A Single Adulteration Limit for Cleaning Validation in a Pharmaceutical Pilot-Plant Environment - Pharmaceutical Technology

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A Single Adulteration Limit for Cleaning Validation in a Pharmaceutical Pilot-Plant Environment


Pharmaceutical Technology


Adulteration-based calculation

The adulteration limit was used when it was lower than the health-based limit. For development compounds in the pilot plant (7), the adulteration limit originally was calculated using the following equation:













in which UAL was the upper acceptance limit; SSA the shared surface area, MBS the minimum batch size for the equipment train, and recovery the fraction of spiked material recovered for assay. The UAL of 10 μg/g (10 ppm) cited by FDA (1) was used in various cleaning-validation programs (3, 9, 10). The SSA was the combined product-contact surface areas of the manufacturing equipment train. The MBS provided the most conservative limit because any residue would be most concentrated in the subsequent batch. The swab area of 25 cm2 was used widely (3, 7, 11, 12) in industry.

Calculation of an allowable adulteration level was a logical cleaning limit for a pilot plant but in the long term proved to be impractical. The number of factors that went into the pilot-plant production schedule, the drug-development formulations, and the residue determination made an adulteration assessment a constantly changing number.

Pilot-plant issues

Number of pilot-plant programs. The pilot plant manufactured varied formulations of numerous compounds. The programs in the pilot plant increased with new compounds and decreased as programs ceased development or were transferred to commercial manufacturing. Schedulers, formulators, equipment cleaners, analytical chemists, and quality personnel were involved. The number of programs and personnel along with the associated ARL calculations, documentation, and communication made it difficult to maintain a consistent, compliant program.

Number of new compounds. The number of new compounds entering the pilot plant was significantly greater than the number of new compounds entering a commercial manufacturing facility. These new programs had to be included in the overall cleaning-assessment program. Validating a new compound required significant analytical method development and validation. In addition, the small, early-phase manufacturing equipment was in great demand, and extended downtime for cleaning validation support was problematic.

Subsequent product. The manufacturing schedule in the pilot plant was variable. Equipment was scheduled for use several weeks in advance, but other programs sometimes took priority. Even knowing the subsequent product was no guarantee that a particular formulation was the same as the previous one manufactured for the product. Calculating an ARL based on the subsequent product manufactured in the equipment was problematic.

Current equipment train versus subsequent equipment train. The equipment train was the order in which equipment was used to manufacture a formulation. Blending, granulation, roller compaction, drying, and tablet pressing were examples of unit operations that together manufactured a clinical formulation. The ARL calculation for the equipment train assumed that the same train was used for the subsequent product. This almost never was the case in a pilot plant, which made the value of the ARL limited. An alternative ARL calculation considered each individual piece of equipment without regard to the manufacturing train. This type of ARL consideration became exceedingly cumbersome without adding increased value to the ARL process.

Formulation-development issues

Formulation changes. The formulation for each research compound evolved during development. A dry-filled capsule for a Phase I compound became a film-coated tablet in Phase II. Refinements in formulation composition also were common. Excipient levels changed to optimize the physical properties of the formulation. Formulation changes also resulted from scale-up issues. Formulation modifications often changed the ARL for the subject compound.


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