Why Early Evaluation Of Process Parameters Matters In OSD Scale-Up

By Katie Anderson, Chief Editor, Pharmaceutical Online

For oral solid dose (OSD) manufacturers, technology transfer often becomes an exercise in managing uncertainty. Differences in equipment, blending conditions, material properties, and tooling design can introduce challenges that may not become apparent until later-stage development or even commercial scale-up.

According to Amit Sharma, senior formulation scientist at Adar Pharmaceuticals, many of those challenges can be mitigated by thoroughly understanding formulation attributes and process parameters long before a product reaches tech transfer.

"When I was involved in development, I understood how to evaluate it, what things needed to be considered, and what challenges I might face," explained Sharma. "I had to dig through all of the process parameters and critical attributes of all the challenges we might face."

That perspective became particularly valuable when evaluating two formulations for development (an Alzheimer's formulation and a smoking cessation product), which became the research base for the poster Sharma and his team presented at PharmSci 360.

"The client came to us at the stage of submission, so we were limited because it had already been developed," he explains. "We just had to do the tech transfer and get what they wanted. Tech transfer is a big field, and it has its own challenges."

Blend Uniformity

For dry-blend formulations, maintaining blend uniformity is one of the most critical process considerations.

Unlike wet granulation processes, dry blending requires direct mixing of active pharmaceutical ingredients (APIs) and excipients, making material characteristics especially important.

"For these dry-blend formulations, we mix the API and excipients without an additional process such as wet granulation," added Sharma. "We need to evaluate material properties, including particle size and density, and select excipients that mix uniformly with the API and maintain that uniformity throughout the process."

The consequences of poor blending can extend directly to finished-product quality.

"Achieving blend uniformity can be challenging, but it is the first step in building confidence in the content uniformity of the finished tablets or capsules," he says. "If the blend shows substantial variability, there is a greater risk that the finished dosage forms will fail content uniformity testing."

Sampling Strategy Matters

Evaluating blend uniformity is only as effective as the sampling method used to measure it.

Sharma's team found that different formulations required different sampling approaches depending on flow characteristics and dose levels.

The Alzheimer's formulation presented poor-flow challenges that complicated sampling.

"We needed a sampling thief that could consistently collect the target sample weight and provide representative samples for assay testing," continued Sharma.

The team evaluated a Powder Tip sampler but found the poorly flowing blend could not consistently enter the collection chamber.

"Powder did not flow into the sampler sufficiently to achieve the target sample weight," explained Sharma "Collecting too little powder can increase variability."

Instead, the team selected a standard dosator sampling thief that collected material more reliably from the challenging blend.

The smoking cessation formulation posed a different challenge. While flowability was better, the low-dose nature of the product meant small losses of material could significantly affect analytical results.

"Even a small amount of blend loss could increase variability," added Sharma. "We needed to collect the target sample weight and obtain reliable assay results without losing API."

Both sampling devices under consideration met blend-uniformity requirements, but one demonstrated superior consistency.

"Although both samplers passed, the UD-Cohesive sampler's more consistent sample weights and recovery closer to 100% made it the better choice for this formulation," said Sharma.

The lesson, according to Sharma, is that passing results alone do not necessarily identify the best sampling method for future scale-up activities. Consistency and recovery can provide additional confidence when moving between scales.

Using The Kushner Factor To Support Scale-Up

Among the tools Sharma uses to compare blending performance across different manufacturing scales is the Kushner factor.

While mixing time and rotational speed remain key process variables, the Kushner factor incorporates additional parameters that can become significant during scale-up.

"Standard practice is to establish the blend mixing time and rotational speed," noted Sharma. "The Kushner factor also accounts for blender volume and headspace, the space available for the blend to move."

Because larger equipment rarely operates under identical conditions to development-scale machinery, manufacturers often need a way to determine whether different operating parameters still create comparable blending environments.

"Achieving a similar Kushner factor during scale-up gives us confidence that the mixing conditions are comparable, although we still need to validate the results," he explained.

The calculation becomes particularly valuable when moving between drastically different blender sizes.

"A small blender might run at 25 rpm, while a 300-liter bin blender runs at 10 rpm," said Sharma. "Comparing the Kushner factors helps us assess whether the different operating conditions provide comparable mixing conditions."

For challenging formulations, the approach provides an additional framework for developing scalable process parameters before manufacturing larger batches.

Evaluating Tablet Tooling Early

Process development does not stop at blend uniformity. Tablet tooling can also become a critical factor, particularly when manufacturers encounter sticking or picking during compression.

"When we encounter sticking or picking, we first check material properties such as melting point and moisture content that could contribute to the problem," explained Sharma. "If those properties are within acceptable ranges and do not explain the issue, we evaluate the tooling design."

One project highlighted how subtle tooling features can create significant manufacturing problems.

"Sharp edges in a logo can create vulnerable areas, sometimes called peninsulas, where picking is more likely to occur," he explained.

In one case, the team identified a problematic area located within an embossed logo.

"We observed picking at a sharp edge near the middle of the '3' logo," noted Sharma.

Rather than focusing exclusively on formulation changes, the team modified the tooling design itself.

"We modified the logo to give it a more gradual slope rather than a sharp edge," he says. "We also changed the steel used for the tooling. Together, these changes resolved the picking issue."

The experience reinforced a principle Sharma believes developers should adopt early.

"The key lesson is to evaluate potential tooling problems early in development rather than discover them at a later stage."

Small Tooling Changes Can Have A Big Impact

While major tooling redesigns are uncommon, Sharma says small modifications frequently help improve manufacturability.

"Sometimes with tapering or peninsula features, when we have sharp slopes, we'll adjust the design to create steeper or more gradual transitions," he said.

Other common adjustments include reducing embossing depth, increasing logo width, or slightly raising embossed features to reduce localized stress.

"We'll reduce the depth, raise the logo slightly, and sometimes increase the logo width as well so we don't create excess stress in that specific area."

Material selection for the tooling itself can also affect performance.

"We often change the steel grade because higher chromium content generally performs better," explained Sharma.

He points to chromium-rich tooling materials as a way to reduce sticking and picking issues.

"Compared to S7 steel, M330 contains significantly more chromium, and that additional chromium helps minimize sticking and picking problems."

The Tech Transfer Mindset

Ultimately, Amit believes successful technology transfer depends on understanding both the science and the manufacturing process long before commercial production begins.

"For tech transfer, it's always challenging because we don't have much room to make changes during development," he says. "Our job is really to bring the process over and compare what was done at the sending site with what we can do at the receiving site."

That means evaluating equipment differences, blending parameters, formulation characteristics, and tooling considerations as early as possible.

"Every site has different challenges," he says. "We have to look at whether we have the same equipment, the same dimensions, and the same setup, because those factors can play a critical role."

His biggest takeaway from the work is straightforward.

"It's always better to understand your formulation and process as early as possible," said Sharma. "Take the time to identify and evaluate the critical attributes of all your excipients and assess the process upfront."

With timelines tightening and development costs continuing to rise, manufacturers can no longer afford to discover critical process issues late in development.

"If we evaluate those factors during development, it definitely helps ensure we're meeting all the critical quality attributes of the product and achieving the desired outcome the first time," he says. "Saving time is very important, but efficiency can't come at the expense of quality."

For OSD manufacturers navigating scale-up and technology transfer, that philosophy may be the most important process parameter of all.