Hypothetical ATP case study
In this example, a specific impurity "X" has been identified as a critical material attribute (CMA) of a drug substance (input
variable) that must be controlled to a level of not more than 1.0% as part of the definition of the design space for the drug
product. Through knowledge gained during the design and development phases, it has been determined that it is useful for the
process chemists to be able to accurately measure the level of this specific impurity down to a level of 0.1% with a relative
standard deviation (RSD) of not more than 10% across the range of measurements. This information essentially forms the ATP.
By sharing this knowledge with the process-development and analytical scientists during the initial phases of development,
a classical high-performance liquid chromatography (HPLC) method (Method 1) was developed, optimized, and validated to measure
the level of Impurity X in the drug substance. Method 1 was used to support registration-stability studies and was successfully
transferred under appropriate quality oversight and change-management systems to the quality-control laboratories that support
commercial manufacturing of the drug substance and drug product.
An improved method.
During the knowledge-transfer phase of the process, an opportunity for improved control of Impurity X was identified at the
drug-substance manufacturing site (Site A) and the technical-services scientists requested a shorter turnaround time for the
analytical results. Analytical scientists took this request for improvement into consideration and were able to design and
develop a fast-LC (liquid chromatography) method using recent improvements in efficiencies of chromatographic systems. Method
2 was then designed, developed, and validated to meet the original ATP as stated in the regulatory submission and met the
reduced cycle-time requirements of the process engineers and chemists. The new method would allow for improvement in the control
of the manufacturing process as well. As with Method 1, Method 2 was implemented with the appropriate quality oversight under
change management at Site A.
In addition, Method 2 was successfully transferred to Site B, where the newer technology equipment and chromatographic columns
were readily available. Unlike Site A, the drug-product testing laboratory at Site B was not required to meet a faster cycle
time. The reduction in assay time, however, freed up analyst and instrument time. Also, the use of higher efficiency LC systems
resulted in less solvent consumption and less waste.
A "real-time" method.
There is continued emphasis on process improvement in the typical life cycle of a drug substance. Improvements in process
control can often be achieved by using on-line or at-line technologies, also known as process analytical technology (PAT).
Site A was interested in pursuing this opportunity for the real-time measurement of Impurity X.
Once again, process engineers and chemists worked together with the analytical scientists, this time to investigate the use
of Raman spectroscopy for the measurement of Impurity X in the drug substance as it was off-loaded from the dryer. Raman spectroscopy
has been shown to be amenable to measurement of analytes "in" or "at" the processing line so further efforts were pursued
to determine feasibility.
Site A was able to implement Method 3, an at-line Raman method, after completion of appropriate method development, validation,
and change-management processes and procedures. An at-line Raman method could now be used to measure the level of Impurity
X in the drug substance at Site A. Meanwhile Site B used the fast-LC Method 2 to confirm the level of Impurity X in the drug
substance before manufacturing the final drug product.
Three very different analytical methods were shown to be capable of meeting the ATP set forth in the regulatory submission
document, each one with the added benefit of meeting the very specific needs of the particular business unit being supported
by the testing site.
A company similar to the one in the case study presented above that operates a pharmaceutical quality system in line with
ICH Q10 and adopts a structured risk-assessment process to ensure any new method's suitability for use, should not be required
to seek prior regulatory approval before implementing any of the three methods described because there was no change to the
ATP contained in the regulatory submission. However, a change to the ATP could be handled in an annual product update or similar
communication mechanism to the competent authority. All three methods (1—classical HPLC, 2—fast LC, 3—Raman) would have appropriate
documentation in place to be reviewed upon preapproval or routine inspections and all three were designed, developed, validated,
and implemented under well-founded quality and change-management systems. In addition, documentation would be available to
share with a regulatory agency's laboratories if needed. The methods would be appropriate for use as an example in their laboratories
for measurement of Impurity X in the drug substance.