Stephanie Sutton was an assistant editor at Pharmaceutical Technology Europe.

Stephanie Sutton

The FDA has released a new draft guidance that offers recommendations to companies wishing to respond to unsolicited requests for off-label information, including requests made via social media websites. The 

Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices

 and will be available for comment for 90 days from the date of publication.

According to the guidance, many firms encounter requests for off-label information about their products through websites, discussion boards, chat rooms or other electronic forums, and the FDA recognizes that firms are capable of responding to such requests in a “truthful, non-misleading, and accurate manner”. The guidance states, “Furthermore, as these firms are regulated by the FDA and have their own robust and current information about their products, FDA recognizes that it can be in the best interest of public health for a firm to respond to unsolicited requests for information about off-label uses of the firm’s products that are addressed to a public forum, as other participants... may not provide or have access to the most accurate and up to date information...”

The guidance describes how to determine whether a request is unsolicited or solicited (solicited requests may be considered evidence of a firm’s intent that a drug be used for off-label purposes), and provides recommendations on responding to non-public requests, such as a one-on-one email or telephone call where the request is not made available to the public, and public requests, such as a request on a public internet forum. 

With regards to public requests, however, the FDA is concerned that firms may post detailed public responses to questions about off-label uses of their products in a way that are communicating unapproved information to those who have not asked for it. The FDA recommends that firms only respond to public requests that pertain specifically to its own named product. Caution should also be taken when responding to more general questions. For example, for a question such as “What drug/device can be used for Condition Y”, the firm should not respond if its product has not been FDA-approved or cleared for the mentioned condition. Meanwhile, a company wishing to respond to a more specific question such as “Can Drug/Device X be used for Condition Y”, where X is a named product of the company, should limit its reply to providing the firm’s contact information and shout not include any off-label information. Further information and recommendations are detailed in the guidance.

If a firm responds to unsolicited requests for off-label information in the manner described in the draft guidance, the FDA said that it will not use such responses as evidence of a firm’s intent that the product be used for unapproved or cleared uses. 

Articles

The FDA has released a new draft guidance that offers recommendations to companies wishing to respond to unsolicited requests for off-label information, including requests made via social media websites.

FDA Draft Guidance Offers Social Media Insight

PharmTech: What formulation considerations are required for multilayer tablet manufacturing (e.g., levels of fines, bulk densities and granulation properties)? 

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. 

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.  

The level of fines must always be considered, even for nonlayered 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 because 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. Precompression of the first layer is required for clear demarcation lines between the layers. If the press does not have sufficient upper-punch penetration to precompress the first layer, 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.  

PharmTech: How can common formulation challenges (e.g., combining incompatible products), be overcome?

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 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 be based on the functionality of a particular layer (e.g., immediate release).  

PharmTech: 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 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.  

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 sends them to a weight testing unit, which would be included in the press control feedback loop, to provide in-process checks and weight control. 

Tablet press manufactures 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.  

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

This can be avoided in a few ways. 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 setup 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. Skilled press setup 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. 

PharmTech: What are the unique challenges of applying in-process controls and process analytical technologies (PAT) to multilayer 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.  

PAT is best used during development to understand the variables involved in achieving the formulation design for a quality tablet.... 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. 

   Read the full version of this article and other related content online at 

Industry experts discuss formulation and technical challenges in multilayer tablet manufacture.

Multilayer-Tablet Technology

Pfizer and GlaxoSmithKline (GSK) have entered into separate agreements with the GAVI Alliance to supply pneumococcal vaccines to developing countries. Pneumococcal disease can lead to pneumonia, meningitis, and sepsis and is one of the leading causes of death in children under the age of five in developing countries.

Pfizer agreed to supply as many as 480 million doses of its pneumococcal polysaccharide conjugate vaccine Prevenar 13 during the next 12 years to the GAVI Alliance. Pfizer will supply the doses through an advance market commitment (AMC), a financing mechanism that GAVI piloted to encourage vaccine makers to produce suitable and affordable vaccines for the world’s poorest countries. The agreement builds on the company’s March 2010 commitment to supply 300 million vaccine doses.

“Prevenar 13 was introduced into the childhood immunization program of a developing country within one year of its launch in the United States and European Union—an historic precedent given the average 10–15 year lag between the introduction of newer vaccines in developed versus developing countries,” said Mark Swindell, president of vaccines at Pfizer, in a 

. “One year later, Prevenar 13 is now available in 14 of 16 countries which have launched pneumococcal immunization programs under the AMC.”

The vaccine has been approved in more than 100 countries. To meet growing demand, Pfizer will increase its manufacturing capacities through a combination of capital investment, process improvements, and efficiency measures throughout its supply network.

GSK is also building on a previous March 2010 commitment to supply GAVI with 300 million doses of its Synflorix pneumococal vaccine. Under the 

, the company will supply an additional 180 million doses by 2023, bringing the total to 480 million doses. The vaccine will be used in immunization programs in 71 developing countries. The extra doses were committed following GAVI’s decision to support the introduction of pneumococcal vaccination in an additional 18 countries.

Lower Vaccine Prices for Developing Countries

Pfizer and GlaxoSmithKline have announced separate agreements with the GAVI Alliance to supply pneumococcal vaccines to developing countries. Pneumococcal disease can lead to pneumonia, meningitis, and sepsis, and is one of leading causes of death in children under the age of five in developing countries.

Pfizer, GSK Commit to Supplying Developing World with Vaccines

The European Medicines Agency (EMA) has unveiled its 

 for 2012, which forecasts a slight increase in marketing authorization applications for new medicines compared with 2011. In addition, EMA said that it will, where needed, strengthen the quality, regulatory, and scientific consistency of its assessment process.

According to a press statement, the EMA is expecting around 52 marketing authorizations for new medicines, as well as 13 orphan medicines and 39 generic-drug applications (compared with 47, 13, and 45, respectively, in 2011). The EMA also believes that there will be a 10% increase in requests for scientific advice, including joint advice with the EMA and health technology-assessment bodies.

EMA also provided updates on other focuses and ongoing projects. One important focus for EMA in 2012 will be the implementation of the new pharmacovigilance legislation, which was adopted by the Council and the European Parliament last year and comes into effect in July 2012. Among other things, the legislation is expected to strengthen the current pharmacovigilance system and enable patients to report adverse drug reactions directly to the competent authorities. EMA’s implementation plan for the legislation will involve the establishment of the Pharmacovigilance Risk Assessment Committee, which will have its first meeting in July 2012.

Next year, EMA will also be working on improving its policy for handling conflicts of interest for scientific-committee members and experts and staff. EMA introduced a revised policy on handling conflicts of interest last year, but has since then discussed proposals for further revisions on handling conflicts of interests for members of the management board. The revisions are expected to be adopted in March 2012. 

The 2012 work program will be accompanied by a EUR 222.5-million ($291 million) budget, which represents a 6.5% increase over 2011. The budget comes from fee revenue (EUR 171 million [$224 million] in 2011 compared with EUR 161 million [$211 million] in 2010) and the EU, which will contribute EUR 51 million ($70 million) in 2011 compared with EUR 28 million ($37 million) in 2010. In addition, the special orphan medicines fund awarded by the EU will increase to EUR 6 million ($7.85 million) in 2011, up from EUR 4.9 million ($6.4 million) in 2010.

EMA has unveiled its work program for 2012, which forecasts a slight increase in marketing authorization applications for new medicines compared with 2011. In addition, EMA said that it will, where needed, strengthen the quality, regulatory, and scientific consistency of its assessment process.

EMA Plans 2012 Workload

After reviewing the “shortcomings in quality assurance” that were recently identified at Ben Venue Laboratories’s Bedford, Ohio, facility, EMA issued several recommendations, including product recalls for Ecalta, Liminity and Vistide. EMA’s Committee for Medicinal Products for Human Use has been reviewing medicines manufactured at Ben Venue since early November 2011, after a joint GMP inspection by FDA and the UK and French medicines regulatory agencies highlighted several problems in the company’s quality-management system, particularly in relation to the sterile filling process and possible particle contamination during manufacturing.

In two recent updates on the situation, EMA initiated a precautionary recall of 14 batches of Ecalta, an antifungal medicine, one batch of the diagnostic medicine Luminity, which has already been quarantined, and one batch of Vistide, which is used to treat cytomegalovirus infections of the retina. Originally, the EMA had thought that there would be no risk of lack of sterility of Vistide because the medicine is sterilised at the end of the manufacturing process. However, the EMA now believes that there is a possible contamination risk of particles. 

The agency has also advised healthcare professionals to visually inspect the vials of anticancer medicines Ceplene and Torisel for the presence of particles before administration. Both medicines are considered essential for certain cancer patients and can only be acquired from Ben Venue.

The recommendations mark the second time that EMA has provided guidance for dealing with the shortcomings in quality assurance at Ben Venue. In November, the agency released an 

 stating that, as a precautionary measure, only medicines that are “absolutely essential” to patients and unavailable from another source can be used from the Ben Venue site.

In the earlier statement, EMA explained that the supply of oncology medicines Busilvex, Velcade, and Vidaza was nonessential as alternatives are available in the EU market. As a precautionary measure, a recall of all three medicines was also undertaken.

The review of medicines manufactured by Ben Venue is ongoing, and EMA says that it will make further updates as appropriate. For each product, however, the agency will consider whether supply is essential to meet clinical needs and whether alternative options are available. Current EU stock levels will also be taken into account.

Could Ben Venue’s Manufacturing Suspension Have Been Avoided?

Ben Venue Suspends Manufacturing at Bedford Plant

Ben Venue Laboratories Exits Contract Manufacturing Business

After reviewing the "shortcomings in quality assurance" that were recently identified at Ben Venue Laboratories's Bedford, Ohio, facility, EMA issued several recommendations, including product recalls for Ecalta and Liminity.

EMA Addresses Ben Venue Quality Issues

The United Kingdom’s (UK) life-sciences industry this week welcomed a new, multimillion-pound strategy that aims to both support the industry and encourage innovation in the unsettled economic climate. The UK government has 

 two reports: the Life Sciences Strategy and the National Health Service (NHS) Chief Executive Review of Innovation. According to a press statement, the measures bring together the country’s science base and NHS to “ensure the UK is the best place in the world for companies to invest in the discovery, development and commercialization of medical innovations.”

Key measures outlined by the government in the Life Sciences Strategy include:

The Medicines and Healthcare products Regulatory Agency (MHRA) will bring forward consultation proposals for a new Early Access Scheme to accelerate routes to market approval for breakthrough therapies.

The government will invest more than £300 million ($469 million) to support R&D, including £130 million ($203 million) for stratified medicine and £180 million ($281.5 million) for a biomedical catalyst fund. 

The government will consult on an amendment to the NHS constitution that will open up patient data for clinical research.

A national “Bioresource” will become a “go-to” place for experimental medicine. 

Through the MHRA, the government will work with industry and international regulators to help create a more enabling regulatory environment for the adoption of innovative manufacturing technology.

A web-based UK clinical trials gateway will be relaunched in March 2012, which will provide authoritative and accessible information about clinical trials in the UK.

“The Prime Minister has identified the life-sciences sector as an integral part of the UK economy and one which can continue to thrive and prosper if supported in the right way,” Stephen Whitehead, chief executive of the Association of the British Pharmaceutical Industry said in a statement. “The proposals outlined by the government will contribute towards patients receiving better treatments, more quickly, and build the UK’s attractiveness as a leading hub for medical and health research.”

The government also announced this week a review of innovation in the NHS, which may affect the life-sciences sector. Sir Ian Carruthers, chief executive of the NHS South of England, explained that several key themes emerged from the review including the need to reduce variation in the NHS and to improve compliance with the UK’s medicines price regulatory body, the National Institute of Clinical Excellence (NICE). At the moment, medicines that are approved by NICE may not always be available in all parts of England and Wales.

“We are committed to ensuring that NHS patients have access to clinically and cost-effective drugs and technologies, and that NICE appraisal guidance is promptly delivered throughout the NHS,” said the review. “There should be no local barriers to accessing technologies recommended in NICE appraisals.”

Whitehead added: “We welcome the introduction of a NICE compliance regime to reduce variation of medicines uptake, increase compliance with NICE technology appraisals, and ensure rapid and consistent implementation throughout the NHS... We are also pleased that Government will be opening up access to public datasets including health data on prescribing, with appropriate protection for patient confidentiality. This will allow Life Science firms to better understand how patients respond to particular treatments, which in turn will further aid companies’ research and development efforts.”

The United Kingdom's life-sciences industry this week welcomed a new, multimillion-pound strategy that aims to both support the industry and encourage innovation in the unsettled economic climate.