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Immediate-release tablet scale-up
 
Q: What should we do if the scale-up batch for our immediate-release tablet fails dissolution?
 
A: John Facemire, Recro Gainesville, says:
 
imageTo answer this question, I'll describe the troubleshooting process that our scientists used when they faced with this scenario. In this case, the scientists were in the process of scaling up an immediate-release tablet for a customer's first-to-file, abbreviated new drug application (ANDA). The process included aqueous high-shear granulation with a poorly soluble active pharmaceutical ingredient (API), and the product was being scaled up at the same site location where the formula and process had been developed.
 
At pilot scale, the formulation and process were successful, and the in vitro testing data all matched the reference listed drug (RLD). When the scientists transferred the formulation to commercial scale, the in vitro testing for the scale-up batch showed a 10 percent drop in dissolution compared to the prior pilot-scale batches. While there is always the potential for minor changes in dissolution results when transferring from small scale to larger scale, a 10 percent decrease is significant. There had been no indication during the process scale-up that a problem would occur.
 
With the anticipated filing date only a few months away, this problem threatened to derail the schedule and cause the customer to miss the opportunity to be first to file for the generic. Losing first-to-file status would result in reduced market share and the loss of the six-month exclusivity period, significantly impacting the company financially.
 
The scientists looked at a number of possible causes for the out-of-spec dissolution results. The most obvious was a change in the API. However, investigation revealed that the API had come from the same vendor lot for both the scale-up and pilot batches, so the API seemed unlikely to have caused the change in dissolution. They reviewed the excipients—binder, filler, granulating agent, and disintegrant—for possible differences, but each excipient was the same grade and had come from the same supplier and distributor for both batches. That identified the process itself as the major factor for the dissolution variation.
 
The granulation moisture content was the same for both batches, and granulation flow was comparable. All physical testing for the product blend was similar, including the bulk density, tapped density, and particle size. The amount of disintegrant in the formula was at a sufficient level for an immediate-release tablet and was not a concern for the decrease in dissolution.
 
Another possibility the scientists considered was over-lubrication with magnesium stearate or, alternatively, over-blending of the lubricant. They completed blend studies for the finished granules and determined that the lubricant level and mixing time were not causative factors influencing dissolution during scale-up.
 
The scientists then reviewed the design of the equipment used during pilot-scale and scale-up processing and confirmed that the high-shear and tumble mixers had similar designs. Additionally, the scale-up, high-shear mixer used a tip speed similar to the pilot scale mixer's, together with a comparable granulation endpoint, along with a comparable granulation end-point determination. However, the scientists' previous experience suggested that, for high-shear granulation with a poorly soluble API, it's sometimes necessary to reduce the relative amount of binder solution in the formulation as the batch size increases.
 
Based on that knowledge, they made an additional pilot-scale batch with a reduced amount of binder solution to see if it would impact the dissolution while still producing an acceptable tablet. The experiment showed that using less binder solution produced comparable dissolution results and yielded a comparable final tablet. Having achieved good results from the new pilot-scale batch, they produced a second scale-up batch using the reduced relative amount of binder solution. The resulting tablets met the product's dissolution specifications.
 
Because of the scientists' prior experience and thorough investigation, they were able to solve the problem and produce finished tablets that met all the required specifications. While the reformulation caused a slight delay, the customer was still first to file, and the product became very successful.
 

 
John Facemire is process engineer IV at Recro Gainesville, Gainesville, GA. The company provides oral solid dosage form development, regulatory support, clinical and commercial manufacturing, and packaging and logistics services to the global pharmaceutical market. For more information, contact the company.
 
Do you have a question for our experts? Send your questions to pwright@cscpub.com, and we'll have an expert answer them.
June 22, 2020
 
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