Having spent the last five years of my life in Tokyo, I wanted to start this month's Editor's comment by offering my very deepest sympathy to all those who have been affected by the earthquake and tsunami in Japan. 

 Rich WhitworthMany of my friends are based in Tokyo where they have been more directly harmed by sensationalist overseas reporting than actual events. Nevertheless, the threat of nuclear fallout has lifted its ugly head and made its impact felt all over the world, fuelling shortages of potassium iodide and subsequent debates over whether stockpiles of emergency medicine are adequate. How well are we prepared for the unexpected? 

It was heartening, though, to read that many pharma companies, both Japanese and international, responded so very quickly with support in terms of monetary aid and medical supplies. Repercussions of the earthquake will no doubt last for many years to come, and I sincerely hope that such support will continue where needed when fickle news broadcasters move onto fresh stories and the spotlight shifts from the benevolent. 

If you want to read more about pharma's response to the situation in Japan, please check our blog at 

In positive news, I am pleased to announce that this month's issue marks something of an evolution for 

. With a number of new regular columns, and a scientific shift in gear, we hope that 

 now offers an even more detailed insight. We now feature a story by our ingredients specialist Patricia Van Arnum, special reports from around the world, and an article showcasing interesting, surprising and sometimes comical regulatory tales from readers. If you have any stories you wish to share, of course anonymously, please send them to our senior compliance officer at 

; hopefully, others may learn from your company's GMP mishaps. 

As always, and perhaps even more important at this time of change, your feedback is extremely welcome, as is your continued support. 

Articles

Having spent the last five years of my life in Tokyo, I wanted to start this month's Editor's comment by offering my very deepest sympathy to all those who have been affected by the earthquake and tsunami in Japan.

From Tokyo with love

The main challenge for tablet manufacturers processing highly potent APIs (HPAPIs) is to protect equipment operators from the inhalation of airborne particles and prevent skin contact with the product during the entire production process: dispensing, granulation, tablet compression, coating and packaging.  

One of the earliest solutions was the use of air suits, but these are not at all ergonomic and protect only the operator. A tremendous amount of cleaning is also still required; all process equipment is contaminated, as are the processing rooms and corridors. Furthermore, in most Western countries, health and safety laws only allow personal protective equipment as a last resort. 

To that end, isolators were introduced, which got the operator out of the air suit and reduced the amount of cleaning work. Operations, from dispensing to packaging, were integrated into large, sophisticated and highly contained isolators. However, as well as requiring large amounts of space and being impractical in terms of cleaning and product changeover, this solution quickly proved to be very expensive. WIP and CIP capabilities were integrated as much as possible, but this made installations even more complex. Moreover, in many cases, such isolator technology proved to be excessive in relation to HPAPI containment and the concentrations being processed.  

One newer, more cost-effective and practical approach is to design inherently closed process equipment using 'containment at the source'. With this technique, the section of the machine in contact with the product is small and carefully isolated from both the electromechanical part of the machine and the environment. Additionally, it is easy to clean without breaching containment.  

A more rational approach can also be adopted towards containment requirements in the various production stages. Indeed, the containment level required of equipment used at the dispensing stage (where the material handled is pure HPAPI in powder phase) is different from that needed in tablet coating (where the HPAPI is diluted and compressed into a tablet). The concentration of airborne API particles also varies during the different operational steps of the tablet production process. The only correct way to assess risk and determine the appropriate containment level for the various process steps/equipment is to calculate real daily intake (RDI) and compare this with the allowable daily intake (ADI).  

Tablet presses for highly potent drugs need to have a compression zone that: 					

 is highly isolated from the remainder of the machine

contains the smallest possible number of mechanical components (in no case should it contain the cam tracks or compression rollers)

features automatic underpressure monitoring and control

is easily removable from the machine for fast product change-over

can be washed down off-line without breaking containment. 			

These requirements also apply to downstream equipment, including the tablet deduster, metal detector and the automatic tablet sampler (and tester).			

The feeding of powder into the tablet press and the collection of tablets into drums or intermediate bulk containers (IBCs) also need to be conducted in a contained way. I recommend split butterfly valves as a solution to achieve this because such valves offer the requisite containment level, and allow for reliable and fast connection and disconnection, while maintaining  containment. In view of this, a highly integrated solution is preferable from powder in-feed to tablet collection, with high-containment interfaces and connections between them. 

With a growing number of increasingly potent new APIs often targeted at specific niche therapeutic applications, the pharma industry will need flexible medium- to small-scale, highcontainment tablet presses that enable swift product changeover with no risk of product cross-contamination. It follows that future design improvements for potent tablet manufacturing equipment will focus on these trends.  

Special Feature

The main challenge for tablet manufacturers processing highly potent APIs (HPAPIs) is to protect equipment operators from the inhalation of airborne particles and prevent skin contact with the product during the entire production process: dispensing, granulation, tablet compression, coating and packaging.

Ensuring Tabletting Safety For High Potency APIs

The public believes that governments and regulators will ensure the safety of the medicines they use. This means that efforts to improve available drug safety systems are always high on agendas — particularly as zerorisk medicines do not exist — but this often requires considerable investment in new electronic technologies. To achieve drug safety objectives, greater demands have also been placed on the pharmaceutical industry. Since 1995, for instance, EU regulations have required new drug applications to include details of a risk management system. Following the EU's large expansion in 2004, there was increased emphasis on drug safety in new legislation and a number of Directives touch upon key topics in this area. 

In September 2010, the European Parliament approved a new set of pharmacovigilance, which were then adopted by member states' Ministers for Health in November.

  Not everyone, however, is satisfied by the new measures. In December, Health Action International Europe (HAI), Medicines in Europe Forum (MiEF) and the International Society of Drug Bulletins (ISDB) issued a joint press release criticising the new proposals as lacking ambition and having a number of faults.

  One major concern was that member states would no longer be required to support pharmacovigilance systems using public funding. There was also unease at the increased role the pharma industry would play in providing the data for pharmacovigilance systems. 

The full extent of medicinal risk is rarely known at the outset of the application; clinical trials are limited in size and feature restrictions in the scope of patients studied, so full information relating to age, gender, ethnicity, restricted co-morbidities and interactions with other medications is impossible at this stage. As such, risk should be managed over a product's lifecycle and reflect the product's use in the wider population. The processes involved in such programmes include risk detection, risk assessment, risk minimisation and risk communication. Because multiple risks may be associated with a product, however, their combined impact in relation to the benefit conferred by the drug must be assessed. The EMA has published guidelines on risk management systems to help companies meet requirements in this area.

EudraVigilance, a joint effort between the EMA and the competent authorities in member states, is a system that forms an integral part of the European approach to risk management. First developed in 2001, EudraVigilance consists of a data processing network and management system for reporting and evaluating suspected adverse drug reactions across the European Economic Area (EEA). By implementing an electronic approach to pharmacovigilance, the authorities hoped to facilitate early detection of possible safety signals associated with medicines. Data generated cover both the development and postauthorisation periods for products, but some critics of the system worry about an over-reliance on companies to report data that is used in the system. 

The EudraVigilance Clinical Trial Module (EVCTM) focuses on the reporting of suspected unexpected serious adverse reactions (SUSARs) during clinical trials. SUSARs from clinical trials must be reported by the trial sponsor to the regulatory body in the country where the event occurred, and it is then that agency's responsibility to electronically report the event to the EudraVigilance system. Study sponsors in the EU must have a EUDRACT number, which functions as a unique identifier of the trial within the EU's clinical trial database. In this way, SUSARs from the same clinical programme being run at different European sites can be collectively assessed and processed. There is also a EudraVigilance Post-Authorisation Module (EVPM) designed for post-authorisation individual case study reports. Similarly with EVCTM, SUSARs must be reported to the national regulatory body, which then electronically reports the event to the EudraVigilance system.  

Because drug safety issues have an international dimension, efforts have been made to enable the global exchange of relevant safety information. ICH, for example, brings together regulatory agencies from Europe, the US and Japan, along with their industry counterparts. ICH's technical working groups have produced several guidelines and documents on the secure electronic exchange of safety data for pharmacovigilance and the EudraVigilance system makes use of such safety information if it arises from outside Europe. SUSARs occurring in a trial outside the EEA must be reported electronically to the EudraVigilance system by the sponsor rather than the regulatory agency. A similar responsibility is assigned to companies regarding safety issues occurring outside the EEA for authorised products. 

Despite the sophistication of the European pharmacovigilance systems introduced since 2005, many believe that improvements can still be made. In 2007, the European Commission (EC) conducted a public consultation exercise to identify weaknesses in existing systems.

  The feedback obtained highlighted the lack of clarity over roles and responsibilities for pharmacovigilance, as well as a perception of excessive bureaucracy within the regulatory agencies in different member states. 

There were also suggestions that the complex reporting rules were implemented differently by regulatory bodies in the various member states, which was seen as holding back efforts to improve pharmacovigilance in the region, particularly with respect to rapid decision-making. Improvements to existing systems were also seen as representing only an evolutionary approach to pharmacovigilance and there was a sense that new thinking is required; indeed, the continued expansion of the EU and the sophistication of the products emerging from innovative R&D programmes seems to demand it.

As an initial proposal, those behind the consultation exercise suggested a two-pronged approach, centred on implementing the existing framework and changing the legal framework. To improve systems, collaborations would be encouraged with the EC's Directorate General for Research, so that studies could be funded to examine the safety of medicines, as well as to develop new methodologies to conduct pharmacovigilance. Communication would also be initiated with individual regulatory agencies to resolve the administrative issues raised by those responding to the public consultation. On the legal front, there was a promise to strengthen transparency rules relating to pharmacovigilance data, and to introduce a clear drug safety standard. To achieve this, the EC decided to involve the EMA because of its experience in coordinating region-wide measures, with the hope that it would lead to the development of a responsive system that enabled rapid safety decisions to be applied equally across all member states. 

Since the EMA's involvement began, the agency has been promoting the establishment of a European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). The idea behind the network is to better coordinate the monitoring of authorised medicines in Europe and to capture the information revealed by ongoing post-authorisation studies on safety and risk-benefit. To achieve these goals, the EMA will collaborate with European experts in pertinent fields. Those behind ENCePP have emphasized that the network aims to complement and not replace existing pharmacovigilance measures in Europe, such as EudraVigilance.

An initial output of ENCePP was to establish a public, fully searchable electronic index of available EU research resources in the fields of pharmacoepidemiology and pharmacovigilance. At the end of 2010, ENCePP published its Work Plan 2011–2012, which outlined its intended strategy and listed deliverables and target dates.9 A steering group will meet quarterly to oversee delivery and coordination with the EMA. 

While there is considerable activity on reforming the approach to pharmacovigilance across the EU, it is not clear how well this has been communicated to the public and physicians. A number of safety scandals over the years have attracted considerable media attention, and made people suspicious about the transparency of regulatory bodies and their interaction with the pharma industry. For example, the TeGenero TGN1412 incident in 2006 in the UK led to considerable public criticism of the MHRA, with some observers believing that existing information in the public domain concerning immunological mechanisms related to the drug's action should have led to a more cautious attitude.

  Presently, there is also controversy in France regarding Servier's Mediator and the failure of the country's regulatory agency to act on prior concerns raised over the cardiovascular safety of the product. On a wider scale, the pain reliever propoxyphene has been subjected to strong criticism regarding its safety; one European physician, who played a role in having the drug withdrawn from the EU market, described it as the "worst drug in history" and claimed that it was responsible for more deaths than any other drug.

It is precisely because of such safety scandals that the joint December 2010 press release by the HAI, MiEF and ISDB called for a more ambitious approach by the European authorities to pharmacovigilance. If European authorities are to gain the public's confidence, as well as that of physicians, future pharmacovigilance measures should also indicate what the legal sanctions will be for those that fail to meet the necessary safety standards. 

1. International Society of Drug bulletins, "Final proposals on pharmacovigilance: Some progress, but a missed opportunity to genuinely strengthen patient safety" (2010). 

2. EMA, "Guideline on Risk Management Systems for Medicinal Products for Human Use" (2005). 

3. ENCePP, "Strengthening medicines safety monitoring" (2007). 

5. Medscape, "Physicians Say Good Riddance to 'Worst Drug in History'" (2011). 

Industry Insider

Europe's approach to pharmacovigilance has room for improvement that European agencies are working on.

Reforming The Approach To Pharmacovigilance In Europe

Q. What are the key drivers for change in the tabletting industry?

 There are many changes affecting the tabletting industry — many of which stem from those taking place in the pharma industry as a whole. The biggest drivers for change are the number of blockbusters coming off patent, and the inexorable growth of generic drug producers and contract manufactures. Both factors place an immediate demand on suppliers of manufacturing equipment for systems offering better speed of response and better value for money. The drive to optimise growth opportunities in developing markets is also leading to greater globalisation. The relocation of facilities away from traditionally high-cost developed markets to lower-cost developing markets means that suppliers of tabletting machines and other pharma manufacturing equipment must be able to meet the needs of these markets and provide increasing levels of support. 

 I think the main focus of the tabletting industry at the moment is on quality, and boosting productivity and manufacturing efficiency. From a tablet compression tooling standpoint, regulatory affairs are making a stronger presence in medium and large-scale operations with regards to more stringent process controls to ensure tablet quality.  

 Looking at the tabletting industry from the point of view of an excipient supplier, the main drivers for change will be the development of new excipients for solid dosage forms that enable better control over physical properties, ultimately improving the quality of the final product. In particular, tabletting manufacturers' needs for improved powder flowability, compressibility and lubrication are key in driving excipient innovation. 

Q. What are the main challenges facing tabletting manufacturers?

 In anticipation of future patent losses, we are seeing tablet manufacturers trying to boost the productivity of their blockbusters to ensure a robust supply chain as a counter to new generic entrants. The challenge here is to increase capacity and reduce costs, without a massive investment. There are a number of solutions on the market that can help achieve this, including multi-tip tooling, die segment turrets and coatings; all of which can facilitate the speed or output of an existing tablet press. Paying greater attention to the fine detail of tooling design and the effective maintenance of both the tooling and press can also help reduce tablet press down time and increase productivity.  

Globalisation and the relocation of products to alternative plants worldwide can also create problems. For instance, subtle changes in environmental conditions and material supply can hinder process replication at a new site, and there is also the challenge of training new operatives. The knowledge and support of key suppliers with global experience can be vital in supporting this process, and the speed and effectiveness of the supplier's response can be critical.  

Finally, the pharma industry must juggle the margin loss from the former blockbusters with the need to invest in new drug development. The net result of this is increased pressure to reduce cost and increase efficiency in all manufacturing operations.  

 One of the major challenges for the tabletting industry is the competition that is now coming from developing, low-labour index countries. However, competition also has its benefits because it encourages innovation and process improvements. The need for reduced costs and manufacturing times has also led a number of manufacturers to use direct compression, which offers reduced costs and processing times. However, caution is required because some blends using this method result in unfavourable powders that are not suitable for tabletting. 

Looking more in-depth at the tabletting manufacturing process, there are a number of common challenges that must be faced such as capping, sticking and tool binding. To overcome these issues, many tablet manufacturers have their punch or die configurations modified to be better suited for the product being compressed. This isn't a new trend as such, but is becoming more prevalent as tablet manufacturers attempt to reduce costs by minimising powder processing.  

 The manufacturing processes for tablets can be divided into three techniques: wet granulation, dry granulation and direct compression. 

With wet and dry granulation techniques, the challenges relate to the complexity of the many steps involved in obtaining a powder blend exhibiting required flowability and compressibility parameters. For the simpler process of direct compression, the main challenges are to guarantee excipient properties and control any variables. 

According to a survey conducted in 2010, poor formulation design accounts for 34% of common problems encountered during tablet manufacturing, while problems in blend uniformity account for 15%.

  This means that around 50% of the problems encountered by tabletting manufacturers could be solved by adjusting the mechanical properties of powders, such as flowability, dilution potential and compressibility.  

The remaining problems are linked to tabletting equipment. As the excipient's performances should be tested on different tablet presses, the development of a tablet press simulator could help gain a better understanding of the physical behaviour of excipients, and blends thereof, under compression. Conventional presses equipped with data acquisition systems could also provide information on compression cycles, ejection force and heckle plot analysis. 

Q. What has been the greatest innovation in the tabletting industry during the past few years?

 It is difficult to single out one innovation because there have been a number that have had a significant influence on the industry, including direct compression, which is an extremely efficient process in terms of process control and tableting parameters. In-line process inspection is another technology that has significantly impacted tablet production processes by helping to control variability. Tablet coating technologies have also developed considerably and can provide innovative solutions for drug dissolution and controlled release. From a tablet compression tooling perspective, we have seen multi-tip tooling (increasing the number of tablets produced from a single punch), die segments (increasing the number of punches in the tablet press) and tool coatings, all of which have had a positive impact on tablet manufacturing.  

The tablet compression industry has seen many innovations in recent years, such as wash/clean in place technology, product containment, exchangeable die disc and die shells, die segments and tablet-in-tablet technology, to name but a few. In my opinion, the greatest is not so much a new innovation but rather a new acceptance of an older technology: multi-tip tooling. Although multi-tip tooling has been used in tablet compression for over a century, it's only in the past couple of years that it has now been refined and accepted by the pharmaceutical industry. Multi-tip tooling can help manufacturers to significantly increase production; for instance, one tablet manufacturer we were working with was producing six to seven thousand tablets/min using a single tip, but became capable of producing 24 to 30 thousand tablets/min after switching to 4 tip. The number of punch tips per tool is typically related to the punch size and tablet size. Companies can contact their tooling manufacturers to find out if their product is a candidate for multitip tooling. 

 The demand for reduced costs and simpler formulations has led to further development of the direct compression technique. In this technique, powder characteristics are critical. The need for improved powder properties, without having to develop a new chemical entity, has been met by the development of co-processed excipients, where several excipients are processed simultaneously to obtain synergistic effects in functionalities. A number of articles have been published that highlight the advantages of co-processed excipients for tabletting.

Q. What features/improvements would you like to see in future tabletting methods/processes?

 As a supplier of tablet compression tooling, we would welcome tablet press manufacturers embarking on some degree of standardisation (e.g., key positions) in line with global tooling standards across all types of tablet press. This would benefit the end users by increasing the potential for interchangeability of tooling across tablet presses and individual production sites/markets worldwide. Lubrication-free tablet presses would also help tablet manufacturers to minimise product loss caused by contamination. Finally, we would welcome innovation around the in-line monitoring of formulations prior to compression (e.g., humidity and granule size), which could do much to mitigate process variation throughout the tablet production process. 

 There is a strong need for integrated temperature monitoring and controls for high-speed output tablet presses. A growing number of tablet formulas and granulations are sensitive to tablet press operating temperature and the heat generated by tablet compression.  

Sensing functions would also be useful for both new and retrofit tablet presses to give feedback on whether a product has started to pick or stick on the lower punch before producing a barrel of tablets. Also, detecting the necessary forces required to remove a tablet from the lower punch could set new guidelines to eliminate question marks over differences between development and production. Although, maybe this isn't possible! 

 Simplification is the key word! Simplification of formulas and processes will ultimately help save time and costs.  

Among compression techniques, direct compression remains the simplest technique available and requires less time and energy. On the other hand, this technique is highly demanding in the number of required excipient properties. The ideal excipient for direct compression should exhibit constant particle sizes and shapes as these have a strong influence on density and compressibility. Compactability is also affected by tablet size and weight, and the type of press used in manufacture. In the end, in-depth excipient knowledge linked to process equipment will be a win–win strategy for developing innovative excipients for the tabletting industry. 

Pharmaceutical Technology Europe brings together suppliers of tabletting equipment and excipients to discuss the challenges, innovations and latest trends in the tabletting industry.

Tabletting: Expert Views

According to media reports, April could see the long-awaited conclusion to the EU and India's Free Trade Agreement (FTA), but only if arguments about intellectual property provisions and their impact on generic medicines can be resolved! 

The FTA has been under negotiation between the two regions since 2007. According to the European Commission, India is one of the EU's most important trade partners; however, India still maintains "substantial tariff and nontariff barriers that hinder trade with the EU". In 2009, it was estimated that an FTA would help boost bilateral trade between the EU and India to more than €160 billion by 2015.  

In 2009, MEPs hoped that the agreement would be signed by the end of 2010, but negotiations are still ongoing. One particular hurdle has been concern from numerous organisations that the FTA will impact access to generic medicines — particularly for developing countries, which strongly rely on India for cheap alternatives to branded medicines. India has been able to produce so many affordable versions of medicines patented elsewhere because it did not grant patents on medicines until 2005 when it began complying with World Trade Organisation standards. Prior to this time, patents were only offered on processes, which meant that a product or medicine could legally be duplicated as long as it used a different process. Unsurprisingly, this landscape initially deterred many western companies from launching products in India.  

Now, the EU is pushing to further increase India's intellectual property laws to help combat global counterfeiting. According to the European Parliament, India is one of the major sources of counterfeit medicines seized by EU customs — accounting for 30% of total seizures. 

A number of organisations believe that the new laws may potentially affect access to Indian generic medicines. International charity, Medecins sans Frontieres, explained in a statement: "The EU is pushing for intellectual property provisions in the FTA that exceed what international trade rules require. The most damaging measure is so-called 'data exclusivity', which would act like a patent and block more affordable generic medicines from the market, even for drugs that are already off patent, or do not merit a patent to begin with." 

Opposition against the FTA provisions also sparked an international day of action at the beginning of March, with more than 5000 participants. 

The EU has acknowledged these concerns, but believes that the FTA will not affect access. A statement from the EU Delegation to Tanzania explained that it believes the fears are based on a misunderstanding of the EU's objectives and negotiation position. According to the statement, the EU has proposed a clause in the negotiations to ensure that nothing in the FTA prevents India from producing and exporting medicines to developing countries. "The EU is fully aware that India is an important provider of generic medicines to other developing countries; the FTA currently under negotiations between India and the EU is certainly not intended to restrict the ability of India to continue doing the same for domestic and international consumption." 

The next round of talks concerning the FTA will take place in April, and some believe that the agreement could be concluded around this time, although the actual signing is unlikely to take place before the next EU–India summit. European pharma companies will no doubt be watching closely. If pushed through, the provisions will better protect pharmaceutical products and go some way to combating counterfeits.  

Sanofi-aventis has received a Warning Letter for cGMP violations at a facility in Germany. According to the FDA, the company had not established or followed appropriate written procedures to prevent microbiological contamination of sterile drugs.  

Conflict-of-interest rules may have been breached by the EMA's former executive director taking up an advisory role within the private pharma sector only a few weeks after leaving the agency. A letter outlining the reservations has been sent to the European Commissioner. 

The FDA has filed a consent decree of permanent injunction against McNeil, a subsidiary of Johnson & Johnson, for cGMP violations. The action prevents McNeil from manufacturing and distributing drugs from its facility in Fort Washington (PA, USA) until the FDA determines that its operations comply with the law. 

AstraZeneca has discontinued production of its Pulmicort (budesonide) 100 and 200 µg/dose HFA (hydrofluoroalkane) pressurised metereddose inhaler due to manufacturing issues related to technical aspects of the device. This issue is not related to the API. 

News

Particle size is a potentially important variable in pharmaceutical production and efficacy. In solid or suspension delivery systems, for example, dissolution and solubility characteristics, which impact the bioavailability of the API, are often controlled by particle size, though not necessarily in ways that are intuitively obvious. The Noyes-Whitney equation describes dissolution rate as being directly proportional to particle surface area, so one might expect small particles to dissolve more rapidly than large particles; however, actual dissolution studies show that this is not always the case. In the majority of these instances, this phenomenon can largely be explained by the relative surface roughness of the particles, which gives them a larger surface area.  

In suspensions, Stokes' law relates settling velocity (i.e., precipitation or aggregation) to the physical characteristics of the fluid and the size of particles in the suspension. In practice, finer particles create a more stable suspension; however, the stability of particle dispersion also depends on the balance of repulsive and attractive forces. If the particles have little or no repulsive force, there will eventually be some manifestation of instability, such as aggregation. As such, it is not only particle size that matters, but also particle shape, size distribution and zeta potential.  

Particle size can also affect the behaviour of a formulation during processing. In direct compression tabletting, particle size can influence segregation behaviour and the compressibility of a formulation that, in turn, can affect the consistency of tablet weight and composition, how the press operates, and the mechanical properties of the finished product.  

Particle size also has a critical effect on the content uniformity of solid dosage forms, with poor results often arising from a mismatch of drug and excipient particle size and density. Poor content uniformity may also result if drug particle size distribution is too large, but it is generally desirable to approach the upper edge of the permitted drug particle size range because reducing particle size too dramatically can exacerbate drug agglomeration and mixing problems.

Similarly, particle size can affect the flow properties of powders and pastes. Increasing the polydispersity of particle size in powders can improve flow properties; for example, in the case of powders subject to flow in an industrial process, a bimodal distribution of particle sizes can also ensure better flow during processing.

  For pastes, where viscosity is often important, there is usually an optimum particle size distribution (PSD) that yields minimum viscosity whilst maintaining the particle volume fraction. The PSD will also have a direct influence on the texture of the finished product. 

There are several methods, some of which are outlined below, that can be used to investigate particle characteristics. All give useful information on their own, but it is often more instructive, or simply necessary, to use the techniques to complement each other. Using laser diffraction methods to understand particle size distribution, and microscopy to understand shape, for example, helps to build a more detailed picture of why a powder behaves in a certain way. 

It is also important to note that different techniques for measuring particle size can yield different answers. This is not a new observation. In 2004, the AAPS Journal published a report on particle size analysis and called for greater harmonisation of methods and a wider appreciation of the difficulty of reconciling results obtained by different methods of particle sizing.

  Since then, observers have noted that some progress has been made via the Laser Diffraction Measurement of Particle Size USP monograph (USP <429>),

  released in 2005, and the USP written standards regarding lipid emulsions (USP <729>). The European Pharmacopoeia also has a chapter on laser diffraction

  and, more recently, ISO13320:2009 was published, creating a new standard, and guiding the way for robust method development. 

One key factor influencing the choice of technologies for particle size analysis is the desire to correlate lab results with production information gathered at various stages of the product cycle. However, each stage of product development and manufacture has a different focus, meaning that the analytical tools employed will vary.  

Quality by Design (QbD) encourages the development team to identify and quantify correlations between key product variables and clinical performance, and to understand how these are controlled by the manufacturing process from the outset. At this stage, there is an urgent need for detailed knowledge and for instruments that provide a cost-effective route to its acquisition.  

As a project moves through pilot plant development and into manufacture, the focus switches to tracking process dynamics and continuous monitoring, which means the measurement speed of the particle characterisation technology employed becomes critical. In particular, there is a need for systems that enable real-time process scoping, optimisation, monitoring and control. During production, effective analysis allows manufacturers to ensure that product quality targets are met consistently, thereby reducing reliance on pre-release quality control testing.  

When it comes to quality control, the demands on particle characterisation systems change again. Here, one may not need to know the actual size of the particles. It may be enough to have a parameter that can be measured reproducibly and that correlates with a known performance characteristic of the drug. For example, if the particles are non-spherical, a Laser Light Scattering method may give a wildly inaccurate value for the true diameter of the crystals, yet give results that are consistent and, therefore, allow the setting of a specification. 

Because the tools employed will vary at each stage, maintaining a consistent specification during transitions from one technique to another can be complicated. As such, technologies that can be configured for both laboratory and process use, or those that neatly dovetail, are advantageous. Laser diffraction and automated image analysis are two such techniques. 

Laser diffraction is a rapid measurement technique and an established on-line technology that enables real-time, on- or in-line particle size analysis for both wet and dry systems. Off-line laser diffraction can also be highly automated and robust after successful method development. 

Laser diffraction can be used to develop particle size specifications in the early stages of a project, and then transferred into production via on-line technology. Many powders have particle size specifications and laser diffraction is often used as the sizing technique of choice for quality control in this regard. For some applications, however, size data alone will be insufficient to either fully characterise or define a material.  

As imaging technology has become more freely available, the influence of particle shape on performance has become increasingly well appreciated. Automated imaging overlays size data with statistically relevant information about shape, and can be useful for detailed development work in troubleshooting and root cause analysis. If two samples behave differently but are classified as identical by particle size analysis, morphology of the particles may hold the key. 

Imaging is much faster than manual microscopy — data for tens of thousands of particles can be obtained in minutes — and, importantly, it produces more statistically relevant data. Parameters such as circularity, convexity and elongation can be measured and used to precisely define the shape distributions of a particle population. Each image can be scrutinised by eye if necessary, whereas size versus shape plots enable the identification of discreet particle populations like APIs and excipients with overlapping size distribution. The integration of spectroscopy into imaging systems adds a further powerful dimension to automated image analysis; Raman spectroscopy, for example, can characterise particles by size, shape and chemical composition.  

Switching between image analysis and laser diffraction needs care — image analysis software is constrained to two dimensions — but it is entirely feasible and offers many advantages; for example, during method development for laser diffraction, imaging can identify the presence of any agglomerates. Imaging also adds a layer of detail that cannot be obtained through laser diffraction particle size analysis alone. 

There are also times when manual microscopy proves a valuable addition to the particle characterisation armoury. In particular, microscopy plays a valuable role in identifying unknown and unwanted particles, i.e., foreign bodies, when linking X-ray diffraction to the scanning electron microscope to obtain data on chemical composition. In addition, it can be useful for assessing the mixing quality of two ingredients within a tablet. Similarly, infrared imaging microscopy can be used to analyse the distribution of organic molecules or particles in complex mixtures, such as tablet formulations and sediments. In both cases, these techniques can demonstrate whether there is good content uniformity and, by implication, whether there is good distribution of API across a production run. 

It is one thing to know the size, shape and appearance of particles, but one also needs to know how these parameters affect product and process performance. As noted above, small particles don't necessarily dissolve more rapidly than large particles of the same chemical.  

In early phase development, it is critical to investigate how particles of the proposed new API will dissolve in the body. Using methods specified in the pharmacopoeia, one can mimic the environment of the mouth and gut, and determine where in the GI tract an API is likely to dissolve. This information can potentially justify whether the candidate molecule is worth pursuing. One might also investigate whether the particle size within the finished product has an impact on release rates. 

Rheological studies are also valuable because subtle changes to particle size, distribution and shape can affect the rheology positively or negatively. With medicines that are suspensions, for example, it is important to control viscosity to prevent settling during storage, and to mitigate inconsistent dosing.  

Many techniques are available to establish, measure and monitor particle characteristics, and there is much that can be learned about the effect of particle size and morphology on end product performance. However, when using results to set specifications or manage quality control, it is always necessary to seek out the detail of the methodology used to generate data because different methods 'see' particles in different ways. 

To take an obvious example, one might have a particle size specification such as "50% of particles (by mass) must be less than 80 μm" set after sieve tests on representative batches. This would not necessarily be confirmed by analysis of the same batches using laser diffraction and reporting the d50 (diameter of the 50th percentile), even though, at first sight, the two specifications might seem to be equivalent. In the case of laser diffraction, the key parameter is particle volume rather than mass, and particle orientation and shape are not accounted for in the same manner. 

Using techniques that permit the recording of visual images makes it possible to give further supporting evidence to the robustness of a particle characterisation method that generates only numeric data. In this way, it is possible to ensure that the procedure is characterising primary particles and not agglomerates, and that the method of analysis does not have a destructive effect on the distribution being recorded. 

The author would like to acknowledge Malvern Instruments. 

 Laboratory Manager, Physical Science Laboratory, RSSL

3. J. Netterwald, Pharmaceutical Formulation and Quality (December/January 2010). 

, Chapter 2.9.31, Laser Diffraction Measurement of Particle Size, Supplement 5.6 (2006). 

Analytical

Particle characteristics can affect pharmaceutical formulations and products in a number of ways, and a variety of techniques are available that enable particle monitoring and characterisation.

Challenges Of Particle Characterisation

The FDA provides an electronic reading room on its website that provides access to a great deal of useful information, including copies of Warning Letters issued by the FDA. Reviewing these letters can be useful because they provide insight into the inspection techniques and concerns of FDA inspectors. Additionally, they can be used to perform gap analyses of the processes used at your company in preparation for an FDA inspection. This article provides a summary of the review conducted for Warning Letters issued between 2000 and 2010 for products that are aseptically filled and for manufacturing processes identified as non-sterile. 

Employee training in a pharmaceutical company almost always includes instilling a 'healthy fear' of regulatory agency inspections. Most, if not all, countries have established governmental agencies that are responsible for the safety and efficacy of the medicines manufactured, sold and distributed within their country. These agencies typically have the legal authority to go into production facilities to assess various aspects of the manufacturing and distribution facility. As such, employees learn that the company's viability is dependent upon successfully passing these inspections.

The notification that a regulatory inspector is planning a visit to a company site can trigger concern regarding the expected outcome and frantic activities often take place in preparation. Since the implementation of the FDA's Systems Based inspection programme, however, it has become more difficult to successfully prepare for an inspection. 

Originally, the Systems Based Inspection guide was introduced by the FDA as a pilot programme.

  The method for evaluation entailed a portion of the FDA's regional offices using the programme for a 6-month trial period in 2001. The results were successful and the FDA officially implemented the programme in 2002 as the 

Compliance Program Guidance Manual for FDA Staff: Drug Manufacturing Inspections

Prior to the implementation of this guidance, companies prepared for inspections by thoroughly reviewing and assessing products with upcoming pre-approval inspections because these products tended to be the focus of the inspection. Under the new guidance, however, the FDA reviews companies in a systematic approach, which makes it more difficult to prepare. One valuable way to prepare for an inspection is to look at the FDA's inspection findings from other companies to determine which types of observations are also issues at your company.  

For this study, the FDA's website was searched to review the Warning Letters issued between 2000 and mid-2010. The searches were limited to those referencing aseptic processing or non-sterile processing, and the data were summarised.

Data obtained from the Warning Letter review were analysed to determine the appropriate section of the GMPs, as stated in 21 CFR Part 211, that had been violated. This was then summarised to determine how many observations were made for each section of the GMPs. Following determination of the number of observations made, a ranking was performed to determine which section resulted in the most observations (rank = 1) and which resulted in the least (rank = 33 for aseptic; rank = 44 for non-sterile processing). Items with the same number of observations were given the same ranking within the type of processing used. These results are summarised in 

. The top ten categories of observations for each type of processing are summarised in 

Table 1: Number of FDA observations made per section of the Code of Federal Regulations, 21 CFR Part 211.			

Although the product processing types were different (aseptic 

 non-sterile), among the top ten categories of observations, several made the listing for both types of processes; for example: responsibilities of the quality control unit, equipment cleaning and maintenance, written procedures and deviations, general requirements (laboratory controls), testing and release for distribution, batch production and control records, and production record review.  

Table 2: Top ten categories of FDA Warning Letter observations.			

The following sections describe some of the types of observations made by the FDA relative to the cited GMP section. Only sections that ranked in the top five for each process type are covered. 

Design and construction features — Rank number 1 for aseptic

Examples of the types of observations made include: 					

Material flow throughout the building is not designed to prevent contamination.

Lack of separate or defined areas to prevent contamination or mix-ups.

Failure to have an adequate air supply filtered through high efficiency particulate air filters under positive pressure, regardless of whether it is or is not laminar.

Failure to have an adequate system for monitoring environmental conditions or the system established is inadequate. Air sampling is not performed at critical sites. 

Control systems used to prevent contamination do not include floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable.

Failure to establish an adequate system for cleaning and disinfecting the room and equipment.

Studies were not performed to show the adequacy and efficacy of the cleaning and disinfection process used.

Airflow pattern studies were not performed where connections were made.

Inadequate containment control and monitoring programmes.

Appropriate written procedures for prevention of microbiological contamination were not established or followed.

General requirements (laboratory controls) — Rank number 1 for non-sterile manufacturing and number 7 for aseptic processing

Failure to follow scientifically sound and appropriate sampling plans.

Laboratory controls do not include establishment of scientifically sound and appropriate specifications.

Laboratory equipment is not sufficiently calibrated and qualified at suitable intervals, in accordance with an established written programme.

Laboratory controls are deficient. Procedures allow for averaging of out-of-specification (OOS) and within specification analytical test results from separate samples.

New methods do not include sensitivity (limit of quantitation), linearity, accuracy or an appropriate precision method.

Failure to qualify the supplier of the raw material.

Methods used for stability testing are not stability indicating.

Method validation is inadequate. It does not address all variables.

Laboratory controls do not include determination of conformance to written specifications for the acceptance of each lot within a shipment of components used.

Test devices are deficient. They did not meet established specifications and were used.

Failure to ensure that complete data derived from all tests are documented at the time of performance.

Failure to follow your stability programme.

Control of microbiological contamination — Rank number 2 for aseptic processing

Failure to follow procedures designed to prevent microbiological contamination.

Failure to adequately assess and monitor the aseptic environment.

Failure to establish and follow appropriate written procedures.

Manufacturing

The author reviews Warning Letters issued between 2000 and mid-2010 for aseptic processing and non-sterile processing, and determines how many observations were made for each section of the GMPs.