PAT for Pharmaceutical Cleaning

Since its introduction several years ago, the process analytical technologies (PAT) initiative of the U.S. Food and Drug Administration (FDA) has inspired significant reassessment of manufacturing practices in the pharmaceutical industry. Unlike other industries, pharmaceutical producers have been reluctant to adopt cutting edge process control technologies for fear of resistance from FDA and o...

04/01/2007


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FDA on process analytical technologies

Since its introduction several years ago, the process analytical technologies (PAT) initiative of the U.S. Food and Drug Administration (FDA) has inspired significant reassessment of manufacturing practices in the pharmaceutical industry. Unlike other industries, pharmaceutical producers have been reluctant to adopt cutting edge process control technologies for fear of resistance from FDA and other regulatory agencies. The PAT Guidance published in September 2004 clearly indicates FDA’s interest and commitment to development and deployment of advanced technologies for process control that improve product quality and provide savings to consumers by reducing manufacturing costs. Following this path envisioned by FDA involves innovation that yields benefits to manufacturers and consumers through enhanced scientific- and engineering-based process understanding.

So how can PAT be used in the control and ongoing monitoring of equipment cleaning processes, and what are the benefits? Answering these questions requires defining the critical control parameters associated with CIP (clean in place) processes and then analyzing the potential resource savings made possible by more effective cleaning process control.

 


Instrumentation selection and placement for a CIP system are straightforward. All devices can be contained within the system skid for easy access.

Cleaning: control parameters

The critical control parameters for pharmaceutical process equipment cleaning include temperature, concentration, contact time, and energy input. Control of these factors within scientifically determined boundaries provides the basis for the operation of cleaning cycles that are effective, repeatable, and reliable.

Cleaning solution temperature is critical because the cleaning rate is directly proportional to it for many pharmaceutical residues. As cleaning solution temperature increases, phenomena which are directly proportional to the cleaning rate increase, including chemical reaction rates and residue solubility. With increased cleaning solution temperature, phenomena that are inversely proportional to cleaning rate decline, including chemical bond strength and solution viscosity. All this makes temperature control and monitoring a critical factor in the cleaning cycle performance.

Cleaning agent concentration is directly proportional to the cleaning rate for many pharmaceutical residues. As concentration increases, the chemical reactions used for equipment cleaning accelerate. However, while higher concentrations enhance cleaning efficiency, they may also require more extensive rinsing volumes and time. Thus, balancing washing time, concentration, and rinsing time makes the control and monitoring of the cleaning agent a critical factor in overall cleaning cycle performance.

Cleaning solution contact time determines the duration of chemical and physical reactions involved in removing post-production residues from equipment, which is directly proportional to cleaning efficacy. The longer the contact time, the more effective the cleaning cycle, but this is not without cost because time spent cleaning is time not spent in production. Because of these factors, the control and monitoring of cleaning solution contact time is critical for optimal cleaning cycle performance.

Cleaning solution turbulence and impingement are functions of the external energy put into the cleaning solution in the form of turbulence and impingement. These actions are critical for post-production residue removal. The transport phenomenon employed is mass transfer, and since the rate of mass transfer is directly proportional to turbulence (typically reported as a Reynolds Number) higher levels of turbulence generally result in higher cleaning rates. This makes the control and monitoring of cleaning solution turbulence a critical factor. For residues removed by impingement cleaning, the pressure at the contact point between the cleaning solution and the equipment surface is a critical factor. Often CIP solution supply pressures or flow rates are measured and controlled as a means of assuring consistent external energy input for each cleaning operation.

A thorough understanding of each of these critical control parameters and their interactions, with respect to process specific post-production residues, is important as data generated from residue removal studies are an essential component in the development of meaningful high/low alarms, or boundary conditions related to failure. Employing PAT for pharmaceutical manufacturing equipment cleaning processes control requires scientifically established boundary values for cleaning solution temperature, cleaning agent concentration, cleaning solution contact time, and cleaning solution turbulence and impingement. Without this information, using PAT would be very difficult and ineffective because the underlying foundation of PAT is the high level of process understanding that these data provide.

To generate data, residue removal studies are often conducted in a laboratory (see photo) using samples of representative post-production residuals deposited on coupons fabricated to match the materials and surface finish of typical production equipment. Alternatively, data may be collected during production operations at pilot or full scale, but this approach is often less controlled and more expensive than laboratory data. Because it is impractical to use on-line instrumentation to measure surface cleanliness in real time, collected residue removal data provides the basis for modeling cleaning system performance. This allows effectiveness assessment of automated cleaning cycles using indirect measures, such as cleaning solution temperature, contact time, turbulence, and cleaning agent concentration instead of direct methods involving ongoing surface sampling.

Cleaning process control strategy

After establishing critical control parameters, effective control strategies are devised to ensure that cleaning processes operate within established boundary conditions described above. A typical pharmaceutical process CIP system (see graphic) is equipped with instrumentation required to provide key cleaning process data to implement PAT. These instruments include a supply-side temperature sensor TET1, a supply-side high-range conductivity sensor AET1, a supply-side flowmeter FET1, a supply-side pressure sensor PET1, a return-side temperature sensor TET2 and a return-side low-range conductivity sensor AET2. Each has its function with respect to controlling critical cleaning parameters:

Supply and return temperature sensors TET1 and TET2 ensure that the cleaning solution is within boundary value ranges established from residue removal studies. Two temperature sensors are required as the supply-side instrument TET1 is used to provide input to control the heat exchanger steam supply, which heats the cleaning solution delivered to the equipment being cleaned. The return-side instrument TET2 is used to ensure the cleaning solution temperature is within boundary value ranges at the coldest location (worst case) in the system.

High-range conductivity sensor AET1 is typically a 0-100 milli-Siemens/centimeter conductivity sensor, and used to ensure that the cleaning agent concentration is within boundary value ranges. A conductivity, rather than pH sensor is used for this task, because conductivity is relatively linear with concentration of bases and acids typically used for pharmaceutical equipment cleaning. This sensor is installed on the cleaning system supply side where it can monitor both recirculated and single pass cleaning cycles.

Supply-side flowmeter FET1 and pressure sensor PET1 ensure that cleaning solution turbulence is within boundary value ranges established from residue removal studies. The flowmeter FET1 provides input to modulate the supply pump speed which controls the cleaning solution flow rate as it is delivered to the equipment being cleaned. Combining flow rate and pressure sensor PET1 data provides a more complete picture of the cleaning solution turbulence than either measurement alone. With data from both, it is easier to spot problems downstream, such as residue accumulation and plugging.

Low-range conductivity sensor AET2 is typically a 0-100 micro-Siemens/centimeter sensor and ensures that the purity of the final rinsing water is in accordance with established limits for clean equipment. A conductivity sensor is used for this task because conductivity is a criterion established in the U.S. Pharmacopeia (USP) for evaluating water purity and because many cleaning agents and some post-production residues are conductive and easily detected by this instrument. This conductivity sensor is installed on the return side of the cleaning system as this is the point of maximum surface area contact, making it a worst-case location.

The control system uses input data from these instruments to formulate and deliver cleaning solutions to the pharmaceutical manufacturing equipment system being cleaned. The control system also monitors each of the instruments for stable operation within boundary value ranges, and begins counting cleaning solution contact time once all of the instrument inputs are within prescribed ranges. Any deviations from the established boundary value ranges should stop the timing and trigger appropriate alarms.

Ongoing monitoring, assessment

The instrumentation and control algorithms described control cleaning processes to set points within scientifically established boundary values. Collected instrument data are trended and used to evaluate the performance of each cleaning operation in real time. Trended data may be analyzed using statistical techniques against data from previous operations. These analyses can form the basis for accepting a given cleaning operation, and also for ongoing analyses of cleaning system robustness and detecting drift of critical process parameters. This is important because through the use of PAT, re-qualification of cleaning systems can be based on events, such as drift in one or more of the critical cleaning parameters, rather than an arbitrarily established time period.

Using PAT for control and ongoing evaluation of cleaning processes for pharmaceutical manufacturing equipment provides significant advantages, including more robust cleaning operations with the capabilities of real time evaluation and assessment. The cost of implementing PAT for most automated pharmaceutical cleaning systems is related to data collection and analysis tools, which are becoming relatively inexpensive and readily available. The enhancements made possible by implementing PAT can result in substantial benefits to manufacturers and consumers in the form of cost reductions and increases in product quality.


Online Extra

Bibliography

FDA, “Guidance for Industry PAT- A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance.”

FDA, “PAT Team & Manufacturing Science Working Group Report,” 2004

Brunkow, R. et. al., “Cleaning and Cleaning Validation: A Biotechnology Perspective,” PDA, 1996, pp. 48-51.

Davis, J.R., and Wasynczuk, J., “The Four Steps of PAT Implementation,” Pharmaceutical Engineering, January/February 2005, pages pp. 10-22.

Heinze, C.L. and Hansen, J.R., “Implementing PAT Step by Step as a Process Optimization Tool,” Pharmaceutical Engineering, May/June 2005, pp. 8-16.

Shunayder, L. and Khanina, M., “Equipment Cleaning-In-Place in Modern Biopharmaceutical Facilities: Engineering Concepts and Challenges,” Pharmaceutical Engineering, January/February 2005, pp. 58-72.

Seiberling, D.A., and Hyde, J.M., “Pharmaceutical Process Design Criteria or Validatable CIP Cleaning,” Cleaning Validation, An Exclusive Publication, Institute of Validation Technology, 1997, pp. 58-72.


Author Information

John M. Hyde is CEO and founder, JM Hyde Consulting Inc. Peter K. Watler, Ph.D., is VP west coast operations, and Keith Bader is director of quality and technical systems. Reach them at jmhcinfo@jmhyde.com ;


FDA on process analytical technologies

“Pharmaceutical manufacturing will need to employ innovation and cutting-edge scientific and engineering knowledge with the best principles of quality management to respond to the challenges of new discoveries (e.g., novel drugs and nanotechnology) and ways of doing business (e.g., individualized therapy, genetically tailored treatment). Regulatory policies must also rise to the challenge.”

“Manufacturers are encouraged to use the latest scientific advances in pharmaceutical manufacturing and technology.”

Guidance for Industry PAT- A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance , FDA, September 2004

“Only companies that achieve a high level of process understanding will have the opportunity to justify a more flexible regulatory path.”

PAT Team & Manufacturing Science Working Group Report , FDA, 2004



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