Technical barriers
PharmTech: What are the key technical barriers to implementing real-time release of a finished drug product overall?
Godec and Yourkin (GE Analytical Instruments): We believe the primarily barriers (not necessarily in order of priority) include the following:
- The inability of adopters to present a strong business justification to management that can justify the additional expenditures
necessary to do final product RTRT. The lack of strong FDA regulatory action on non-RTRT process is probably a major cause
of this. The basic business question for companies, therefore, is, Why pay the extra expense of using RTRT if a highly reliable
manufacturing process can be established without it? If FDA were to require RTRT, then there would be no business doubt.
- The analytical tools for RTRT implementation are still being developed.
- Many pharmaceutical quality systems are still focused on producing pharmaceuticals using detailed standard operating procedures,
such as recipes, temperatures, and timings with a three-batch process validation. It is difficult for many quality departments
to allow the use of flexible process controls because they require additional subject matter knowledge that is, in many cases,
unknown. Quality personnel therefore may perceive that they will have to cede control to the manufacturing department.
- There is a general lack of direct experience in RTRT projects throughout industry. Only a few pharmaceutical companies have
done the required development and research to automate unit operations (processes), which is needed to implement a finished
drug product RTRT system.
- Quite a few pharmaceutical companies are taking small steps in the implementation of automated controls and real-time sensors
within their facilities' operations. A good example is the adoption of online total organic carbon (TOC) and online conductivity
sensors for pharmaceutical waters. But even in this case, companies generally focus on the high return on investment by decreasing
the number of required laboratory samples using information provided by the on-line analyzers. The additional cost of the
required quality systems for real-time release of the TOC or conductivity water quality attribute is much more expensive and
time consuming than can be justified with the decrease in laboratory samples. There is a new ASTM E55 standard practice, Real-time Release Testing of Pharmaceutical Water for the TOC attribute. This standard may change the number of companies that perform RTRT of their water for the TOC attribute
because it addresses the technical issues involved. However, the standard does not address how to make the required quality-system
changes.
Vaisman (Malvern Instruments): In-process measurements often produce results that differ slightly from QC laboratory results. Process analytical technology
(PAT) equipment may be different from instrumentation used in the laboratory, and materials therefore, may often be characterized
in a different state as it flows through the process. Addressing the issue of specification transfer can ease the transition
of an analytical technique from development through to commercial manufacture.
In addition, RTRT often demands the successful integration of a number of analytical and manufacturing devices, a process
hampered by the lack of collaboration between equipment suppliers and the existence of few applicable standards. The relatively
new OPC Foundation's Analytical Device Integration (ADI) standard will help in this area but there is still work to be done.
Redman (Mettler-Toledo AutoChem): The key technical barrier I see is the integration of measurement technology with appropriate process modeling and control
algorithms for holistic model-based control of the critical quality attributes (CQAS) through direct manipulation of the critical
process parameters (CPPs). There is certainly room for improvement in existing measurement technologies to directly monitor
CQAS and greatly enhance RTRT capabilities. However, with sufficiently reliable control of the CPPs, RTRT does not have to
rely on relocating the quality assurance/quality control laboratory for in-line and at-line analysis. With true QbD, the burden
of testing can theoretically be reduced to a minimal level by ensuring product quality through monitoring and control of the
process itself.
Farquharson (Real-Time Analyzers): The technical barriers associated with RTRT are tied to the PAT tools being used. In addition to material property tools,
spectroscopy tools, specifically Raman, NIR, and infrared analyzers, are being used to monitor the synthesis of a drug or
determine the composition of a pill. Each has advantages and limitations.
For example, Raman and NIR can be interfaced into reactors via highly transmitting fiber optics, IR cannot; Raman and IR provide
exceptional specificity (e.g., distinguishing polymorphs), NIR less so; NIR and IR can measure trace quantities of chemicals
while Raman is typically limited to 0.1% chemical concentrations. In all cases, the variability of the measurement must be
much smaller than the variability of the process. The former depends on the dynamic range and precision of the measurement
(e.g., a spectral peak used to determine concentration that changes intensity significantly is better than an unresolved peak
that changes very little). It also depends on the stability of the analyzer. For this reason, interferometers have dominated
chemical plant installations. A shift in the x-axis, a potential problem with dispersive Raman analyzers, can result in incorrect
analysis and decision making.
The key limitation for these technologies is measurements that do not correctly represent the process or product, such as
the contents of a reactor or the composition of a pill.
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