How quality by design can help pharma manufacturers reduce production issues

Natoli Engineering explains how to help organisations reduce the stress and loss of product development and delivery with Quality by Design.

A significant concern in tablet manufacturing is speed to market. Moving too quickly, however, may cause delayed production, lost product, and missed deadlines. Even under ideal circumstances, tablet development will encounter unknown variables before a final product is realised. To reduce problems, performing several simple experiments and creating characteristic profiles enables R&D and production to accurately evaluate new drugs as oral solid dosages. Experimental data is used to characterise formulation performance with both patients and manufacturing organisations as ultimate customers. Understanding these compaction and compression characteristics is fundamental because they often drive changes in production requirements.

These anticipatory experiments result in less formulation changes prior to full-scale production. Changes to production-ready formulations are the costliest and most time-consuming because they must meet FDA, scale-up and post-approval changes (SUPAC) compliance, or other regulatory guidelines. The pharmaceutical industry benefits from utilising vendor partnerships for troubleshooting techniques and solutions. A quality tooling vendor can provide help to prevent tableting issues with information provided in compactability, tabletability and compressibility profiles. The study completion and analysis outlined below also provides smoother transitions from R&D to full-scale production.

Gathering Powder Performance Data With Single-Station Presses

Single-station tablet presses offer crucial advantages during new tablet early formulation and pre-clinical development. When utilising a single-station press, operations that would otherwise occur automatically are performed manually, such as blending and the die filling process.

The advantage of a single-station press is it allows R&D scientists to perform tableting studies on the active pharmaceutical ingredient (API). Having these data can assist in excipient selection. Use of single-station tablet presses also makes performing formulation studies easier. Each study works harmoniously to provide data about a tablet’s planned components and how well they consolidate and compress.

Compactability Profile

This profile illustrates how readily a material undergoes changes in volume when compressed. It is a measure of how a powder can be changed into a tablet and the resulting strength of the tablet. A simple plot of compression force against the resulting tablet’s breaking strength is often referred to as a manufacturability plot. To compare various sized tablets, the compaction pressure is calculated by using applied force and punch cup area. A tablet’s solid fraction is an important parameter because small changes in solid fraction can affect tablet properties. Figure 1 illustrates a compactability profile for two excipients and a blend of the two generated on a single-station tablet press. The three samples have a magnesium stearate level of 0.5% for lubrication.

Tabletability Profile

To better understand tablet tensile strength’s relationship to force used in tablet compression, it is vital to plot the tablet tensile strength against compaction pressure. Both variables are normalised to the tablet area to facilitate comparison of tablets of different size or tablets compressed on other tablet presses.

In the tabletability profile in Figure 2, we see a typical formulation profile compressed on a single-station press. Each formulation contains a high drug load; one is a direct blend recipe and the other a wet granulated drug product. Tablets with a tensile strength of greater than 2 MPa are desired, and as neither formulation is found to form a suit- able compact at any pressure between 50 MPa and 300 MPa, further study should occur before expending efforts on a rotary tablet press.

Figure 3 illustrates the tabletability of the three samples measured for Figure 1. It is clear that microcrystalline cellulose (MCC), with 0.5% magnesium stearate, provides the strongest compact. This is due to the MCC plastic deformation characteristics. The lactose monohydrate, with 0.5% magnesium stearate, also provides a robust tablet at reasonable compaction pressures. By blending the two excipients, it’s possible to add functions to the formulation’s performance, including plastic and brittle deformation characteristics. A 3-to-1 ratio of lactose-to-MCC provides a slightly stronger tablet than one made from pure lactose.

Compressibility Profile

The compressibility profile illustrates how readily a material undergoes volume changes when compressed, and affects tablet properties like dissolution, hardness, and friability. Analysing tablet compressibility data will ensure the tablet quality throughout the R&D and manufacturing processes.

Figure 4 shows the compressibility profile of the same excipients as Figures 1 and 3.

Importance of the Rotary Tablet Press in R&D

The use of a rotary R&D press is the next step in planning tablet compression scale-up to meet client needs. Integrating this step into tableted product development allows additional study completion and provides data at larger-scale production that can be used for further scale-up and production considerations.

As previously shown in Figure 2, there is a stark contrast between compaction profiles of the direct compression blend compared to the wet granulation when completed on a single-station press versus a rotary press (as presented in Figure 5). The differences in moving to a large press with 30+ tooling stations will significantly change the compaction process even further. These changes can occur due to the pitch circle diameter of the tablet press turret, increases in the tangential punch velocity, and decreases in compression dwell time.

A simple strain rate study helps determine whether a blend produces an acceptable tablet at various turret speeds and dwell times. Figure 6 reveals that the strain rate-sensitive formulation will need almost twice the dwell time to produce a quality tablet compared with the wet granulation.

With respect to API, completing these tests can be costly, so what can be done to reduce costs? Discuss tablet compression tooling options with reputable vendors. Tooling manufacturers offer modifications that may reduce or solve the problem of reduced strain rate.