In-process controls and PAT

PharmTech: The pharma industry is paying increased attention to in-process controls and process analytical technology (PAT). What are the challenges of applying these methodologies to multilayer tablets over standard single layer tablets?

Behrens (IMA Kilian): PAT systems based on transmission or reflection are seldom used on monolayer tablets. The amount of validation is high, and even more complex for bilayer or multilayers. It is also difficult to repeat the measuring results on each layer. The industry has to put more efforts into this issue.

Kirsch (Natoli): PAT is best used during development to understand the variables involved in achieving the formulation design for a quality tablet. Transferring the PAT methods to manufacturing is necessary only when the information generated by the measurements is required to achieve the necessary process control to deliver the desired product. However, PAT measurements can provide information for feedback control, which can offer the manufacturer an opportunity to move toward real-time release of a product. If traditional tablet press variables are properly controlled and a quality granulation is delivered to the tablet press, then the due diligence time spent in process development pays off with a robust manufacturing process that does not require process analytical instrumentation.

Ethirajan (Tedor Pharma): All controls that apply to a single layer tablet must be performed for each different layer in a multilayer tablet. For example, in a bilayer tablet, the granulations for each of the layers are manufactured separately. Both layers have a drug, and then both layers must be monitored and controlled for drug uniformity in the blend/granulation. During compression, in-process controls for weight must be used for both layers. Hardness for the first layer and hardness for the final tablet must also be monitored. If controlling the specification for one of the layers is more challenging, it also affects the formulation and scale-up of the entire process.

PharmTech: Batch yields for multilayer tablets can often be lower. What future improvements would help increase yields?

Behrens (IMA Kilian): Vendors have developed many new systems and machines that can help in this area. I believe that one important feature of such systems is user-friendly software. In addition, simple features that enable shorter set-up times can be beneficial.

Calvin (Elizabeth Companies): I disagree; the batch yield is not affected by the reduced tableting speed, but it is reduced by several other factors. Operating a layer press is the same as operating several presses at the same time; for example, in the case of a three-layer press, you have three different powder feeders possibly containing three different granulations that can contribute to reduced yield. The feeders can contribute to the loss if care is not taken during set up, or if they are not properly adjusted to the die table and are allowed to leak powder. The second major contributing factor to batch yield is the vacuum. If the vacuum applied to the die table to eliminate cross contamination is not correctly balanced, then granulation may actually be vacuumed from the feedframe during operation.

In particular, tablet layer sampling can be one of the foremost contributors to batch yield loss. During tablet sampling, powder loss cannot be avoided because of the compressions that must be removed and discarded due to the 'sampled' layer that is missing during the collection process. Batch yields can be increased by simply taking the time to properly adjust the powder feeders to the die table, correctly balancing the vacuum and by collecting the minimum amount of layer samples needed for the in-process inspection requirement.

Kirsch (Natoli): Bilayer tableting speeds are reduced by at least 50% as double-sided presses function as single-sided presses due to the second layer. Layer cohesion issues, tablet hardness, cross contamination, or other compression issues may result in a further slowing of the press. Press manufacturers are always researching ways to improve multilayer press efficiency. Layer sampling typically slows production. Fette has introduced several methods to reduce sampling delays and a 'punches up' option to eliminate second layer only tablets. Older layer presses discarded excess product whereas product recirculation of individual layers is now possible, which greatly increases yields. Improved load cell resolution will more accurately control weight for individual layers allowing for higher speeds. Presses are available with 100 or more stations of tooling which will certainly increase output. It would be advisable to invest in a purpose built press engineered for layered tablets. Retro-fitted or converted presses do not function as efficiently.

Ethirajan (Tedor Pharma): Production rate yields are generally lower. This is because a two- or three-sided machine only makes a single tablet with each head revolution. Also, the need for vacuuming off the granulation that passes the scrape off after each fill station causes higher granulation loss relating to low batch yield.