Germany's pharmaceutical market is currently valued at around €38 billion, making it the largest pharmaceutical market in Europe (1). Historically, the country has been attractive for launching new medicines because companies were largely free to set their own prices. In addition, Germany possesses comprehensive pharmaceutical coverage and a high level of public funding. In general, most pharmaceuticals are eligible for reimbursement through Statutory Health Insurance, which covers about 90% of the German population. 

In 2008, German pharmaceutical prices were described by the Organisation of Economic Cooperation and Development as the highest among its 30 member countries (OECD now has 34 member countries), for both patented and generic drugs (2). Not surprisingly, in 2008, the number of products possessing a marketing authorisation in Germany far exceeded that of any other European market. Physician freedom in prescribing has helped drive pharmaceutical sales as well and even when measures were introduced to set volume targets for physicians, they had limited impact. In particular, it was difficult to hold physicians to account because the collection of data to convincingly prove overspending was problematic and because physicians would claim exceptional circumstances for their choice of prescribing (2). Similarly, in 2002, measures were introduced to allow pharmacists to substitute a cheaper drug whenever possible, but physicians still retained the right to oppose the decision. 

Despite market successes in Germany, the pharmaceutical industry expressed concerns that there were unnecessary delays in the approval of medicines. In 2003, a task force representing both industry and the government was convened to look at enhancing innovation in the German pharmaceutical market by examining steps to accelerate the national marketing authorisation procedure. Following recommendations in 2007, structural changes were made to the Federal Institute for Pharmaceuticals and Medical products (Bundesinstitut für Arzneimittel and Medizinprodukte, BfArM) to make it more independent and efficient in its decision-making. Some of the outcomes were, however, unfavourable for the industry, such as proposals for increased private funding of BfArM's activities, mainly coming from application fees related to the applicants' turnover (2). Pharmaceutical companies complained about the measures, but the changes appear to be representative of the steady shift in government decisions that do not necessarily align with industry viewpoints. 

The key sign that times were about to get tougher for pharmaceutical companies in Germany came with the introduction of a new healthcare bill known as AMNOG (Arzneimittelmarkt-Neuordnungsgesetz) in 2010. AMNOG formally signalled the end to the free pricing era in Germany, much to the displeasure of the pharmaceutical industry, which has complained that the reforms will lead to €2 billion in lost revenue per year (3). 

In contrast to the previous freepricing environment, companies are now required to demonstrate the benefits of their drugs early in the development process. Following an independent appraisal, these benefits are factored into the permitted price. AMNOG reforms required these data for all new reimbursable drugs and combination therapies launched after 1 January 2011. Although pharmaceutical companies have constantly opposed the measures, they are now firmly established.  

Under the new system, companies must compile a cost–benefit dossier comprising a variety of information about their product that must be submitted within three months of product launch. The Federal Joint Committee (G–BA), a group featuring representatives from the medical profession, insurance companies and hospitals, examines the evidence for the product to decide whether any added value will be recognised (3). The G–BA may decide that another body known as IQWiG (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen) should conduct the cost–benefit analysis. The resulting outcomes for a product can be major added benefit, significant added benefit, unquantifiable additional benefit, or no added benefit. Although the evolving German system may seem to bear some resemblance to the work of the National Institute for Health and Clinical Excellence (NICE) in England and Wales, IQWiG has refuted such comparisons. Unlike NICE, IQWiG does not use the quality-adjusted life year (QALY) measure in its assessments. 

One of the irritations for the pharmaceutical industry is that it believes it has already demonstrated the value of its product by receiving regulatory approval in Germany, and yet is now being asked to compile an independent set of information to convince another official body to obtain a price. Companies see the measures as additional bureaucracy and a means by which the government can steadily pressure the industry into reducing its prices to curb spending. Now when companies prepare for product launch in the German market, they must also plan ahead and invest in the compilation of a cost–benefit dossier, as well as construct value arguments to satisfy the designated experts at the G–BA and IQWiG. They must proactively source a range of information, which they may be called upon to justify, from clinical therapeutic data and product costs through to information on potentially comparable products. For smaller companies, this process is particularly burdensome and there is little experience that they can draw upon. A further complication is that there continues to be legal debate in Germany about whether the new cost-benefit methods are consistent with federal social law (4). 

According to the current system, if it is decided that a product does not demonstrate medical value, then the reimbursement amounts are set by the G–BA at prices for a selected "comparably effective drug." If the G–BA decides that a product demonstrates medical value then companies must enter into negotiations with the Federal Association of Statutory Health Insurance Funds to set the price. Although full details of the pricing negotiations are not made public, it can be presumed that a higher level of benefit being granted by the G–BA should give companies greater negotiation power in such discussions. This is likely to have been the case for AstraZeneca's antiplatelet treatment Brilique (ticagrelor), which was deemed cost-effective for people with acute coronary syndromes. 

If agreement is not possible in pricing negotiations then the decision goes to arbitration, during which period the price is capped at a level dictated by the price in other European markets. This aspect is worrying because many other European countries use Germany as a reference when considering what is appropriate for their markets. In the past, with free pricing, companies benefitted from inclusion of the high German price. However, if a product is capped during arbitration, other countries could use the lower price as a reference rather than waiting for a final German pricing decision. 

In June 2012, the European Federation of Pharmaceutical Industry Associations (EFPIA) called for a revision of the new German system after consultations with its member companies (5). EFPIA stated that Germany had previously been a leader in Europe in providing quick access to new treatments and that the new system was threatening this benefit (5). It cited its members' opinion that early experience with AMNOG had been disappointing and that the underlying law around this legislation was flawed and ambiguous (5). EFPIA also called AMNOG inflexible and stated that there was unwillingness on the part of the authorities to consider creative solutions for the problems it was creating. A particular criticism centred on the choice of comparators needed to convince assessors in the cost benefit dossiers. EFPIA noted that this often differed from the comparator selected after consultation with the EMA when planning ahead for regulatory approval. They argued that by choosing comparators that had little relation to those selected for a drug's development programme, the German authorities were in effect trying to drive prices of innovative products down towards those of generics. EFPIA has called for more consultation and discussion on how decisions are reached. 

The change in the German pricing environment brings the country in line with developments elsewhere in the world, where prices are being linked to cost–benefit analyses. Companies have become concerned that these systems bear no relation to requirements in seeking regulatory approval for a product, but have a huge bearing on the success of a product when launched. They consider these measures to be bureaucratic and confusing. At an early stage in a drug's lifecycle, the availability of information on a product's benefit in different populations is limited, but companies are being asked to generate this information almost in parallel with regulatory approval. Furthermore, if Germany reaches an unfavourable pricing decision then this may have a bearing on the prices in countries that use the German market as a reference point. Critics, however, will point to the benefits that companies can derive from the system. If they can impress the assessors in Germany, as may be the case with AstraZeneca and Brilique, they will have a powerful argument in convincing other countries that their drug is of value and merits a higher price. 

1.  Business Monitor International, "Germany Pharmaceuticals and Healthcare Report Q3 2012" (Business Monitor International, 2012).  

2. V. Paris et al., "Pharmaceutical Pricing and Reimbursement Policies in Germany" (Organisation for Economic Co-operation and Development website, 2008). 

3. vfa, "AMNOG: Key Issues and Consequences" (vfa website, 2010). 

4. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR), "Germany – Pharmaceutical" (ISPOR website, 2009). 

5. EFPIA, "EU Pharmaceutical Industry Leaders Call for Revision of German Model for assessment of New Medicines" (EFPIA website, 2012). 

Articles

Industry Insider

Germany has shifted from a market where the pharmaceutical industry could enjoy considerable pricing freedom to a sensitive market influenced by cost-containment policies.

Changing German Market Depresses the Pharma Industry

Most of the products affected by growing drug and ingredient shortages are cancer medications, anesthetics used for patients undergoing surgery, emergency medications and intravenous electrolytes. Sterile injectables, which dominate short-supply lists globally, are prime targets for shortages because of limited production lines and capacity challenges. Everything from manufacturing delays, to increased market demand, to product discontinuation can cause a shortage problem. Unfortunately, it's the patients who need these crucial drugs who are bearing the brunt of the problem. 

In the US, FDA is tackling the issue with new guidance. A recently issued draft document, 

Notification to FDA of Issues That May Result in a Prescription Drug or Biological Product Shortage,

 is meant to address growing concerns by increasing communication between industry and regulators. The draft guidance clarifies that the "sole manufacturer" (i.e., the only applicant currently supplying the market with the drug product) holds responsibility for reporting such information. The document also calls out certain actions that may lead to a temporary or permanent drug supply problem, such as delays in acquiring active or inactive ingredients, equipment failures and manufacturing shutdowns. Manufacturers will need to notify FDA of these issues if they could lead to disruption in supply. The agency also asks industry to notify it on a voluntary basis when certain problems (e.g., stability concerns, facility transfer) could "reasonably" be expected to lead to a shortage or disruption.  

I have high hopes for solving the global drug supply problem. In 2010, for example, 38 shortages were prevented in the US alone because companies notified FDA of potential problems. Meanwhile, in the UK, where parallel trade has led to certain drug shortages, the Medicines and Healthcare products Regulatory Agency has pledged to address shortages and is working to better track which products are in short supply and who is exporting them. As long as companies do their part, these regulatory efforts should pay off. Just as we tell our children, it's always best to tell the truth—even if it hurts a little to do so—because in the end, it's simply the right thing to do. 

Angie Drakulich is the editorial director of PharmTech Europe.

Most of the products affected by growing drug and ingredient shortages are cancer medications, anesthetics used for patients undergoing surgery, emergency medications and intravenous electrolytes.

The Truth About Drug Shortages

Monday 2 July saw the implementation of Europe's pharmacovigilance legislation, which comprises Regulation (EU) No 1235/2010 and Directive 2010/84/EU. In line with the new legislation, EMA has released a series of modules that together will form guidance on good pharmacovigilance practices (GVP). Each module will cover one major process in the safety monitoring of medicines. 

 Jeff Spielman/Photographer's Choice RF/GettyImages			

Seven modules have been finalised so far and another two are open for public consultation until 24 August 2012. The guidance is expected to comprise 16 modules in total, with the remaining ones to be released later this year, and will apply to marketing-authorisation holders, as well as to EMA and other regulatory authorities in the EU.  

The seven finalised modules cover the core processes of the new pharmacovigilance legislation that needed to be published for the 2-July implementation deadline. They are: 					

Module I: Pharmacovigilance systems and their quality systems

Module II: Pharmacovigilance systems master files

Module VI: Management and reporting of adverse reactions to medicinal products

Module VII: Periodic safety update reports

Module VIII: Post-authorisation safety studies

All of the modules were open for consultation earlier this year and the received comments have been incorporated into the final versions. 

At the end of June, EMA also released Module III on pharmacovigilance inspections and Module X on additional monitoring for public consultation.  

Module III provides guidance on planning, conducting, reporting and following up on pharmacovigilance inspections in the EU. The objectives of the inspections will be to determine that the marketing authorisation holder has appropriate personnel, systems and facilities in place to meet pharmacovigilance obligations. Inspection results will be used as a basis for enforcement action (if necessary) and information on the conduct, outcome and follow-up evaluation will be made publicly available as part of the overall transparency of pharmacovigilance activities.  

The aim of Module X is to rapidly detect and respond to any potential safety hazards associated with the use of medicinal products by collecting additional information as early as possible. The module is divided into two sections; one providing general principles for assigning additional monitoring status; and the second describing the operation of the EU network regarding supervision of monitoring status. 

According to EMA, the pharmacovigilance legislation is the biggest change to the regulation of human medicines in the EU since 1995 and will establish a clear legal framework for postauthorisation monitoring. In addition, EMA hopes the legislation will make roles and responsibilities clear, minimise duplication of effort and free up resources by rationalising and simplifying adverse drug reaction reporting and periodic safety update reporting. 

In June, the European Commission also published Regulation (EU) 520/2012 in the Official Journal of the European Union. The regulation complements the 2010 pharmacovigilance legislation by providing more technical details that will need to be observed by marketing authorisation holders, EMA and national authorities in day-to-day application of the new legislation. 

The EMA has launched an investigation into Roche after an inspection found that thousands of potential safety reports, including 15161 deaths, connected to Roche medicines had not been evaluated to determine whether they should be reported to regulators as adverse drug reactions.  

GlaxoSmithKline has agreed to plead guilty and pay $3 billion (2.4 billion Euros) to resolve criminal and civil liability resulting from the unlawful promotion of certain drugs, failure to report safety data and alleged false price reporting practices. According to the Justice Department, it is the largest healthcare fraud settlement in US history. 

The US Supreme Court has upheld the provision of the country's Affordable Care Act. Among other points, the decision means that FDA can continue to implement the new biosimilars programme. Implementation of US reform now depends on who controls the White House and Congress after the elections, as well as individual states implementing the law.  

Merck Serono has revealed its "final efficiency program" for operations in Switzerland, which includes confirmation of the closure of sites in Geneva and Coinsins. The majority of job transfers and cuts are expected to be completed later this year. Closure of the Geneva site is planned for mid-2013 and for 2014 for the Coinsins site. 

News

Pharmacovigilance rules enter into effect.

The challenges of conducting cleaning validation are documented in the literature. R. Baffi et al., for example, described the diverse analytical challenges arising in validating cleaning procedures for biopharmaceutical products produced by recombinant DNA, in which a broad range of potential residual cellular components and trace levels of detergents must be quantified (1). M.A. Strege et al. described the total organic carbon (TOC) analysis of swab samples for cleaning validation of bioprocess fermentation equipment and discussed accuracy, limits of detection, limit of quantitation, linearity and precision (2). K.M. Jenkins et al. compared the advantages and disadvantages of multiple methods for cleaning validation, including high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), spectrometry, TOC and conductivity (3). A.J. Holmes et al. described the TOC method for measuring residual aspirin on aluminum, stainless steel, painted carbon steel and Plexiglas (4). The latter two authors describe the swab challenge as noted in the FDA guide to inspections of cleaning surfaces. 

For cleaning validation using a TOC analyser, the following types of sampling methods are available: 					

These methods were compared using a total organic carbon analyser (TOC-LCPH, Shimadzu) to measure residual pharmaceutical products and their constituent substances.  

Residue samples were prepared by applying various types of pharmaceutical products and their constituents to stainless steel pots. Compounds with varying levels of water solubility (i.e., soluble, insoluble and very insoluble) were evaluated to determine how each method performed. The water-soluble substances were dissolved in water and the water-insoluble substances were dissolved in ethanol or acetone, as shown in 

. Solution concentrations were adjusted to 2,000 mgC/L (i.e., carbon concentration of 2000 mg/L). 

Table I: Substances used for residue measurements.			

The carbon contents of tranexamic acid (C

) were estimated by molecular formula. Carbon contents of Gentashin ointment (aminoglycoside antibiotic) and Rinderon ointment (corticosteroid) were determined with the TOC analyser by adding samples of the ointments directly into a solid-sample combustion unit (SSM-5000A, Shimadzu) since molecular formula for these compounds are unknown. 

  area on the surface of a pot to which 100 µL of each solution was applied and dried. Thus, there were 200 µg carbon in the sample at each application site.  

In rinse sampling, the final rinse water from the cleaning of a production-equipment unit is used as the TOC measurement sample. This method is suitable for systems that cannot easily be disassembled, such as clean-in-place (CIP) equipment and narrow tubing. Sampling is considered to be difficult if the residues are not soluble in water. 

To evaluate recovery of the various substances using this method, 100 mL of pure water was stirred for 15 min in the stainless steel pot that contained a patch of dried sample. TOC measurement was conducted on the rinse solution using a TOC analyser (TOC-LCPH, Shimadzu) with a high-sensitivity catalyst. The analysis of TOC was by acidify and sparge method. The calibration curve was a 2-point curve using 0–3 mgC/L potassium hydrogen phthalate aqueous solution. A 500-µL injection volume was used. Because the carbon content in each of the residue measurement samples was 200 µg, the theoretical TOC concentration (i.e., if all carbon were to dissolve in rinse water) would be 2 mgC/L. 

 shows the measured TOC concentrations for representatives of water-soluble samples (a, tranexamic acid), water-insoluble samples (b, isopropylantipyrine) and water-insoluble ointments (c, Gentashin ointment). The other samples (i.e., anhydrous caffeine, nifedipine, and Rinderon ointment) have similar profiles to the samples with corresponding solubility. 

For the blank, measurement was conducted in the same way using water in a stainless steel pot without dried sample applied to its surface. The measured blank concentration was subtracted from each TOC concentration and divided by the theoretical value of 2 mgC/L (i.e., the theoretical concentration if all of the sample were to dissolve in the water) to determine the rate of recovery, as shown in 

Figure 1: Total organic carbon (TOC) concentrations for (a) tranexamic acid, (b) isopropylantirine, and (c) Gentashin ointment using rinse sampling.			

All samples were run in triplicate, and the coefficient of variation values (CV) are shown in 

 along with the TOC concentrations and the recovery rates. 

Table II: Measurements using rinse sampling.			

Water-soluble tranexamic acid and water-insoluble anhydrous caffeine had high recovery rates, as expected. Moreover, water-insoluble isopropylantipyrine and nifedipine had high recovery rates. However, recovery rates of Gentashin ointment and Rinderon ointment were both low, at less than 20%. Consequently, the TOC rinse method, while acceptable for some substances, is unsuitable for ointments and other similar substances. 			

Swab-sampling with water-extraction method

Swab sampling with water extraction consists of wiping the inside surface of the production apparatus with a fibrous swab material, extracting the adhering material with water and conducting TOC measurement of the extract solution. Since the residue is physically wiped off from a fixed area of the surface, sampling efficiency is high. Residues that are insoluble in water, however, are difficult to extract with water. Accordingly, evaluating water-insoluble residues with this method may present similar difficulties to the rinse-sampling method. 	

Figure 2: Total organic carbon (TOC) concentrations for (a) tranexamic acid, (b)isopropylantirine and (c) Gentashin ointment using swab sampling with water extraction.										

To evaluate the recovery of the various substances using swab sampling with water extraction, the sample applied to the stainless-steel pot was wiped off with a 5-cm

  piece of fibrous swab material, which was placed in a glass jar containing 100 mL of pure water. The fibrous swab material (Texwipe Alpha 10 swab washed in pure water and dried) consists of polyester so that very little organic material is extracted from the swab itself. The residue was extracted by stirring for 1 h, and TOC measurement was conducted using the same equipment and conditions used for the rinse-sampling method. Three replicates of each sample were run. As in the rinse-sampling method, because the carbon content in each of the residue measurement samples is 200 µg, the TOC concentration (i.e., theoretical TOC) in the extraction solution would be 2 mgC/L if all of the sample were wiped off. Representative data are shown in 

. For the blank, measurement was conducted in the same way by wiping the stainless pot, which had no sample applied before conducting extraction. Recovery rate was determined using 

Table III: Measurements using swab sampling with water extraction. 			

Water-soluble tranexamic acid and anhydrous caffeine had high recovery rates as expected. Moreover, water-insoluble isopropylantipyrine and nifedipine had high recovery rates of approximately 90%. However, recovery rates of Gentashin ointment and Rinderon ointment were both low, at less than 10%. These results show that the TOC water-extraction rinse method is reliable and accurate for some substances, but unsuitable for ointments and perhaps other such substances due to the low recovery rates. 			

Swab-sampling with direct-combustion method

Swab sampling with direct combustion consists of wiping the inside surface of the production apparatus with a piece of quartz filter-paper swab material, and then conducting measurement using a direct-combustion carbon-measurement system. The swab material with adhering residue is measured directly (i.e., without first extracting with water) in a TOC analyser using a connected solid-sample combustion unit or module (SSM). 

Figure 3: Total organic carbon (TOC) concentrations for (a) tranexamic acid, (b) isopropylantirine and (c) Gentashin ointment using swab sampling with direct combustion.			

To evaluate the rate of recovery of the different types of substances using this method, paper swab material (45-mm diameter Advantec quartz glass paper QR-100, heat treated at 600 °C for 15 min) was used to wipe the sample adhering to the stainless steel pot and placed in the sample boat, which is then placed in the SSM (SSM-5000A, Shimadzu) connected to the TOC analyser (TOC-LCPH, Shimadzu). Three replicates of each sample were run. The SSM uses 400 mL/min oxygen as a carrier gas. The calibration curve is a 1-point calibration using 1% C glucose aqueous solution. The total carbon (TC) content on the swab was measured directly by the TOC analyser. Selected measurement data are shown in 

Table IV: Measurements using swab sampling with direct combustion.			

Since the carbon content in each of the residue measurement samples is 200 µg, the TC value would be 200 µg if all of the sample were wiped off. For the blank, measurement was conducted in the same way by wiping the stainless pot, which had no sample applied. The measured blank value was subtracted from each TC value, and then divided by the theoretical value of 200 µg using 

 to determine the rate of recovery. The results are shown in 

. A high recovery rate of about 100% was obtained for all the substances, regardless of whether they were water soluble or water insoluble. 

Table V: Summary of measurement results.			

The measurement methods used here and their respective recovery rates are summarised in 

. When using the rinse- and swab-sampling methods, some of the water-insoluble substances had high recovery rates while others had low recovery rates. It is thought that this may be due to differences in the affinity with which the substances adhere to the stainless steel pot. Accordingly, it is possible that residue evaluation using these methods would be difficult for substances with low recovery rates.  

In contrast, high recovery rates were obtained for all the substances when using the swab sampling with direct-combustion method, regardless of whether the substances were water soluble or water insoluble. Therefore, this method is considered to be the most versatile measurement method for conducting cleaning validation, especially when multiple compounds are being manufactured in the same vat, if the compounds are unknown, or if there is a possibility the known compounds will decompose into other compounds. 

 is industrial business unit manager at Shimadzu Scientific Instruments, 7102 Riverwood Drive, Columbia, MD 21046, tel. 800.447.1227, 

 is a scientist at Shimadzu Applications Development Center, Kyoto, Japan, 

*To whom all correspondence should be addressed.  

Submitted: 17 Nov. 2011. Accepted: 12 March 2012. 

Peer review

Cleaning validation provides assurance that the quantity of residual substances collected from equipment surfaces are within permissible limits, helping to ensure quality control and safety in pharmaceutical manufacturing facilities. Three different cleaning validation methods for measuring the carbon in residual samples of various pharmaceutical substances were compared.

Carbon Measurement Methods for Cleaning Validation: Comparing Direct Combustion with Rinse and Swab Sampling Methods.

PTE: One tool for bioavailability enhancement is to create amorphous solid dispersions through processes such as hot-melt extrusion (HME) or spray drying. What factors come into play to decide whether to produce the amorphous solid dispersions through HME or spray drying?  

 Both spray drying and HME can be used to produce amorphous dispersions that enhance the bioavailability of poorly soluble compounds. There are a number of factors that come into play when deciding to progress an amorphous dispersion. These include performance, projected dose, stability and manufacturability. When choosing which technology to employ for optimising the amorphous dispersion formulation's performance, two key factors are the physical-chemical properties of the API and the phase of development, which influences the amount of API available for formulation development. 

Important physical–chemical properties include the solubility of the API in either a solvent (for spray drying) or polymer (for HME), the melting temperature of the API and the LogP value of the API. For spray drying, the solubility of the API in the solvent is crucial to ensure a readily scalable and viable process, whereas for HME, the solubility of the API in the polymer is crucial to ensure a thermodynamically stable system. The particle size of the API, which influences the dissolution rate during processing, can also be crucial for complete dissolution into the polymer melt. 

The processing temperature is important for HME because the API must either melt to form a dispersion or dissolve through high shear forces into the molten polymer. If the processing temperature is too high, the compound or the polymer used in the formulation can degrade. Typically, 200 °C to 225 °C is regarded as the upper processing-temperature limit for an effective HME process. Although compounds can be extruded at higher processing temperatures, this physical situation often produces a partially crystalline formulation instead of an amorphous dispersion. 

The phase of development is also an important factor in process selection. For example, for early-stage or discovery-support activities, API availability is often limited. This limited API availability tends to make spray drying the preferable process because its feasibility can be determined with as little as 50 to 100 mg of API, whereas several grams of API are typically required to develop an initial HME process. For APIs that are amenable to HME, typically after proof-of-concept clinical studies, when hundreds of grams of API are available, an initial spray-drying process can be converted from spray drying to HME. 

Advantages and disadvantages of each technique

PTE: What are the advantages and disadvantages of using HME compared with spray drying to produce the amorphous solid dispersion? 

 HME has two primary advantages. First, no solvents are used, so solvent cost and recovery are not a factor in cost-of-goods or environmental health and safety considerations. Second, the equipment footprint for HME is relatively small when the process is scaled up. 

The primary disadvantage of HME is that the compound must be melted or dissolved in molten polymer at high temperatures. Thus, it is less applicable to compounds with higher melting temperatures or those that are thermally labile. This disadvantage can be partially remedied by including nonvolatile and volatile plasticisers in the formulation, which lower the temperatures required to produce an amorphous dispersion. Because an ideal amorphous dispersion is homogeneous at the molecular level, a second disadvantage is that the homogeneity of the final dispersion can be affected by process parameters such as temperature, screw configuration, screw speed and feed rates; this aspect, combined with the relatively large minimum batch size, results in cost and risk during early development. 

PTE: What are the advantages and disadvantages of using spray drying compared with HME to produce the amorphous solid dispersion? 

 Spray drying offers the following advantages: it is applicable to a broader chemical space for the API and types of dispersion polymers that can be used (due to dissolution of the API in a volatile organic solvent), it does not expose the API to excessive heat during manufacture of the amorphous dispersion and it can be scaled down, requiring smaller quantities of API during formulation screening. 

Spray drying has a few disadvantages as well: solvents are used and must be recovered, equipment footprints are larger, and capital and operating costs are higher. These considerations must be taken into account when designing later-stage or commercial processes and facilities, but they are not insurmountable—as evidenced by successful operation of Hovione's PSD-4 and PSD-5 spray-drying facilities and the fact that spray drying is used extensively outside of the pharmaceutical industry at large scales.  

PTE: Can you be specific in terms of achieving desired bioavailability/solubility of the resulting product, stability of the resulting product, the ease and/or scalability of the manufacturing process, and other process conditions that are important in deciding which approach to use?

As mentioned previously, both spray drying and HME can be used effectively to manufacture amorphous dispersions. A formulation produced by either process would be expected to yield similar bioavailability and physical stability as long as both processes yield a homogeneous amorphous dispersion with appropriate final-powder particle size, which generally requires milling for HME. If either of the processes fails to produce a homogeneous amorphous dispersion, the resulting formulation will likely underperform. This situation is most common when a compound fails to completely dissolve during the hot-melt-extrusion process due to either the high melting temperature of the compound, or the low solubility of the compound in the molten polymer, resulting in crystallisation or phase separation when the melt cools. 

Spray drying and HME are readily scaled and commercial-scale equipment is available at many pharmaceutical organisations and several contract research organisations. 

PTE: On an industry level, can you highlight recent advances in HME with respect to improvements in the manufacturing process and its application to different types of APIs? 

 HME is a technology that has been widely used in pharmaceutical and nonpharmaceutical industries for decades. Recent advances in HME include efforts to reduce processing temperatures by including plasticisers and reduce the residence time of the compound and polymer during processing. Numerous research groups are looking at nonvolatile plasticisers, such as vitamin E or triethyl citrate, to reduce processing temperatures. Others have reported the use of volatile excipients, such as supercritical carbon dioxide, to avoid decreases in the final dispersion's glass-transition temperature that occur with traditional plasticisers. There have also been recent reports of the use of equipment that has significantly reduced residence time. Professor McGinity's research group at the University of Texas has developed a process called Kinetisol to make amorphous dispersions. It is based on equipment that was developed to recycle plastics, which can reduce the residence time of the API and polymer at processing temperatures from minutes to tens of seconds. 

PTE: On an industry-wide level, can you highlight recent advances in spray drying with respect to improvements in the manufacturing process and its application to different types of APIs? 

While spray drying is a well-established process, innovations in formulation approaches and process equipment are occurring. In formulation, there is an increasing need for a third component in the dispersions to help deliver challenging compounds aimed at novel biological targets. Often, a surfactant is added to help increase the dissolution rate or dispersion-particle wetting or to provide an alternate micelle source to enhance drug solubility in vivo.  

Equipment advances include novel spray-dryer and cyclone designs to collect the dispersion particles more efficiently. This is especially significant for particle-engineering applications such as inhalation, which requires the manufacture and collection of particles with a narrow particle-size distribution for delivery to the lung. As part of the effort to formulate compounds with low solubility in organic solvents, Bend Research has developed a "hot process," which allows a drug suspension to be heated to high temperatures—often well above the ambient-pressure boiling point of the solvent—in a heat exchanger to dissolve the drug immediately before it is introduced into the spray dryer. This decreases solvent use and results in a more scalable process. 

Special Report

Enhancing bioavailability can be achieved through hot-melt extrusion (HME) or spray drying.

Bioavailability Enhancement: When to Use Hot-Melt Extrusion versus Spray Drying

Approaches centre on ways to optimise process conditions and operability.

Process chemists face the challenge of developing cost-effective and efficient commercial manufacturing routes for APIs. They encounter the challenges of increasing product yield, achieving greater stereoselectivity and regioselectivity, and improving process conditions, such as temperature and pressure, all in a means to produce a high-quality pharmaceutical compound in a safe manner A variety of tools may be used in this effort, including the application of green-chemistry approaches, such as biocatalysis, solvent replacement and continuous-flow chemistry, to help achieve more efficient chemical transformations under improved reaction conditions. 

In June 2012, Codexis, a company specialising in biocatalysis, and Yi Tang, professor in the Department of Chemical and Biomolecular Engineering at the University of California at Los Angeles (UCLA) (US), were awarded the "2012 Greener Synthetic Pathways Award" as part of the US Environmental Protection Agency's (EPA) Presidential Green Chemistry Challenge Awards for developing a biocatalytic route for making simvastatin, the active ingredient in Merck & Co.'s anticholesterol drug Zocor, which is now off patent (1). Codexis and Tang won the award this year after having made prior submissions of the new process in 2010 and 2011 (2–4).			

For the simvastatin route, Codexis licensed technology from Tang. The previous synthetic routes to simvastatin involved converting lovastatin into simvastatin by adding a methyl group that required protecting and then deprotecting other functionalities in the lovastatin molecule in a multistep synthesis. In the first route, lovastatin was hydrolysed to the triol, monacolin J, followed by protection with selective silylation, esterification with dimethyl butyryl chloride and deprotection. The second route involved protecting the carboxylic acid and alcohol functionalities, methylating the C2' carbon with methyl iodide and deprotecting the product. These routes were inefficient because they produced less than 70% overall yield and were mass-intensive due to protection and deprotection (1–4). 

The route developed by Tang and his group circumvented protection and deprotection and resulted in greater atom economy, reduced waste and overall less hazardous reaction conditions. First, they cloned LovD, a natural acyltransferase produced by 

 that is involved in synthesising lovastatin and that can accept nonnatural acyl donors. Recognising that LovD might be a type of simvastatin synthase and a starting point for creating a new biocatalytic process, they evolved the enzyme toward commercial utility (1–5). Codexis licensed Tang's technology, engineered the enzyme further and optimised the simvastatin manufacture. 

The biocatalyst LovD selectively transferred the 2-methylbutyryl side chain to the C8 alcohol of monacolin J sodium or ammonium salt. The acyl donor, dimethylbutyryl-S-methylmercaptopropionate (DMB-SMMP), is efficient for the LovD-catalysed reaction, is safer than traditional alternatives and is prepared in a single step from inexpensive precursors, according to the awards summary report (1). Codexis licensed this process from UCLA and subsequently optimised the enzyme and the chemical process for commercial manufacture. Codexis carried out nine iterations of 

 evolution, creating 216 libraries and screening 61,779 variants to develop a LovD variant with improved activity, in-process stability and tolerance to product inhibition (1). The approximately 1000-fold improved enzyme and the new process pushed the reaction to completion at high substrate loading and minimised the amounts of acyl donor and of solvents for extraction and product separation. In the new route, lovastatin is hydrolysed and converted to the water-soluble ammonium salt of monacolin J. (1–5). 

As specified in the Presidential Green Chemistry Challenge Awards summary report, the genetically evolved variant of LovD acyltransferase from E. coli uses DMB-SMMP as the acyl donor to make the water-insoluble ammonium salt of simvastatin. The only coproduct of simvastatin synthesis is methyl 3-mercaptopropionic acid, which is recycled. The final yield of simvastatin ammonium salt is more than 97% at a loading of 75 g/L of monacolin J. It avoids the use of several hazardous chemicals including 

-butyl dimethyl silane chloride, methyl iodide and 

-butyl lithium. More than 10 metric tons of simvastatin have been manufactured using this new process (1).  

Pfizer also employed a more environmentally approach in developing a biocatalytic route to making atorvastatin, the active ingredient of Lipitor and submitted the process as an entry for consideration to the US EPA's Presidential Green Chemistry Challenge Awards (1). The new process incorporated a waterbased 2-deoxyribose-5-phosphate aldolase (DERA) enzyme at the beginning of the route to make a lactol from an amino aldehyde (i.e., 3-phthalimidopropionaldehyde; PPA) and acetaldehyde (1). The synthesis eliminated the use of cyanide or azide moieties to introduce nitrogen because it is already present in the lactol. In contrast to the original synthesis, the DERA enzyme set both stereocenters with high selectivity in water at room temperature. Converting the resulting lactol into isopropyl acetonide atorvastatin (IAA) involved only four high-yield chemical steps (oxidation, esterification, deprotection, Paal Knorr). The IAA product was isolated as a solid and IAA was converted to atorvastatin (1). The new synthesis eliminated the previous high-pressure hydrogenation step with its associated metal catalysts. It also avoided pyrophoric n-butyl lithium and its associated butane waste gas. FDA approved the new manufacturing process in April 2010, and Pfizer manufactured commercial-scale validation batches in 2011 and is currently transitioning to full-scale commercial manufacture, according to the US EPA's Presidential Green Chemistry Challenge Awards summary report (1). 

The Grignard reaction is a well established reaction in organic chemistry, but it poses some challenges in scaling up to commercial scale: strongly exothermic activation and reaction steps; heterogeneous reactions with potential problems suspending and mixing the reaction mixture; and operational hazards posed by ethereal solvents such as diethyl ether (1). Eli Lilly developed safer Grignard chemistry using a continuous stirred tank reactor (CSTR) that allows continuous formation of Grignard reagents with continuous coupling and quenching operations, a process in which the company submitted an entry to the 2012 US EPA Presidential Green Chemistry Challenge Awards (1). According to the entry, the CSTR approach mitigated hazards by operating at small reaction volumes, performed metal activation only once for each campaign, and used 2-methyltetrahydrofuran as a Grignard reagent and reaction solvent, resulting in products with enhanced chemo- and stereo-selectivity. Relative to batch processing, the continuous approach allowed steady-state control and overall reductions up to 43% in magnesium, 10% in Grignard reagent stoichiometry and 30% in process mass intensity (1).  

Improved solvents for making diaryl aldimines

Imines are intermediates used in many pharmaceutical syntheses. Diaryl aldimines, for example, are used in the synthesis of the anticancer drug Taxol (paclitaxel) and the anticholesterol drug Zetia (ezetimibe) (1). Traditional syntheses of diaryl aldimines often require hazardous solvents and include energy-intensive, multihour reflux steps. Although some imine syntheses use more benign solvents or conditions, they still require long reaction times, recrystallisation, or other environmentally harsher procedures. Jacqueline Bennett, professor in the Department of Chemistry and Biochemistry, State University of New York (SUNY) Oneonta (US) and the SUNY Research Foundation (US), developed a process that used ethyl L-lactate as a solvent to synthesize imines. The process was submitted as an enty to the 2012 US EPA's Presidential Green Chemistry Challenge Awards (1). According to the awards summary report, the method was efficient under ambient conditions, required less solvent than other methods, had a median yield of more than 92% and had a median reaction time of less than 10 min (1). The resulting imines were generally sufficiently pure h without recrystallisation as the polarity of ethyl L-lactate was modulated by adding water. The starting materials remained dissolved, but the imine crystallised out of solution as it formed (1). Although traditional methods often drive reactions forward by removing water, this method drove the reaction forward by removing the product through crystallisation, according to the summary report (1). Bennett and her research team have synthesised nearly 200 imines using this method and filed a US patent for the process (1, 6). 

Another interesting entry to the US EPA's Presidential Green Chemistry Challenge Awards involved the use of ethylene in fine-chemical synthesis developed by T. V. RajanBabu, professor in the Department of Chemistry, Ohio State University (US) (1). According to the awards summary report, practical methods using carbon feedstock sources as starting materials to form enantioselective carbon–carbon bonds are not common. A broadly applicable reaction using ethylene to install vinyl groups enantiomerically, as developed by RajanBabu, could have significant impact in fine-chemical synthesis.  

RajanBabu and his team developed highly catalytic (substrate–catalyst ratio up to 7,412:1) protocols for nearly quantitative (isolated yields of more than 99% and highly selective (approximately 100% regioselectivity; enantiomeric ratios of more than 99:1) codimerisation of ethylene and various functionalised vinylarenes, 1,3-dienes, and strained alkenes. These reactions proceeded under mild conditions (–52 °C to 25 °C; 1 atmosphere of ethylene) to produce intermediates, such as 3-arylbutenes, which can be transformed to nonsteroidal anti-inflammatory drugs (NSAIDs) in two steps. These reactions consume both starting materials, leaving no side products. Successes include highly enantioselective syntheses of common NSAIDs, such as ibuprofen, naproxen, flurbiprofen and fenoprofen, from the corresponding styrenes and ethylene (1).  

Cyclic and acyclic 1,3-dienes also underwent efficient enantioselective addition of ethylene. Syntheses of several 1-vinylcycloalkenes and 1-substituted-1,3-butadienes achieved yields up to 99%, according to the awards summary report (1). The approach has also been applied to other biologically relevant classes of compounds, including bisabolanes, herbindoles, trikentrins, steroid D-ring 20S- or 20R-derivatives, (–)-desoxyeseroline, pseudopterosin A–F, G–J and K–L aglycones, and helioporins (1).  

Chemicals, intermediates, and reagents as well as byproducts of synthetic processes can have toxic properties and be present as impurities at low levels in an API or final drug formulation. The detection and removal of these impurities are of crucial importance to process chemists, particularly in the case of genotoxic impurities. One of the potentially genotoxic impurities based on structural alerts is acrolein, an a, -unsaturated aldehyde that is used as a building block in the production of pharmaceuticals (7). Researchers at MIP Technologies, a subsidiary of Biotage, and the Universität Dortmund in Germany recently reported on an approach for selective removal of acrolein from APIs using iodixanol as a model API. The acrolein scavenging performance of polystyrene- and silica- based aldehyde scavengers in organic media in the presence of the API iodixanol was tested. Several scavengers were tested, and the resins that the showed highest binding efficiency and selectivity were further evaluated. The most effective and selective scavenging was obtained with polystryene–amine, which removed up to 97.8% of acrolein and only 2.0% of iodixanol within 20 min using a batch-mode extraction procedure (7). 

1. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2012 Award Entries and Recipients" (Washington, DC, 2012) 

3. US EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2010 Award Entries and Recipients" (Washington, DC, 2010). 

4. US EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2011 Award Entries and Recipients" (Washington, DC, 2011). 

6. J. Bennett, Green Synthesis of Aryl Aldimines Using Ethyl Lactate, US Patent Application 20110196174 (Aug. 11, 2011).  

Ingredients

Scaling Up API Syntheses

Issue PDF

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Pharmaceutical Technology Europe, August 2012 Issue (PDF)

Why has nanoparticle engineering become an important strategy for tackling solubility, stability and other drug delivery challenges?

Wu: For poorly soluble drug candidates, various enabling techniques have been used to enhance the apparent solubility and dissolution rate. Bioavailability can benefit from a higher API concentration achieved by the formation of a supersaturated solution. However, some compounds exhibit very fast crystallisation and it is extremely difficult to inhibit this property from a compound’s meta-stable solid-state form (e.g., amorphous or solid dispersions) during shelf-life periods. Moreover, these compounds will quickly precipitate and/or crystallise in the body, which can significantly reduce the in vivo drug concentration leading to poor drug efficacy. 

Nanoparticle engineering is an alternative method for such compounds in a formulation that uses the special physical property of nanoparticles. The high-surface area to volume ratio of nanoparticles provides a tremendous driving force for diffusion so that nanoparticles of a poorly soluble compound can be distributed as nano-sized particles in the body, thereby avoiding crystallisation or precipitate issues. The smaller size helps to improve the surface–volume ratio of drug candidates, increasing the dissolution rate and improving API bioavailability. 

What advantages does nanoparticle engineering offer over other approaches being used to address solubility and drug delivery issues? 

Wu: Several commercialised nanoparticle drug products have successfully demonstrated that nanoparticle engineering can increase bioavailability and improve pharmacokinetic profile, reducing the frequency of dosing. Furthermore, food–drug interactions (the food effect) can be reduced because the pharmacokinetic profile of nanoparticle formulations are not affected by the Fed and Fasted state, as exampled by the cholesterol lowering drug, TriCor (Abbott Laboratories). By using nanoparticle technology, Janssen’s Invega Sustenna (Xeplion in Europe) became the first once-monthly atypical antipsychotic medicine approved for schizophrenia in the US. All of these advantages were achieved using nanocrystal technology. Various nanocarrier techniques have also been used to provide extra benefits in controlled release and targeting delivery. 

What popular nanoparticle approaches are currently being exploited by researchers and pharmaceutical companies as part of efforts to improve drug solubility? 

Wu: Two different nanoparticle approaches, nanocrystals and nanocarriers, are being well used by researchers and pharmaceutical companies. The nanocrystals technique involves decreasing the particle size of a crystalline drug to improve the bioavailability. Nanocrystals are one of the most successful nanoparticle approaches used so far, evidenced by several commercial drug products, including Pfizer’s Rapamune, Merck and Co’s Emend, Abbott Laboratories’s TriCor, and Janssen’s Invega Sustenna. They are also a popular method for proof-of-concept studies, with laboratory-milling equipment and ultrasonic assisted methods being introduced into laboratories specifically for nanoparticle preparations. 

Nanocarriers can be used to deliver drugs more effectively to targeted cells. The use of liposomes is well established in drug-delivery applications and polymer-based nanocarriers have progressed enormously in recent years, with several applications demonstrating advantages in targeting delivery, such as Regulon’s Lipop (Liposomal Cisplatin), Cerulean’s CRLX288 (biodegradable polymeric nanoparticle conjugated to docetaxel and BIND’s Accurin technique for BIND-014 docetaxel. 

How are advances in nanoparticle engineering and crystal engineering being combined to tackle the challenges of poor solubility? What new techniques are emerging that show promise in this area?

Wu: There are two emerging techniques showing promise in the field of nanocrystal techniques. Nanococrystals combines nanoparticle engineering and crystal engineering for the formulation of nanoparticles. Conventional nanocrystals technology usually focuses on improving the dissolution rate to enhance bioavailability. Amorphous nanoparticle engineering has also been studied to increase API concentration. However, the use of nanoparticles of the amorphous drug in the formulation needs to overcome the challenge in stabilising the amorphous form during both manufacture and the shelf life of the drug product. Nanococrystal application can potentially increase API concentration without creating disadvantages in the stability and powder properties of the amorphous form. Another emerging application to the nanocystals technique is the layer-by-layer coating technique applied to nanoparticles. Coated nanoparticles will not only improve particle stability, but also offer the possibility of designing nanopaticle surfaces that can achieve controlled release and targeted delivery. 

Interview

Dedong Wu, senior scientist at AstraZeneca, explains how nanoparticle engineering and crystal engineering can aid solubility.

Pharmaceutical Technology Europe-08-01-2012