Cross-contamination

PharmTech: How can common formulation issues, such as the combination of incompatible products, be overcome?

Calvin (Elizabeth Companies): The incompatibility of multiple drug matrixes is often paramount in the decision of a new product design process. As mentioned, however, this issue can be overcome by keeping the matrices separated by an inert 'barrier' layer to prevent drug interaction.

Ethirajan (Tedor Pharma): Incompatibility between the tablet components can be overcome by having the incompatible ingredients in different layers. It is critical to understand the physicochemical properties of the drug substance, and preformulation compatibility studies will help identify such incompatibilities so that certain excipients can be avoided or be separated into different layers for better drug product stability. Multilayered technology is used in many instances to overcome incompatibilities between drug substances that need to be administered in a single dosage. Occasionally, in the case of three-layer tablets, a thin placebo layer may be used between the outer active layers to avoid incompatibilities.

Another vital part in developing multilayered tablets is excipient selection. It is preferable to use excipients that are compatible with the drug substances in both the layers to maximize drug product stability. Generally, scrapers present in the multilayered machines are non-metallic in nature; hence, it is imperative that the use of abrasive excipients that may ruin these scrapers is avoided. Using excessive amounts of lubricants should also be avoided because these may interfere with adhesion between layers. Excipient choices should also be based on the functionality of a particular layer (immediate release versus controlled release).

PharmTech: How can layer cross contamination be avoided?

Behrens (IMA Kilian): Product losses can be very high when making layered tablets. Usually strong vacuum aspiration is used to clean the residual product on the die table after the dosage of each layer, thus preventing cross contamination. Over the years, vendors have developed several technical solutions that minimize the quantity of powder remaining on the die plate that needs to be removed by suction.

Calvin (Elizabeth Companies): Layer cross-contamination can be avoided in a few different ways. For example, ensuring the feed frame is correctly adjusted and not leaking powder, properly adjusting the vacuum being applied to the front of the feedframe to keep the die table clean, and installing dies that are manufactured to the high limit on overall die height. Whenever the granulation characteristics and tablet size deem it necessary, a 'Tail Over Die Scraper' (a delrin cover that is held in place against the die table with spring steel to keep any granulation form slinging out of the die through centrifugal force) may be needed if any powder loss is incurred due to centrifugal force.

Kirsch (Natoli): Proper press set up is essential. Turret die tables have a certain amount of vertical run out. Often overlooked is the simple task of indicating a die table to locate the high point. Feeder clearance must be set at this point to achieve a minimal amount of clearance between the feeder and die table to reduce granulation loss. Scraper blades must be in good condition and free floating on the die table to reduce cross contamination. Die tables must also be in excellent condition as any wear or damage will contribute to granulation crossover. Proper dust extraction is also needed as presses suited for layered tablets generally have more and/or specifically designed vacuum nozzles. Again, reduced fines would be important. Another crucial point is that skilled press set-up technicians and operators are a must.

Ethirajan (Tedor Pharma): Scraper and seal conditions of the feed frames are very important. It is also essential that excess granulation passing the scrape-off be vacuum cleaned so that fines from one layer don't cross contaminate the other. Reduced fill cams may be used to reduce the amount of granulation that needs to be scraped off from overfill of the die.