O2 , CO2 , Process Air);

● Fermentation Neutralization Drain System.

In support of construction, functional testing, and Startup, the Team performed system analyses and seismic analysis/qualification on two as-built tanks which had been modified from the original design to comply with Zone IV requirements. The analysis applied finite element methods to the Unified Building Code load definition and ANSI/ASME acceptance criteria.

During system validation, the Team developed a number of novel solutions to problems, such as:

Water Hammer Mitigation

A strategy was developed to eliminate air-blow-induced water-hammer during CIP operation. A soft-start procedure was developed to attenuate water hammer due to water-column separation and rejoining. A procedure was also developed to preclude water-hammer phenomena in WFI and Purified Water Systems, eliminating the frequent burst of system rupture discs.

Nonlinear Temperature Compensation

A nonlinear correlation for acid and caustic conductivity temperature compensation was developed for the CIP skids to allow the use of a single conductivity probe.

Flow Control Strategy

An expression for determining the controllable flow rate range for any CIP delivery drop was developed using linear regression techniques.

Viral Inactivation Thermal Cycle

A two-step heating cycle was developed for viral inactivation in a 4° C cold room environment. A series of jacketed and insulated components were designed and validated to eliminate cold spots.

2.7 Bayer Pharmaceutical Factor VIII Fermenter System Startup

The Team provided engineering support in the startup and installation of the production fermenter systems. Dissolved oxygen, pH, and temperature were controlled through a plant wide DCS system. The testing included: OQ execution, gas system operation, CO2 flow control, the mixed air/O2 flow characteristics, gas diffusion mass transfer coefficient Kla measurement, heating system operation, weight control, and vibration performance on inclined settlers. Calibration of peristaltic media, harvest, and recirculation pumps were confirmed. The results of the tests were documented for each fermenter system.

2.8 Bayer Pharmaceutical B49 Plasma Facility Reverse Engineering

The Team performed reverse engineering work for the plasma production facility in Building 49. This value added engineering work included:

● Complete walkdown of systems and equipment;

● Conception of the Use-Matrix strategy for the representation of non-dedicated portable equipment;

● Development of P&IDs;

● Determination of the complete production procedure for PFD development;

● Development of PFDs for fractionation, centrifugation, ultrafiltration, diafiltration, pasteurization, and cryo – precipitation;

● Determination of current equipment specifications through contact with vendors and manufacturers;

● Development of equipment and instrumentation lists;

● Development of equipment specification sheets;

● Compliance to current Good Manufacturer Practices (cGMP) as detailed by the Code of Federal Regulations, Title 21;

● Evaluation and replacement of process equipment;

● Development of a database containing the data from the field Engineering Summary Reports (ESRs);

● Generation and revision of equipment preventive maintenance SOPs;

Process improvement.

2.9 Bayer Pharmaceutical PCS Engineering Support

The Team personnel has provided project management services to execute the PCS portion of Bayer Corporation capital and infrastructure projects. The project included master plan, scope definition, estimating, appropriation request (AFE), scheduling, engineering, design, installation, cost control, Startup support and checkout. The Team personnel prepared CSRs, SDDs, STPs, IQs, OQs, PDs, PPQs, and instrument calibration procedures and developed software concepts for control. The Team personnel assisted in manpower planning and evaluated and selected engineering contractors. The Team was frequently involved with the development of PCS concepts for complicated projects, evaluation of manpower planning and cost to maintain PCS budget and the interpretation of standards, polices and procedures. The Team personnel reviewed and revised software test plans for the ABB MOD 300 DCS at Bayer. These projects included:

● KG-2 Expansion Project;

● Cold Purification Chromatographic Column Inlet Control;

● Portable Column Area Flowmeters;

● 200 L Fermenter Upgrade.

2.10 Bayer Pharmaceutical B60 Thermal Mapping

The Team personnel participated in an extensive temperature mapping effort of the Viral Inactivation Tank. The Team designed a custom thermocouple tree that allowed mapping of the tank’s internal components and product inventory. Kay DIGIs were programmed to provide alarm messages and reports. Pre- and Post-Calibration was performed on Type T thermocouples. A thorough knowledge of heat transfer was instrumental in identifying cold spots and hot spots within the tank environs.

2.11 Westinghouse Hanford Company, Resolution of Surveillance for Suspect Bolts Installed in the 105 KWest Basin Roof Addition Structure

Department of Energy (DOE) Nonconformance Report (NCR) No. PAD-BDW-95-004 was addressed by an analysis of laboratory test results (chemical composition, proof load, wedge tensile load to failure, and Rockwell hardness) for a lot sample inspection in accordance with ASTM A325 Paragraph 9.3.3 and 9.3.4. The sample size was established considering the requirements of ASME/ANSI B18.18.1M through 4M for Level A inspection and quality assurance for fasteners. The confidence in the sample inspection plan was demonstrated based on ANSI/ASQC Z1.9-1980 for the reduced inspection Level II with variability unknown and range method (sample size n=7 and AQL=0.15%). The inspection plan demonstrated that the quality assurance of all tested specimens were within the limits imposed by ASTM A325 for Type 1 high strength bolts. The sample inspection procedure is a standardized procedure which is largely applied and well known for quality assurance of process product such as: plates, shapes, fasteners, pipes, etc.