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

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 drug-free 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:  

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 utilises 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.

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 taller-than-wide tablet, breaking the tablet through the middle drug-free layer separates the dose into exact halves. Unique fixed-dose 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.

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

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.  

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

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. 

is technical consultant for formulation development and manufacturing at Accu-Break Pharmaceuticals. 

Articles

Special Feature

PTE interviews Accu-Break's David Beach about using multilayer technology to create accurate breakable tablets and flexible fixed-dose combination drugs.

Breaking The Mould

Q: Why have FDCs been criticised in the past? 

 The use of FDC 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.  

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. 

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

 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.  

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. 

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

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.  

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.

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

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.  

 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. 

is based at the International Centre for Circulatory Research, Imperial College London (UK).

is Professor and Principal at Manipal College of Pharmaceutical Sciences, Manipal University (India). 

is Assistant Professor in the Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, Manipal University (India). 

1. A.K. Gupta, S. Arshad and N.R. Poulter, 

3. ADVANCE, "ADVANCE Trial — Blood pressure lowering arm results". 

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

Fixed-dose combinations (FDCs) reduce the number of pills that must be taken, but they have also been a topic of concern, mainly because of the perceived potential for increased adverse events. PTE speaks with researchers to explore the benefits and concerns of FDCs.

Fixed-Dose Combinations

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

 Fixed dose combination drugs are becoming increasingly popular, particularly as lifecycle management strategies seek to extend intellectual property and minimise 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 avoid interactions between different drugs and optimise each formulation in terms of pharmacokinetics and manufacturability.  

 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.  

 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.  

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

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 optimised to be combined, minimising possible interactions. 

 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.  

Multilayer tablets have been manufactured for a long time; more than 50 years that I know of. They are not going away—even though many companies including press manufactures wish they would!  

A new possible need for layered tablets is the recent FDA Draft Guidance for Industry 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 tri-layer tablet with an inactive centre layer for split dose combinations has also been developed. Simple, yet brilliant. Wish I'd thought of it! What other future possibilities are there for layered tablets? 

 Multilayer technology will continue to be an option in the future for several reasons:   

Pharma 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 recognised 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.  

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

For efficient tabletting, 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 tabletting 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. 

 When utilising 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.  

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 pre-compression. 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.  

 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.  

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

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

 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. 

 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 maximise 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).  

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

 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 specialised 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.  

Usually, two different process control methods are employed to achieve this. The first, standard method is to utilise 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. 

 Tablet press manufactures will be responsible for this through improved technology and engineering. By utilising 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. 

Q: How can layer cross contamination be avoided? 

 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 minimise the quantity of powder remaining on the die plate that needs to be removed by suction.  

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. 

 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 I need to emphasise is that skilled press set up technicians and operators are a must! 

 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. 

Q: Aesthetically, what consideration should be given to colour? 

 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? Colours as well as flavours 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 colour or flavour 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.  

Colours 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 colours are mixed during compression. When a colour coating is not present, coloured tablets also give a visual description to the drug product. In the case of over-the-counter products, colour and aesthetics play a major role in consumer choice. 

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

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.  

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.  

 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.  

 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. 

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

 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.  

Multilayer tablets: A piece of cake or just a passing fad? We bring experts together to find out.

Multilayer Tablets: A Piece Of Cake?

Firstly, Happy New Year! Please help yourself to a slice of cake. 

Towards the end of last year, I attended the 8th bioProcessUK conference in Glasgow, Scotland, with the tagline "Advancing Next Generation Therapies." The meeting was held in the very fitting Glasgow Science Centre, a place where children young and old can be inspired by the science around them—the next generation of pharma industry employees perhaps? There was a clear agenda to the conference—how to ensure that advances made in research result in actual therapies. 

In all areas of pharmaceutical development, one of the recurring challenges is scale-up, so of particular interest was a thought-provoking talk given by Roslin Cell's Aidan Courtney on scaling up cell manufacture from the point of view of translating research protocols into GMP processes. He noted, "the destination defines the journey," i.e., depending on the application of a particular cell therapy, the quantity of cells required for treatment becomes a crucial parameter. Courtney went on to provide numbers for a couple of example scale-up scenarios; ischemia therapy would probably require 10

  cells per treatment, so estimating perhaps 10,000 treatments per year, the numbers start multiplying faster than the cells... He concluded that GMP translation and scale-up are challenges best addressed in tandem. 

Bridging the gap between discovery into development and onto commercial scale manufacturing is something that our sister publication, BioPharm International, is addressing in collaboration with BIO SmartBrief: "Drug Development Basic Training". I encourage you to check out some of the weekly articles and podcasts at 

I leave you with the passionate words of this year's winner of the Peter Dunnill Award, Professor Mike Hoare from University College London, who concluded in his bioProcessUK presentation on ultra scale-down for enhanced bioprocess discovery: "Design for manufacture; design for lower cost." 

Firstly, Happy New Year! Please help yourself to a slice of cake.

Go UK Bio

The past few years have witnessed some dreary numbers in both Europe and the US when it comes to new products, but 2011 figures released by the European Medicines Agency may be early indicators for a 2012 upturn. At the time of going to print, statistics were only available for January–September 2011, but these nine months alone show higher numbers of approval rates compared with the whole of 2010.  

During January–September 2011, the EMA issued 74 positive opinions for marketing-authorisation applications compared with only 51 in 2010. Overall, the EMA finalised 79 applications in 2011 compared with 54 in 2010, with the number of applications for both new products and generics increasing over 2010.  

Analysts have been moping over pharma's seemingly drying pipelines for some time, but although the above statistics paint a bright picture for innovation there's still a long way to go before we can safely say that the pharma industry is on an upturn. Although the number of finalised applications has increased in 2011 compared with 2010, it's unclear whether the same can be said for started applications. The currently available statistics show that the EMA started 76 marketing-authorisation applications compared with 90 in 2010. With the 2011 statistics only representing nine months, there's obviously a chance that the 2011 numbers will increase, although it's unlikely that they will far exceed those for 2010.  

There's also a lot of ground to make up before the industry can outdo 2009's 125 finalised applications, although this high number was mainly driven by a large number of applications (51) for generic products. Twenty eight generic-drug applications were finalised in 2011, compared with 20 in 2010. Importantly, however, 2011 also showed a strong increase in the number of applications for new products, which is positive considering the amount of criticism that has been directed at the pharma industry's innovation pipeline. The 2011 statistics show that 32 applications have been finalised for new drugs compared just 21 in 2010. New orphan medicinal products are also on the rise: 11 applications in 2011 versus six in 2010. 

In the US, there has also been an upward trajectory for drug approvals. In August 2011, the FDA announced that it had approved 21 new molecular entities and new biologics license applications; the same number that the agency approved in the whole of 2010. By November, the number of new FDA approved drugs had risen to 35, which is among the highest number of FDA approvals in the past decade, surpassed only by 2009 when the agency approved 37 new products.  

There's still a long way to go before anyone can safely say that the innovation drought is over. In August 2011, financial services firm Burrill & Company released a statement urging the industry to be cautious. "We're on our way to breaking the anaemic pace of new drug approvals of recent years, but the problems underlying the relatively low rate of approvals since 2004 still need to be addressed," explained G. Steven Burrill, CEO. 

Fortunately, this is something that the FDA is working towards. According to an FDA statement, the agency has been trying to expedite approval times and increase flexibility in clinical trials while maintaining drug safety standards.  

Burrill is correct in that we should probably be cautious when looking towards the future, but given that both Europe and US have seen greater drug approval rates this year compared with last, perhaps 2011 marks an important step towards a more productive and innovative pharmaceutical industry. 

The FDA and EMA are moving from "confidence-building to reliance upon" each other in a step-up in cooperation on GMP inspections; the latest move following 0completion of pilot projects this summer. The initiative will begin in January 2012. 

Merck & Co. has agreed to pay $950 million to resolve criminal charges and civil claims related to its promotion and marketing of the painkiller Vioxx. The charges relate to off-label marketing. Under the agreement, Merck will plead guilty to a misdemeanor for its illegal promotional activity and will pay a $321,636,000 criminal fine. 

The breast cancer indication for Avastin has been revoked in the US after the FDA Commissioner concluded that the drug has not been shown to be safe and effective for this use. The drug will, however, remain on the US market as an approved treatment for certain types of colon, lung, kidney and brain cancer. 

The EC has unveiled an action plan against antimicrobial resistance, including provisions to promote R&D as well as the possibility of establishing fast-track procedures for marketing authorisations. Among other areas, the EC has highlighted the development of new antimicrobials for treatment as a priority. 

News

The past few years have witnessed some dreary numbers in both Europe and the US when it comes to new products, but 2011 figures released by the European Medicines Agency may be early indicators for a 2012 upturn.

Although the leading pharmaceutical companies are often termed multinationals, their regional origins are still important. Several studies have suggested that the idea of a global company that transcends national boundaries is an oversimplification of how businesses operate because such companies still retain many features of their national origin when expanding internationally. This effect is observed in the work culture that reflects operational decisions and a perceived preference for home-country nationals at the top of the organisation. This position is illustrated by GlaxoSmithKline, which originated in the UK. Although the company generates 96% of its sales elsewhere in the world, its British CEO, Andrew Witty, has reiterated that the company remains British and that it will maintain its main base in the UK despite the difficult operating environment (1). 

US pharmaceutical companies have tended to be high in the industry sales rankings. Therefore, as 2011 drew to a close, predictions that US company Pfizer was about to be displaced by French firm Sanofi as the world's leading pharmaceutical company in terms of sales came as a surprise and drew considerable media attention (2,3). After nine years of staying ahead of its rivals and being active on the merger and acquisition front, little evidence had indicated that Pfizer would be surpassed.  

Evaluate Pharma analysed companies' sales forecasts to 2016 and revealed the likelihood of a general shake-up in the rankings, with a number of European companies set to perform strongly against their previously dominant US rivals (4). The analysis suggested that by 2014, Pfizer would be the only remaining US pharmaceutical company in the top five. Pfizer is expected to slide to third, while Swiss companies Novartis and Roche will take second and fourth places, respectively. Meanwhile, GlaxoSmithKline will come in fifth, while US company Merck & Co. will slip to sixth, despite its $41-billion (€30.8 billion) acquisition of Schering-Plough in 2009.  

The major factor in Pfizer's commercial dip is considered to be the loss of US-patent protection for its blockbuster cholesterol-lowering statin Lipitor (atorvastatin), which occurred in November 2011. Launched in 1998, Lipitor reached peak sales of $12.9 billion (€9.7 billion) in 2006, accounting for 27% of Pfizer's revenue (5). In 2009, Pfizer acquired Wyeth in a $68-billion deal (€51 billion) to offset the impending loss of Lipitor's patent, but the product continued to represent a major source of sales; in 2010, Lipitor achieved sales of $10.8 billion (€8.1 billion), representing 15.8% of Pfizer's sales (5). 

The impending loss of patent protection led to India's Ranbaxy to develop a generic atorvastatin for the US and other markets. Starting in 2003, the company began launching patent challenges against Lipitor patents in several markets (6). Pfizer resisted strongly through its own legal counterattacks, but in 2008 it agreed to give Ranbaxy a license to sell atorvastatin in the US market, which became effective 30 November 2011. In addition, Ranbaxy will have exclusivity for 180 days before other companies can enter the market (6), while other agreements with Pfizer will also give Ranbaxy a license to sell atorvastatin in Canada, Belgium, the Netherlands, Germany, Sweden, Italy and Australia (6).  

The US is a key market for Ranbaxy, as it represents 70% of Pfizer's Lipitor sales (6). During its 180-day exclusivity period, Ranbaxy could generate as much as $650 million (€488 million) in sales. Ranbaxy also formed a partnership with Israel's Teva, which is the world's largest generic manufacturer. Teva has a strong distribution network in the US that should help Ranbaxy keep ahead of other competition such as Watson Pharmaceuticals, which is also seeking to introduce a generic version of atorvastatin.  

Although most attention has focused on Lipitor, Pfizer has several other products that have either recently lost patent protection, or will do shortly. Between 2010 and 2012, it was estimated that drugs representing 42% of Pfizer's pharmaceutical revenue were set to lose patent protection, including the antipsychotic Geodon (ziprasidone HCl), erectile-dysfunction drug Viagra (sildenafil citrate), overactivebladder drug Detrol (tolterodine) and eye-pressure lowering drug Xalatan (latanoprost ophthalmic solution) (5). 

Sanofi's rise in the rankings has been achieved through a steady focus on mergers and acquisitions, which started in 1999 with an allFrench tie-up with Synthélabo in a $30-billion (€22.5billion) deal (4). Then in 2004, while Novartis was still considering a bid for Aventis, Sanofi moved in to create Sanofi-Aventis in a $63-billion (€47billion) winning deal that the French government supported strongly to preserve jobs in France (7).  

Sanofi eventually dropped the name Aventis, thus signifying that it was the driving force within the merged company. In February 2011, Sanofi bought Genyzme with a $20.1-billion (€15.1billion) cash offer, which was seen as a shrewd move to replenish its R&D pipeline, due to Genyzme's strong biotech focus (8). In November 2011, Sanofi announced a 26% rise in third-quarter net profit, which included sales from newly acquired Genzyme. 

The manner in which the Genzyme acquisition went ahead has been contrasted with the way in which Sanofi took over Aventis. The Genzyme deal was very long and drawn out (taking 9 months), but Sanofi was the only company involved. It was obvious the merger would go ahead, but there were many negotiations over price. In contrast, there was never a clear cut regarding the winner of Aventis as the company had also been approached by Novartis (and there were rumours that GlaxoSmithKline was interested too) (1). The deal was about politics as well as price because a lot of outside players were involved, with the critical one being the French government. The SanofiAventis merger is often considered a messy affair because of the French government's heavyhanded intervention; French politicians were quoted as saying that they wanted to create a "national champion" (7, 9). In Europe, the final decision regarding mergers tends to rest with shareholders, whereas in the US, the directors have the major say. While the US process would not feature overt involvement from the government, the Genzyme merger shows that it can still result in a very long and drawn out process. 

Like Pfizer, Sanofi has faced its own patentexpiry challenges and has been scouring the market for a source of new revenuegenerating products. It lost a US patent challenge for its topselling blood-thinner product, Lovenox (enoxaparin), in a legal case in 2007 (1), and Sandoz, the generic arm of Novartis, has been selling a generic enoxaparin and eroding sales for Sanofi's product since 2010. In 2010, Sanofi generated around $30.1 billion (€22.6 billion)—around 7% of its revenue—from its anti-clotting drug Plavix (clopidogrel), which is marketed jointly with BristolMyers Squibb, but faces patent expiry in May 2012 (8). In 2006, Canadian generics manufacturer Apotex marketed a generic Plavix, but was ordered to halt production in November 2011. 

Interestingly, in September 2011, Pfizer agreed to let Sanofi sell a generic version of Lipitor in France (8). This agreement was part of a programme designed by France's Strategic Council of Health Industries, which fosters agreements between business and government. Such deals give the original manufacturer a tax break if it allows a genericsdrug manufacturer to produce and sell copies as the branded drug's patent expires. Specifically, the French government hopes that this will keep local production sites open and boost employment (10). 

Regarding future growth, another area Sanofi sees as important is emerging markets. In 2010, Sanofi's emergingmarket sales rose by 16% (11). However, some have criticised the company as being too optimistic. In 2011, Sanofi admitted that it had underperformed in Turkey due to "significant price decreases", as well as in eastern European markets because of the ongoing economic crisis (10). Even so, the company retains faith in emerging markets, pointing out that 2010 sales increased by 47% in China and by 19% in Brazil (11). 

The idea that European pharmaceutical companies are set to outperform their US counterparts should be welcome news to politicians, who are eager for the pharmaceutical industry to continue to invest in Europe. According to the European Federation of Pharmaceutical Industries and Associations (EFPIA), the European pharmaceutical industry represents 19.2% of total EU private R&D expenditure and 3.5% of EU manufactured exports (12). For several years, EFPIA has been lobbying European politicians to move away from harsh costcontainment approaches and to create a friendlier environment for the pharmaceutical industry, particularly as some companies have chosen to make new investments elsewhere, such as in the US or emerging markets. Between 1990 and 2008, for example, R&D investment in the US grew 5.6 times, compared with only 3.5 times in Europe (12). 

Whether Sanofi's surge to the top of the rankings, followed by some of its European colleagues, represents a true strengthening of European pharmaceutical competitiveness is hard to say. Pharmaceutical companies remain unhappy with operating conditions in Europe, even if they have their origins in the region. Over the next couple of years, it will be interesting to see whether European companies such as Sanofi, GlaxoSmithKline, Novartis and Roche decide to increase their investment in Europe now that their future financial performance looks promising.  

1. A. Clark, "Big firms have allowed themselves to be seen as detached from society" (The Guardian, 2011). 

2. T. Staton, "Sanofi set to rev past Pfizer in pharma rankings" (FiercePharma, 2011). 

3. K. Grogan, "Sanofi to topple Pfizer as sales league leader next year" (PharmaTimes, 2011). 

4. Evaluate Pharma, "Pfizer to lose crown to Sanofi as world's biggest drug maker" (2011). 

5. M. Alazraki, "The 10 Biggest-Selling Drugs That Are About to Lose Their Patent" (Daily Finance, 2011). 

6. Ranbaxy, "Ranbaxy and Pfizer settle Lipitor litigation worldwide" (2008). 

7. BBC News, "Aventis and Sanofi set for merger". (2004). 

8. Reuters, "Sanofi to buy Genzyme for more than $20 billion" (2011). 

9. The Pharmaletter, "Agreement on Sanofi-Aventis/Genzyme deal prompts lawyer comment on Europe/USA differences on takeovers" (2011). 

10. K. Grogan, "Sanofi signs deal with Pfizer to sell generic Lipitor" (PharmaTimes, 2011). 

11. A. Torsoli, "Sanofi May Be Too Optimistic in Emerging-Markets Forecast" (Bloomberg, 2011). 

12. EFPIA, "Improving Europe's competitiveness" (2011). 

Industry Insider

The next two years may see a shake up in the world's current top pharmaceutical companies, with Pfizer likely to be the only US firm to remain in the top five by sales.

European Pharma Companies Set To Surge Ahead Of US Rivals

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

Improvement in the understanding of the material science (physical, chemical and mechanical) and the engineering of the tabletting 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.

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

Vilayat A. Sayeed, Ph.D, is Director, Division of Chemistry III, FDA/CDER/OPS/OGD.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 tabletting, and press speed. Both of these factors have to be fully understood for making a quality multilayer tablet. 

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

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. 

How can manufacturer/s best use a Quality by Design approach to support the development of a new multilayer tablet?

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.

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

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 tablets can be challenging, but meeting regulatory expectations is crucial. We speak with Vilayat Sayeed from the FDA, to find out more about the critical factors that need to be fully understood.