Multilayer Tablets: Key Challenges and Trends

Solid dosage forms are the most popular method of drug delivery and although tablets are widely established throughout the pharmaceutical industry, this doesn't mean it is an unmoving area. According to a recent Pharmaceutical Tehnology poll, manufacturers are seeking to reformulate or reinvent their currently marketed solid-dose products to both renew patents and improve efficacy (see Figure 1).

N. EVELEIGH/PHOTODISC/GETTY

One possible way to achieve these goals is to reformulate tablets into more exotic forms such as multilayer tablets, fixed-dose combinations, and other innovative dosages.

Pharmaceutical Technology brought together experts in solid dosage for a special roundtable on the formulation and manufacture of multilayer tablets. We also spoke to researchers about fixed-dose combinations, an area that has raised controversy, regarding adverse effects. Participants in the roundtable include: Marcus Behrens, sales director at IMA Kilian; James Calvin, Elizabeth Companies; Doug Kirsch, Technical Service Manager at Natoli Engineering Company; and LakshmiDevi Ethirajan, Manager, Formulation Development at Tedor Pharma.

Figure 1: Demand for reformulation (PharmTech poll).

Industry demand

PharmTech: How has demand for multilayer tablets altered in recent years? What factors have influenced this trend?

Behrens (IMA Kilian): Fixed-dose combination drugs are becoming increasingly popular, particularly as life-cycle management strategies seek to extend intellectual property and minimize generic exposure by creating an innovative dosage form. The multilayer tablet is a viable way to combine different actives for a synergic therapeutic effect, or different formulations of the same active in order to achieve a specific release profile. Furthermore, multilayer tablets can help avoid interactions between different drugs and optimize each formulation in terms of pharmacokinetics and manufacturability.

From left to right: Marcus Behrens (IMA Kilian), James Calvin (Elizabeth Companies), Doug Kirsch (Natoli); LakshmiDevi Ethirajan (Tedor Pharma) is not shown.

Calvin (Elizabeth Companies): The growth of high-potency and combination drug products over the last decade has made multilayer and tablet in tablet (core tablet) hot topics in the pharma industry. These novel delivery systems have been essential not only in formulating new products, but also in helping pharmaceutical companies to extend patents.

Ethirajan (Tedor Pharma): Among other advantages, triple-combination therapy in a single-dosage form is being used to promote better treatment adherence by providing a convenient single tablet. As well as increasing patient compliance, multilayer tablets can help to reduce the cost of medication.

Future success

PharmTech: Considering the split drivers of compliance and patent extension, do you think multilayer tablets will continue to be successful in the future?

Behrens (IMA Kilian): If we think of fixed-dose combination drugs as a way to treat two closely related diseases, or to improve compliance and thus efficacy of prescribed medicines, we believe that this trend will continue. However, multilayer tablets could be a less frequent option if, in the future, the drugs are designed to be mixed into a unique powder that can be processed in a standard tablet press.

Today, most combined actives are existing drugs. In the future, a higher number of combinations will be achieved with new formulations that are specifically designed to be combined from the development stage. In this case, the properties of the different compounds can be optimized to be combined, minimizing possible interactions.

Calvin (Elizabeth Companies): I believe that the demand for multilayer and tablet-in-tablet technology will continue for many years to come, particularly as new high-potency drugs, which are often combined with other drugs in a single multilayer tablet generate a demand for layer technology. Many matrices are incompatible with one another, but with multilayer tablets, formulators can insert an inert barrier layer between the incompatible matrices to prevent an interaction. Also, developments in the technology have made multilayer tablets easier to produce. For instance, for core tablets, developments now enable the core to be positioned more precisely within the tablet.

Kirsch (Natoli): Multilayer tablets have been manufactured for a long time; more than 50 years that I know of. They are not going away.

A new possible need for layered tablets is the recent FDA draft guidance for industry on tablet scoring. Uniform dosage and assurance that a patient is capable of splitting the tablet properly are two of its concerns. Accu-Break Pharmaceuticals developed and patented a unique method using layered tablets to address these issues. The first (bottom) layer is a drug-free placebo. The second (top) layer containing the API(s) is scored deep enough to reach the second layer. The first inactive layer is merely a holder for the active second layer and when broken, result in a uniform dose. A trilayer tablet with an inactive center layer for split dose combinations has also been developed. Simple, yet brilliant.

Ethirajan (Tedor Pharma): Multilayer technology will continue to be an option in the future for several reasons:

• Pharmaceutical companies will file new patents or extend existing patents on their company name on combination product to win market exclusivities.

• Generic-drug makers may use new technology as an option to work around existing patents for markets product.

• Advancements in the technology by equipment manufacturers who recognized the importance of meeting regulatory requirements to market their high speed machines for production.

Most importantly, a single tablet containing multiple medications can be both cheaper and more convenient than separate tablets.

Formulation

PharmTech: When formulating multilayer tablets, what special considerations are required for factors such as levels of fines, bulk densities, and granulation properties?

Behrens (IMA Kilian): For efficient tableting, granule flow is crucial and a certain amount of fines is needed to guarantee proper filling and binding of the tablet. It is also important that the tableting machine is designed so that the filling range can cope with bulk density. In addition, the system should avoid the carry-over of particles or fines.

Calvin (Elizabeth Companies): When utilizing a tablet press with the proper powder-feed system, there is usually no need for any special considerations or factors such as levels of fines or granulation properties to be determined. The only consideration would be the bulk density of the granulation. Depending upon which layer is the lighter density granulation, it would normally be used on the first layer if the tableting press has a limitation of the upper punch penetration of the layer tamping stations that regulate the depth of fill of the consecutive layers.

Kirsch (Natoli): The level of fines must always be considered, even for non-layered tablets. Excessive fines will result in poor tablet quality, as well as tool binding and tablet press overheating, which exacerbates sticking and picking issues. Although fines are a necessary evil for proper tablet compressibility, it is critical that these are kept to a minimum when compressing layered tablets otherwise cross contamination from one layer to the next will be increased as fines will pass under feeders and scraper blades. Bulk densities are also a consideration because light or airy granulations require increased depth of fill and precompression. Pre-compression of the first layer is required for clear demarcation lines between the layers. If the press does not have sufficient upper punch penetration to pre-compress/tamp the first layer, then the desired weight may not be achieved and there will be insufficient volume in the die bore for the next layer. Some modern presses are only capable of 4 mm upper punch penetration, whereas many older presses were capable of almost 10 mm penetration, which, in many cases, made them better suited for layered tablets. Granulation properties would be much the same as with non-layered tablets with the exception of reduced fines; good flow and compressibility are always desired.

Ethirajan (Tedor Pharma): It is beneficial if both layers have relatively equal physical properties, such as the amount of fines, bulk density and granulation properties. It is also ideal to maintain granule size less than one half of the layer thickness to achieve a clear scrape-off. Specifically, fines below 200 meshes can smear or coat the turntable surface and it may not be possible to achieve a clean scrape-off, which can lead to layer cross-contamination.

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.

Kirsch (Natoli): Incompatible APIs are the main driver for layered tablets. They enable incompatible ingredients to be administered in the same tablet without degrading the actives. As for excipient choice, this is why we have R&D; use what works.

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.

Control

PharmTech: How can the weight of individual layers be monitored and controlled accurately?

Behrens (IMA Kilian): When producing bilayer tablets, the in-line control of production, combining compression force measurement and statistical weight check are challenging for several reasons. If the compaction force for layer one is extremely low, it could be very difficult to obtain a clear signal from the strain gauges. Low force compression rollers are available to help deal with this. The reduced mass ensures more accurate and reliable measurements. Another critical point is statistical sampling of the layers for weight checking. For sampling, the first layer has to be compressed at a higher force to achieve enough hardness to make sampling and weighing possible. Some systems can achieve this by using specialized systems. For example, to avoid the production of second-layer-only tablets during layer one sampling, lower punches can remain in the up position while the fill-shoe for layer two is stopped.

Calvin (Elizabeth Companies): Usually, two different process control methods are employed to achieve this. The first, standard method is to utilize force control, which monitors the layer tamping pressure by means of a strain gauge transducer that, in turn, provides feedback to the press controller. This information is used to automatically adjust the metering cam to keep the set pressure constant to maintain the correct weight and tamping pressure. The strain gauge should be sized so that it will be sensitive enough to 'sense' the lighter tamping pressures required for producing a tablet layer compared to the strain gauge that would be required for final tablet compression.

The secondary method is to select a multilayer tablet press that automatically collects sample tablets from each layer at regular intervals and then sends them to a weight testing unit, which would be included in the press control feedback loop, to provide in-process checks along with weight control.

Kirsch (Natoli): Tablet press manufacturers will be responsible for this through improved technology and engineering. By utilizing quality by design, the science of the formulation is understood and the design space can be exploited to deliver a controllable process. Controlled processes deliver a product with the required critical quality attributes that define what is to be delivered to the patient.

Aesthetics

PharmTech: Aesthetically, what consideration should be given to color?

Kirsch (Natoli): Aesthetics are always important to the consumer. However, as a manufacturer, the first concern would be, what the cost is and how well does it compress? Colors as well as flavors can affect tablet compression. Some may be more heat sensitive than others, resulting in picking or sticking issues. Others may have excessive fines resulting in punch and die binding, which increases tool and press wear.

A common error is developing a new product in R&D on a slow, partially tooled press and then submitting a New Drug Application before testing it on a production machine. The R&D press may not even have the same type tooling. If the product was developed on a 'D' tooling press and the production press was a 'B', dwell time would be reduced, resulting in poor layer cohesion or soft tablets. Partial sets of tooling will result in more time under pressure, therefore increasing tablet hardness. Again, poor layer cohesion and soft tablets could be an issue on a high-speed press. Production presses run at higher speeds and temperatures, increasing possible sticking, picking, laminating, and capping issues.

The criteria for color or flavor choice should be what is least costly and runs best on a production press and not just what 'looks pretty.' There is a middle ground somewhere for marketing and production. Marketing will not have to deal with the production headaches. It may cost thousands or hundreds of thousands to do a trial on a production press, but would be more cost effective than wasting millions fighting it in full-scale production.

Ethirajan (Tedor Pharma): Colors play an important role in multilayered tablets. Firstly, it is a method of visual process control during compression. The extent of cross contamination, if any, can be easily seen when granulations of different colors are mixed during compression. When a color coating is not present, colored tablets also give a visual description to the drug product. In the case of over-the-counter products, color and aesthetics play a major role in consumer choice.

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.

Calvin (Elizabeth Companies): The only additional challenge when pressing a multilayer tablet versus a standard tablet relates to process control to ensure that the prior layer is at the correct weight before allowing any automatic weight change to occur. The first layer must be in the correct weight range before any changes happen to the second layer. In the case of a three-layer tablet, the first and second layers must be in the correct weight range before allowing the third layer to make any weight adjustment.

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.

Fixed-Dose Combinations

A single dosage form that combines two or more active ingredients is known as a combination drug or fixed-dose combination (FDC). One benefit of an FDC is that it reduces the number of pills that must be taken, which can lead to improved patient compliance. However, FDCs have also been a topic of concern, mainly because of the perceived potential for increased adverse events. Pharmaceutical Technology speaks with researchers to explore the benefits and concerns of FDCs, and some of the challenges involved in their formulation. Participants include Dr. Ajay K. Gupta of International Center for Circulatory Research, Imperial College London; Dr. N. Udupa, professor and principal at Manipal College of Pharmaceutical Sciences, Manipal University in India; and Dr. D. Sreedhar, assistant professor in the Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, Manipal University in India.

PharmTech: Why have FDCs been criticized in the past?

Gupta (Imperial College London): The use of FDCs was previously discouraged because of cost considerations, lack of flexibility in dose titration, and doubts over the bioavailability of the individual components (compared with the bioavailability of the constituent components, when given separately). Another concern was that the use of FDCs would be associated with the increased risk of adverse events. Over the last few years, however, the findings of several clinical trials and observational studies have refuted most of these concerns (1–4).

Findings from recently conducted clinical trials have virtually removed any doubts over the comparative efficacy and safety of an FDC versus its corresponding free-drug combination. Moreover, in several situations, the use of FDC was associated with significantly improved efficacy. For example, in the ACCOMPLISH Trial, blood pressure control rates (within first six months) improved significantly among previously treated hypertensive patients, from 37% to 73%, with the use of a single pill FDC of two antihypertensive agents. Another trial using a low-dose FDC, STITCH Trial (Simplified Treatment Intervention to Control Hypertension), found that those allocated to treatment with an FDC compared with the usual care were more likely to have a better blood pressure control, with no adverse effect on tolerability.

Other studies have also shown that the total costs (direct and indirect) related to the use of any FDC is likely to be lower than the use of its corresponding free-drug combination, particularly because of a reduction of indirect costs related to disease complications. Indeed, a quick look at the costs of available FDCs in the UK shows that the direct cost of several FDCs is similar or cheaper than the cost of the two constituent components given separately. Additionally, the cost to patients at the point of delivery is cheaper with an FDC compared with the prescription of two components separately when patients have to pay for prescription. A recent study has also shown that costs incurred by the patient (either as co-payment or otherwise) has an inverse relationship with adherence and concordance with medication. Lastly, the improved and easy availability of several different dose compositions of an FDC have made it easier for physicians to up-titrate medications with little difficulty.

In summary, I believe, it is no longer justified to persist with an attitude of disdain against the use of FDCs.

Udupa/Sreedhar (Manipal University): The single most important factor that FDCs have been criticised for is dose titration. Dose titration of one or all the active ingredients present in an FDC is not possible, which is crucial when both actives require dose titration. However, manufacturers have taken note of this and addressed the problem in certain cases, but the criticism is justified because the very existence of the FDC discourages adjustment of doses to the patient's needs, and may also lead to overdosing or underdosing of one or more of the active ingredients present. Moreover, busy prescribers may not notice the dose of each active ingredient present in an FDC and it could encourage polypharmacy.

PharmTech: Despite criticism, some data have suggested that compliance is increased. Could you explain why you agree or disagree with this statement?

Gupta (Imperial College London): I agree that there is a significant body of evidence confirming directly or indirectly that the use of an FDC is associated with improvement in compliance. Several observational studies have shown an inverse relationship between the number of prescribed medications and concordance with them. A few qualitative surveys on patient perception have largely produced supportive data, suggesting that the use of an FDC would be more convenient for patients, and encourage compliance and adherence with medications. The findings of our meta-analysis, using evidence from cohort studies and clinical trials, have confirmed previous indirect findings: our analyses found that, compared with a free-drug combination, the use of an FDC was associated with a 21% significant increase in compliance and a 54% increase in persistence with therapy.

Udupa/Sreedhar (Manipal University): There are several advantages offered by FDCs. Many studies have shown that FDCs increase both patient compliance and adherence. FDCs also simplify treatment regimens. Physicians feel that it is convenient to prescribe FDCs rather than single component products, and this sentiment is often shared by patients. It is also generally believed that FDCs are cheaper and reduce the costs of logistics, which is especially important when FDCs need to be distributed to remote places.

PharmTech: Can you give examples of successful, rational FDCs?

Gupta (Imperial College London): Currently there are numerous examples of success stories with FDCs. An FDC of antituberculosis medications, compared with the corresponding free-drug combinations, was associated with significantly higher treatment rates and significantly lower adverse effects. Similarly, among those with HIV, the use of an FDC of anti-HIV drugs has shown greater rates of remission. In comparison to these examples, the success stories with the use of FDC in the field of cardiovascular medicine are not that dramatic. However, there is a rapidly growing body of data, suggesting that the usefulness of FDCs in cardiovascular and metabolic medicine is likely to be no different than that seen in other fields of medicine.

In cardiovascular medicine, the main utility of FDCs is mediated through improved compliance, which in turn may increase the treatment efficacy and decrease the outcomes. This hypothesis is partially supported by findings of our meta-analyses: the use of FDCs (compared with the use of corresponding free-drug combination) was associated with a greater (albeit statistically insignificant) reduction. Elsewhere, a few observational studies have shown that the improved adherence with medications is likely to be associated with greater cardiovascular benefits.

Another potential advantage with the use of FDC is a possible reduction in adverse effects. In our meta-analysis, compared with the corresponding free-drug combination given separately, allocation to FDC was associated with lower adverse event rates. The use of a low-dose FDC of two drugs as an initial therapy (in several situations) may have significantly lower adverse events and a better tolerability, than either of the medication alone. A classic example of this is an FDC combination of an angiotensin-converting enzyme (ACE) inhibitor and a calcium-channel blocker (CCB) is likely to be associated with lower incidence of ankle swelling, compared with the same dose of CCB alone.

Udupa/Sreedhar (Manipal University): Fixed-dose combinations are especially useful when treating diseases like human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), malaria, and tuberculosis where more than one drug is usually recommended. There are also certain other conditions and diseases, such as cancer, cardiovascular diseases, diabetes, neuropsychiatry and pain where FDCs may offer benefits. Some successful and rational FDCs include:

• Antiretroviral combinations: abacavir + lamivudine, tenofovir disoproxil fumarate + emtricitabine and efavirenz + tenofovir + emtricitabine.

• Antimalarial combinations: artesunate + amodiaquine, artemether + lumefantrine and amodiaquine + sulphadoxine + pyrimethamine.

• Antitubercular combinations: Rifampicin + Isoniazid + Pyrazinamide.

• Hypertensive combinations that provide better blood pressure control: Amlodepine + Atenolol, Amlodepine + Losatan and Irbesartan + Hydrochlorthiazide.

• Antidiabetic combinations that provide better glycaemic control: Glibenclamide + Metformin, Glipizide + Metformin and Pioglitazone + Metformin.

PharmTech: How do you think the benefits and disadvantages of FDCs shape up against one another? Should the industry pay more attention to potential FDCs or would the time be better spent on other areas of innovation?

Gupta (Imperial College London): This is an interesting question, but there is no readily available answer. In my opinion, each new FDC formulation should be based on a thorough understanding of disease mechanism, as well as the mechanism of action, pharmacokinetics and pharmacodynamics of each constituent component—separately and in combination.

There are a few FDCs that are more frequently prescribed over the other because of the prevalence of the clinical situations that they are most effective in. However, given the numerous clinical prescribing situations, I believe all FDCs will have their own niche in treatment settings. Having said that, I believe that there are only a finite number of possible FDCs and with the rapid introduction of new FDCs, the market will probably be saturated in the next few years or so. For long-term sustainability, the pharma industry should spend a significant amount of time on other areas of innovation, including the development of new drugs and effective drug delivery mechanisms.

Udupa/Sreedhar (Manipal University): Benefits and disadvantages should be looked at simultaneously and not individually when evaluating an FDC. If there is considerable evidence that the proposed FDC has more benefits than disadvantages, then it's a definite 'go' situation.

The pharma industry should definitely explore the potential benefits FDCs offer over their individual component products. It is difficult for small- to medium-scale companies to bear R&D costs and even larger companies are finding it risky to develop new drugs and so most pharma companies are now in search of new business models. One of these options is to develop FDCs of existing individual components that are co-prescribed in order to help preserve patents.

When developing FDCs, however, companies must consider the safety and efficacy of the active components in combination, the benefits of simultaneous use of active ingredients and possible interaction between the components. Fixed-ratio combination products are usually considered for marketing approval by regulatory authorities only when the dosage of each ingredient meets the requirements of a defined population group and when the combination has a proven advantage over single compounds administered separately in its therapeutic effects, safety, or compliance.

References

1. A.K. Gupta, S. Arshad and N.R. Poulter, Hypertension, 55(2), 399–407 (2010).

2. K. Jamerson et al., N Engl J Med., 359, 2417–2428 (2008).

3. ADVANCE, "ADVANCE Trial — Blood pressure lowering arm results". www.advance-trial.com

4. R.D. Feldman et al., presentation at Scientific Sessions 2007 of the American Heart Association (Orlando, 2007).

Key Formulation Factors

There are several formulation and manufacturing challenges that need to be addressed when working with multilayer tablets, but meeting regulatory expectations is crucial. Pharmaceutical Technology speaks with Vilayat A. Sayeed, PhD, director of the Division of Chemistry III at the US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Office of Generic Drugs, to find out more about critical formulation factors.

FDA's Vilayat A. Sayeed

PharmTech: How have advances in pharmaceutical manufacturing technology influenced the development of multilayer tablets?

Sayeed (FDA): Improvement in the understanding of the material science (physical, chemical, and mechanical) and the engineering of the tableting machine to control weight of individual layer/s, total tablet weight, and compression factors for the layers are responsible for the advancement in pharmaceutical technology of the multilayer tablets.

PharmTech: What critical factors do manufacturers need to be aware of when producing multilayer tablets?

Sayeed (FDA): Critical factors can be broadly divided into material attributes and process parameters. Material attributes such as: compatibility, compressibility, compactability, adhesion, tensile strength, flow properties, porosity, density, layer relaxation during shelf-life and storage and propensity for in-vitro and in-vivo delamination are some of the factors a manufacturer must understand in producing a multilayer tablet. The process parameters includes impact of lubricant in each blend, tamping force for initial layer(s) compression, final compression force for tableting, and press speed. Both of these factors have to be fully understood for making a quality multilayer tablet.

PharmTech: Which regulations, in particular, are applicable to determining these critical factors?

Sayeed (FDA): Regulations are written to address and capture the safety, efficacy and quality concerns, regardless of how the product is designed and manufactured. It is the responsibility of the sponsor to study, understand, and establish controls in the process to ensure that the manufacture of a drug product can provide the intended product performance and clinical outcome over its shelf life. There are no specific regulations for multilayer tablets or any other pharmaceutical dosage form, but 21 CFR 314 and 21 CFR 320 address the various issues that should be addressed in the submission.

PharmTech: How can manufacturers best use a quality-by-design approach to support the development of a new multilayer tablet?

Sayeed (FDA): Quality by design can be used to comprehensively put forth the understanding of the product formulation (drug substance inherent properties, excipient properties, and variability) and manufacturing process on product performance. The design elements should be based on prior knowledge, risk assessment, and process controls in achieving the multilayer tablet of desired quality. To further enhance the understanding where applicable, the manufacturer should conduct design of experiment studies to develop and identify critical to quality attributes and process parameters. This systematic approach of building quality by having a mechanistic understanding of variables and their impact on the manufacturing process and the performance of the product with limited dependence on the end-product testing should be the focus and the intended use of quality by design.

PharmTech: Are there any other issues specific to multilayer tablets that companies will need to address in regulatory submissions?

Sayeed (FDA): The knowledge gained by applying the scientific principles and risk management tools during the pharmaceutical development must be fully discussed and those functional relationships that are linked to product performance must be clearly presented in the regulatory submission. In addition to providing a complete mechanistic understanding supported by data developed through the application of scientific and quality risk management tools, the applicant should also provide the relevance and justification of the product design to the product performance and clinical outcome. The established controls and specifications should be based on the sound scientific principles, ICH and regulatory agency guidance, and should be fully justified.

Multilayer Technology

A Q&A with Accu-Break

Pharmaceutical Technology speaks with David Breach, a technical consultant for formulation development and manufacturing at Accu-Break Pharmaceuticals.

David Breach, Accu-Break

PharmTech: Accu-Break has used multilayer technology in an innovative way, could you please describe the reasoning behind the drug-free layer?

Beach (Accu-Break): We have developed two distinct multilayer tablet technologies, known as Accu-B and Accu-T, which incorporate a drug-free layer. With the Accu-B technology, the dosage form has two layers, one of which is drug-free. The second layer contains drug and is deeply scored. The drug-free layer provides several unique features: first and foremost, given the deep score in the drug layer, the drugfree layer forms a backbone that gives the finished dosage form mechanical strength to withstand packaging and shipping operations. Secondly, the drug-free layer is the fracture plane for the Accu-B tablet. The tablet can be broken through the score and the fracture occurs in the drug-free layer. Compared with a conventionally scored tablet, the Accu-B bilayer design ensures partial dosing accuracy and eliminates concerns over loss of mass. Using the Accu-B technology, scored tablets can be made that would satisfy the testing and data requirements for both the European Pharmacopeia's Monograph 0478 and the FDA's recently proposed Guidance for Industry, Tablet Scoring: Nomenclature, Labeling, and Data Evaluation.

Our Accu-T technology uses up to five layers in a taller-than-wide tablet, and the incorporation of drug-free layers serve one of two purposes:

1. The drug-free layer provides a physical barrier between active ingredients. This barrier allows the formulation of incompatible actives with no worries about co-mixing and resultant physical or chemical stability issues. The technology utilizes machinery that can produce tablets with up to five compressed layers so the use of more than one drug-free layer can facilitate a "poly pill" with three different API-containing formulations.

1. A drug-free breaking layer is incorporated into the middle of an Accu-T tablet and can be used to separate the drug-containing layers. Since the drug-containing layers are physically located at the top and bottom of this tallerthanwide tablet, breaking the tablet through the middle drug-free layer separates the dose into exact halves. Unique fixeddose combination (FDC) tablets can be made where the top and bottom layers contain different actives. In this configuration, the two different drug layers can be separated if desired by splitting the tablet through the middle-drug free layer. Patients taking antihypertensive FDCs can be confronted with side effects that result from one of the drugs within the FDC, resulting in prescription discontinuation. With the Accu-T FDC tablet design, a patient could suspend treatment with one of the drugs in the FDC by simply breaking the tablet through the middle drug-free layer. When appropriate, the patient could then resume taking the whole tablet, which allows some dose flexibility without having to stop the prescription entirely. The tablet could also be used to initiate treatment with a single agent and then add the second and, thus, efficiently transitioning the patient into a convenient FDC without the need for separate prescriptions during the titration phase.

PharmTech: Does the use of a drug-free layer to separate incompatible APIs require further consideration specific to the choice of excipient(s)?

Beach (Accu-Break): Excipient choices are broad and specific requirements are not unique to the technology, meaning common excipients are readily adaptable for use in Accu-Break technologies. For Accu-B tablets, the requirement for a strong backbone in the drug free layer necessitates the use of excipient materials with good compressibility (e.g., microcrystalline cellulose). Typical finished tablet hardnesses are more than 20 Kp. In addition, in an immediate release product, the desire to have the drug free layer separate rapidly from the active containing layer typically requires the use of higher levels of disintegrant in the drug-free layer.

PharmTech: Why have fixed-dose combination (FDC) drugs been criticised in the past?

Beach (Accu-Break): The largest historical criticism of FDCs has come from the lack of dose flexibility. Taking antihypertensive FDCs as an example, treatment is typically initiated with a single agent, which is titrated to a maximum tolerated dose. If the desired effect on lowering blood pressure is not achieved, a second agent is added, which also requires titration and can lead to lowering the dose of the first agent. A third agent is sometimes added to the mix, or substituted for one of the initial drugs. This process continues until the patient's blood pressure is within the target range, and then the physician looks for an option to transition the patient to an FDC that contains APIs at the effective dose for that patient. This is done of course to simplify the dosing regimen for the patient in an attempt to maintain adherence to the regimen. Problems arise when a dose adjustment is necessary due to the inflexibility of traditional FDCs. The convenience of a single dosage form is offset by the inability to manage dose adjustments without the need for new prescriptions. If a patient is transitioned to an FDC, inevitably an adjustment will be made to their dose(s), their regimen, the specific drugs being used, or all of the above. So, from that perspective, the criticism is justified. However, for those patients who are effectively managed using FDCs, the ability to take lower doses of two or more medications in a single dosage form is highly desired, especially if it is a once-a-day regimen.