Establishing effective dose.
The effective dose of an API was unknown when clinical trials began. Dose levels could cover several orders of magnitude
for early clinical trials. The results of the ongoing trials determined the dose for the next phase of testing and the eventual
market-dose level. Formulations of early-development compounds had different dose levels and batch sizes. The amount of API
in a formulation had a direct effect on the ability to clean the equipment. Therefore, cleaning could be assessed after every
batch, based on the API factors involved.
Scale-up.
Each clinical trial required a larger batch size than the previous trial, which necessitated equipment with a larger capacity.
The physical interactions of the formulation components for larger batches often resulted in changes to the formulation or
required a different type of manufacturing equipment. Each time the batch size or the equipment train changed, the ARL was
reassessed.
Adulteration-determination issues
Effect of small batch size or unit operations.
In the pilot-plant environment, initial batch sizes were very small, often on the order of several hundred grams. Calculating
an ARL based on the smallest batch size reduced the cleaning limit to a low level and potentially affected a Phase II compound
manufactured just before a Phase I compound. Similarly, calculating an ARL for each individual piece of equipment in the manufacturing
train resulted in very low cleaning limits for small surface-area equipment.
Rather than calculate the ARL for every clinical batch manufactured, certain assumptions were made to generalize the equation.
The most conservative assumption used the minimum batch size for the equipment. This assumption made the generalized ARL lower
than a specifically calculated ARL under most circumstances.
The adulteration limit calculation was the following:
Table II: Product-contact surface areas (SSA) for typical equipment trains by phase.
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Table II shows the product-contact surface areas for a typical equipment train for Phase I (small), Phase II (medium), and
Phase III (large) formulations. Table III shows the range of ARLs for a constant UAL of 10 μg/g, a swab area of 25 cm2 , and a recovery of 100%. The calculated adulteration limit varied from 17 to 216 μg/swab for the same compound, depending
on the manufacturing train. The adulteration limit varied from batch to batch for the same compound, making reassessment a
routine occurrence.
Table II: Product-contact surface areas (SSA) for typical equipment trains by phase.
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The variable adulteration limit also brought into question the value of the calculated limit to the overall cleaning program.
For small batches, the limit was far below the 10 μg/g level. For larger batches, the calculated adulteration limit was greater
than the visually clean level, thus making it obsolete.
Analytical limits.
High-performance liquid chromatography and total organic carbon methods were used most frequently. Each analytical test method
had very low detection limits, either in the ppm or ppb range. Analytical limits were lower than the calculated health-based
and adulteration-based limits. On the basis of instrumental capabilities, the use of analytical limits was considered for
the adulteration limit.
Using 0.1% of the subsequent API as the adulteration limit was not appropriate. The 0.1% limit, determined during release
testing, was intended for qualifying impurities that were associated with the manufacturing process or related compounds,
and not for extraneous impurities caused by cross-contamination. Acceptance limits should reflect the capability of the cleaning
processes (13).
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