Expanding CIP System Functionality to Meet FDA Requirements
What do this cow and these lips have in common? Hint: It improves the lips' appearance but does little for the cow.Televised events, such as the Grammys or Academy Awards, show the public more than a few "baby boom" entertainers still sporting Generation-X faces. If we asked how they do it, they might tell us it's their relationship with their personal trainer, a vegetarian diet, or yoga.
What do this cow and these lips have in common? Hint: It improves the lips' appearance but does little for the cow.
Televised events, such as the Grammys or Academy Awards, show the public more than a few 'baby boom' entertainers still sporting Generation-X faces. If we asked how they do it, they might tell us it's their relationship with their personal trainer, a vegetarian diet, or yoga. But their real ally against time, gravity, or 'bad-face' genes is often super-purified bovine collagen.
Collagen is an animal protein found in the subcutaneous (just beneath the skin) tissues of all mammals-though it is particularly abundant in cows. Collagen is a safe and easily injected tissue thickener used in cosmetic and remedial medicine. Its most common cosmetic uses are to enhance lip borders and fill in wrinkles due to aging or injury. It is also used in sphincter resizing as a treatment for stress-induced incontinence. Because it has few side effects, is of 'natural'' origin, and relatively inexpensive, collagen competes favorably with more invasive alternatives such as surgery.
On the surface-no pun intended-producing collagen is simple. Medical products company, McGhan Medical (Fremont, Calif.), gets some cowhides, removes the hair; chops the hide into fine pieces, soaks them in a series of emulsifiers at the right temperatures for the right amount of time. This mixture is then centrifuged to separate the collagen from the soup, which is then purified to specification, packaged in disposable syringes, and shipped to physician customers.
Once a batch is complete, the process equipment must be thoroughly cleaned before a new batch can be started. Interestingly, the Clean-In-Place (CIP) procedure gets the same amount of attention as the rest of the process by the U.S. Food and Drug Administration (FDA).
Taking the high road
Because McGhan Medical needed to meet FDA product safety requirements consistently, it decided against a minimally functioned CIP control system for its collagen manufacturing line. McGhan opted for as much control and data acquisition capability as possible that could be easily supported by its in-house staff and third-party suppliers. The new CIP monitoring and control system was expected to meet the following criteria.
Ensure that the CIP system works reliably, rendering the process vessels and piping molecularly spotless after every product run-or alarm loudly if it isn't second.
Verify CIP reliability by documenting the system's operational and production history, and archive this information in FDA-acceptable formats for periodic comparisons with original IQ/OQ benchmark documentation. (See accompanying sidebar.)
Allow for process expansion to include new products or increased product outputs.
Multiple (as many as 10) wash and rinse cycles are required to thoroughly remove leftover material from 36 locations in the process piping and vessels. Each location, which can range from a 2-ft pipe section with a 2-in. diameter to a 1,000 gal tank, requires its own set of cleaning recipes. The key component in the rinse cycles is water pure enough for human injection or Water For Injection (WFI).
Critical CIP parameters controlled include pressure, temperature, flow, and solution conductivity (mS or
This Clean-In-Place process has four parts.
Step one -the CIP system performs a test WFI rinse cycle to ensure safe piping installation and proper valve orientation. The control system monitors required parameters, alarms any nonconformance, validates the configuration, and triggers the next step.
Step two -piping and tanks are washed with a low-concentrate acid solution. During this cycle, the system precisely measures the amount of solution used and its electrical conductivity. If the conductivity threshold is met, the control system advances the CIP to the next step. If not, this step is repeated.
Step three -piping and vessels are neutralized and cleaned with steam-heated caustic solution. The control system now monitors this solution's temperature, conductivity, and flow rate. When all parameters are satisfied, the system moves to the next step in the cycle.
Step four -this last step is a series of WFI rinses, monitored for time and conductivity. Steps one through four are repeated as long as conductivity values indicate process residue or nonconforming pH levels.
Flexibility in an inflexible world
System security is vital in pharmaceutical manufacturing. Maintaining security while increasing flexibility may seem oxymoronic, but flexible security is just what McGhan wanted. Hence the project's system integrator, DST Controls (Benicia, Calif.), designed into the system three levels of critical access security. Each security level (administration, engineering, or operation) allows only personnel logged-in and cleared for that level to perform associated actions. All critical operational changes require someone from each security level to be on hand. Additionally, a database stores every authorized and unauthorized system login or logout.
For additional safety, alarms report system failures, hardware failures, process warnings and failures, and system-resource (CPU load, archive space, etc.) warnings. On one screen, alarms display chronologically by importance and system-impact. Alarm acknowledgements, and when-cleared, are also logged into the alarm database. Report capability includes daily summary, user logins, alarms, messaging, process and batch data, and user activities.
In case of system malfunction, unsafe conditions and unknown states are prevented by the system's ability to trigger specific behavior for each control system level. These levels include the I/O modules, PLC, operator stations, including the computer system, its power source, data storage, and printer. Additionally, the system is designed to execute a series of actions (status check of sensors, valves, and pumps) that prepare the process for a safe and efficient restart in case of an in-process shutdown.
The system's PLC continually monitors the PC's 'heart beat.' If, for any reason, the PLC doesn't sense the PC's presence, ordered shutdown is commenced so that the process won't continue without FDA-required data acquisition. In case of power failure, an uninterruptible power supply provides a minimum of five minutes of continued system power. This allows a safe shutdown, prevents data loss, enables storage of current configuration data, and properly auto-configures various I/O devices for the eventual re-start.
Help and communication
The CIP system is equipped with messaging, on-line help, user prompts, and 'entry validity checks.' This support structure leads users through correct operation, assists in training new staff, and minimizes 'pilot error' and consequent shutdowns. As messages prompt users through necessary process steps and advise them on current system conditions, the HMI system's embedded safety interlocks prevent users from overlapping (covering) a more critical screen with a less critical one. This is especially helpful on those rare occasions when 'stuff really happens.'
The control system also performs validity checks of process values and user-entered set points. For example, if a set point entered by a user is out of range, the system rejects the entry and restores the default value. The user is then notified on-screen with an explanation of the rejection. All attempted invalid entries and process values are logged and reported.
Additionally, DST Controls provided complete FDA-ready validation packages for the IQ and OQ. These packages included test protocols, formal change control procedures, and factory and site-acceptance tests for installation and operation.
An Intellution (Norwood, Mass.) Fix Dynamics package tracks 300 tags via 20 process screens, including alarm, login, tending, and recipe selection screens. A Microsoft Visual Basic application interface sends data to and from a Microsoft Access database, serves as data acquisition software, and provides an operator interface for the recipe engine.
The Rockwell Automation/Allen-Bradley (Mayfield Heights, O.) SLC 505-based control system, for CIP functions, consists of 350 analog and digital I/O points. PLC communications with the I/O screens, remote I/O modules, and the manufacturing process are through Data Highway 485 and Ethernet communications. The PLC executes variable recipes, monitors alarm conditions, and controls output devices.
The Microsoft Windows NT- based system maintains data generated by the process and runs on an Intel Pentium 300 industrial computer with 256 Mb RAM and two redundant 800 Mb (RAID-1) hard drives. The visual interface is handled by two color touchscreens mounted in custom NEMA-4X stainless steel panels. A redundant second screen allows remote CIP start/run/stop and monitoring from the manufacturing process' clean room.
So, what do this cow and these lips have in common? For patients in need, or those just aesthetically so inclined, collagen products manufactured using this system offer a less invasive alternative to the surgeon's scalpel or laser knife. In either case, this control solution ensures that alternative is safe - and provides the data to prove it.
Read Hayward is vp of operations and Mike Shulim, engineeing director, for DST Controls, a systems integrator located in Benicia, Calif. Bruce Watts is project leader for McGhan Medical, a medical products manufacturer, located in Fremont, Calif.
Protecting the medical consumer
Two regulatory mechanisms the U.S. Food and Drug Administration (FDA) uses to ensure pharmaceutical product quality and safety are the Installation Qualification (IQ) and the Operations Qualification (OQ).
IQ requires complete documentation of all system components immediately upon installation. This 'photograph' of the physical system becomes the process benchmark to which the FDA holds the user responsible. Once the IQ documentation or 'validation' has been submitted to the FDA, any component change requires all parts of the affected system to be revalidated.
OQ dictates that all software functions and instructions are also reduced to a defining documentation package to be approved and archived by the FDA. As with the IQ, no functional OQ changes can be made without voiding FDA approval and triggering a new validation process before sellable product can be run. This micro-scrutiny ensures that once a pharmaceutical process is proven to consistently produce acceptable (i.e., safe) product, it is not allowed to drift out of its FDA-approved configuration, which could call output quality into question.