By Christophe Massip, marketing manager, binders, and Brian Carlin, Ph.D., global manager, pharmaceutical R&D, FMC Corp.
What is PAT?
One of the FDA definitions of PAT is: “a system for designing, analyzing and controlling manufacturing through timely measurements (during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.” [1]
The advantages of PAT include:
- Reduction of production cycle times
- Reduction/prevention of rejects, scrap or reprocessing
- Faster release of products
- Facilitation of continuous processing
- Improved efficiency and reduced variability
- Increase in production capacity.
The FDA considers PAT to be critical to efforts for improving pharmaceutical industry manufacturing efficiencies and ensuring superior product quality.
PAT is the new rule of the game
The pharmaceutical industry is currently facing more challenges than ever before. Competition is fierce and continues to intensify. Pharmaceutical firms, whether research-oriented, generic or OTC, can no longer rely exclusively on research and new product launches to deliver shareholder value.
A greater emphasis on cost control has become essential and the industry is now focusing on optimizing both production and the utilization of capital-intensive facilities. In other words, manufacturing efficiencies now offer the greatest cost savings potential for pharmaceutical companies.
This has not always been the case. It is generally fair to say that, due to the regulatory constraints under which pharmaceutical companies operate, manufacturing efficiencies are relatively low compared to other industries.
Non-pharmaceutical industries have been reaping the benefits of PAT for years, while pharmaceuticals, operating under regulatory oversight, have been unable to realize similar advantages. Recognizing this adverse impact, the FDA issued a draft guidance document in September 2003, which was finalized in October. This document, “PAT—a Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance,” allows pharmaceuticals to explore PAT more fully.
Most pharmaceutical companies, eager to take advantage of this opportunity, are now investing in PAT . We view PAT as the vehicle that will boost manufacturing efficiencies to the next level, by establishing new rules for the game of modern pharmaceutical production.
How will PAT impact the future of pharmaceutical manufacturing?
We imagine that 10 or 20 years from now, many OTC or prescription drugs will be produced continuously and that most quality control will be completed on-line in a non-destructive manner, on PAT-validated production lines, with non-parametric release. PAT will allow the pharmaceutical industry to deliver superior asset utilization and financial value for shareholders.
PAT is here to stay
Many in the pharmaceutical industry may think that PAT is the latest trend-- a new approach that will fade away in a few years. FMC, however, believes that PAT is here to stay. As evidence, consider the unprecedented cooperation between the FDA, the pharmaceutical industry, suppliers and academia.
To ensure successful implementation, the FDA’s Advisory Committee for Pharmaceutical Science has created a PAT subcommittee represented by all sectors. [1] The creation of the ASTM Technical Committee E55 on Pharmaceutical Application of PAT is an additional piece of evidence. PAT is, indeed, here to stay and regulatory authorities are creating infrastructures to ensure its successful implementation.
FMC BioPolymer’s experience with PAT
For many years, FMC BioPolymer has utilized PAT in Avicel® PH production, at
For instance, Malvern laser diffraction technology, a type of PAT, has been used for many years to make quick and precise particle size measurements. Both sites also utilize on-line technologies to monitor and control the process, ensuring consistency and compliance with product specifications.
On-line technologies enhance process understanding and control of variability. They also help increase process capability to industry leading standards. Below is an example of how these PAT technologies have helped FMC achieve outstanding process capability results, as expressed by the Capability Index Cp.
Table 1 shows the capability indices for several Avicel® PH quality parameters. The capability index Cp states how many times the process can fit inside the specification, being the ratio of the specification limits to 6s. A higher Cp means a greater probability that the process will meet customer requirements. A value above 1.5 is considered very good. Values above 2.5 are considered outstanding.
Table 1
|
| Particle size D50 Avicel PH-101 2003 | Degree of Polymerisation (2001-2003) | Ether Soluble Substances (2001-2003) |
| No. of samples | 2000 | 1600 | 500 |
| Monograph Specifications | Label parameter only | NMT 350 | NMT 5mg/5g |
| FMC Specifications | 40-60 microns | 210-270 | NMT 5mg/5g |
| Average | 47 microns | 225 | 0.40 mg/5g |
| STDV | 1.94 | 4.0 | 0.33 |
| Cp Value (FMC specs.) | 1.71 | 2.5 | 2.52 |
STDV, Standard Deviation
NMT, Not More Than
Cp, Capability Index
PAT and pharmaceutical excipients
There are various ways to obtain higher manufacturing efficiencies. One strategy is the implementation of “just-in-time” manufacturing, which drives the reduction of raw material inventories. Consequently, over the last decade, the pharmaceutical industry has demanded more from their excipient and/or API suppliers.
In addition, consistent quality has become paramount for the pharmaceutical industry. In such a highly regulated environment, current manufacturing processes allow limited flexibility to cope with the raw material fluctuations which can generate quality issues and batch failures. The value of Avicel® PH and other high quality excipients to the pharmaceutical industry is directly correlated with supplier capability to consistently produce the same quality.
Tomorrow, PAT initiatives could potentially correct small variations in excipient variability. Nevertheless, many think that PAT, when used to control incoming raw materials, will add another layer to the quality requirements imposed upon excipient and API suppliers. PAT will demand more consistent raw materials in terms of conventional physical and chemical specifications and will also impose new demands in terms of the PAT signature of these raw materials. If a PAT signature of a raw material is critical to process control consistency, the raw material will be subject to new layers of scrutiny. Therefore, it is logical to think that PAT will not decrease the current level of quality requirements of excipients, but rather increase it.
Future PAT-validated processing will be more efficient than current batch processing. However, it will also become increasingly cost-prohibitive to fail during production since PAT allows quick added-value accumulation throughout the production line. Production failures at the end of a batch process will cost very little compared to production failures in continuous processes. The much greater cost of downtime on a continuous (as opposed to batch) process, coupled with failsafe PATs, will make any interruption due to raw material quality totally unacceptable.
New collaborations
FMC BioPolymer has found that pharmaceutical companies are interested in partnering with excipient suppliers to increase product consistency for new PAT applications. Recently, GSK and Mathis Instruments [5] have reported the use of thermal effusivity to measure excipient lot-to-lot consistency. Effusivity is related to a material’s ability to transfer heat, and is a function of a powder composition as well as particle size, particle size distribution and density. Because of the influences of these physical properties, effusivity values differ for each grade of Avicel®, even though they are chemically indistinguishable. This creates an opportunity for effusivity to be used in identifying incoming raw materials. Also, by monitoring the variability in effusivity measurements on several lots of Avicel®, it is possible to determine its consistency compared to other excipients or other sources of microcrystalline cellulose. The chart below shows consistency as a low relative standard deviation (RSD). A value of 5 is normally acceptable. RSDs below 1 demonstrate outstanding consistency.
Thermal effusivity -- Inter-lot variabilityfor commonly used pharmaceutical excipientsProduct Mean of 3 Lots SD RSD
Avicel® PH-101 369 2.14 0.58
Avicel® PH-102 353 1.20 0.34
Avicel® PH-105 336 0.38 0.11
Avicel® PH-112 382 2.16 0.56
Avicel® PH-200 355 1.70 0.48
Avicel® PH-302 449 1.75 0.39
Ac-Di-Sol® 308 3.00 0.97
Conclusion
It is difficult to predict how PAT will influence excipients manufacturing in the future. However, it is certain that PAT is changing the pharmaceutical industry. PAT appears to be the most recent tool for increasing product quality while delivering superior asset utilization and financial value for shareholders.
The authors will be delighted to share additional views, information and data with pharmaceutical manufacturers.
Christophe Massip Brian Carlin, PhD
Phone: +1 (215) 299 6835 Phone: +1 (609) 951 3741
[email protected] [email protected]
References:
- Process Analytical Technology and ASTM Committee E55 by Christopher Watts, PH.D., Ali Afnan, PH.D. and Ajaz Hussain, PH.D.
- PricewaterhouseCoopers Consulting, Pharma Manufacturing “Why there is a need to improve The role of PAT” by Dr. Doug Dean, PWC Consulting 2001.
- FDA, “PAT—a Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance”, September 2003.
- FMC Quality LIMS data,
Cork Newark - Mathis Instruments “A Novel Technique for Determination of Real Time Blend Uniformity Using Thermal Effusivity,” Satish Dipali1, Christina Chandler2, Ligi Mathews1, Prasad Adusumilli1,
Stanley Nancy Parsippany ,NJ 07054 New Brunswick ,Canada E3B 6C2
