european Industrial Pharmacy Issue 16 (March 2013) by European Industrial Pharmacists Group (EIPG)

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GENERICS UPTAKE IN EUROPE – THE IMPACT OF PRICING AND REIMBURSEMENT POLICIES Results of a survey on pricing and reimbursement policies regarding generics in Europe are described and discussed. by Nina Schafroth and Marco Meuri

IMPROVING THE QUALITY OF INJECTABLES Primary packaging, such as elastomeric closures for injectables, need to be strictly controlled to reduce particles and the rejection of finished product. by Mike Schaefers

THE FUTURE OF PHARMA? The author applies evolutionary theory to pharmaceutical companies, whereby they need to adapt to survive. by Brian Smith

WORKING TOWARDS A STANDARDISED IDENTIFICATION Identification and coding of products is essential to avoid counterfeiting and so ensuring the safety of the supply chain. by Peter Belden

TRAINING – DOING IT WRONG Training in Good Manufacturing Practices is not just a matter of learning the regulations but of understanding them. by Michael Anisfeld

COST VERSUS QUALITY IN PV It may be false economy to choose a pharmacovigilance service provider based on cost rather than quality. The author suggests ways of avoiding problems. by Steve Proudlove

AN INDUSTRY CAREER FOR A YOUNG PHARMACIST A young Portuguese pharmacist shows that with the right skills and passion, it is possible to enter the European Pharmaceutical Industry by João da Silva Duarte

regulars 3 21 22 25

EDITORIAL COMMENT REGULATORY REVIEW NEWS FROM THE EIPG EVENTS

ISSUE 16 • MARCH 2013 www.industrialpharmacy.eu www.eipg.eu

associate editors

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PHARMACY

Belgium: Philippe Bollen

Issue 16 March 2013 Bulgaria: Valentina Belcheva

ISSN 1759-202X

Czech Republic: Ales Franc

EDITOR Joe Ridge, MRPharmS

Denmark: Marie Fog

PRODUCTION Dave Johnson

Finland: Anni Svala

SUBSCRIPTIONS Jill Monk

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european INDUSTRIAL PHARMACY is the official publication of the European Industrial Pharmacists Group (Groupement des Pharmaciens de l’Industrie en Europe) www.eipg.eu

Cover picture: Vials in use (see pages 9-12). Image: Fotolia

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editorial Final Editorial as President of the EIPG As I write this final editorial as President of the EIPG I can only reflect on the changes which have occurred within the EIPG and within the Pharmaceutical Industry. It is against a back drop of yet more significant site closures being announced by GlaxoSmithKline and more markedly AstraZeneca with the wholesale relocation of its R&D Centre and Corporate Headquarters to Cambridge. What does that mean for the Pharmacist wanting to enter the Industry or an Industrial Pharmacist being faced with relocation? For me, having already made a job transition from Big Pharma to Academia and SME Director, it is about opportunity and the urge to do something different – I am afraid that there has been an ‘entitlement mentality’ of a ‘job for life’ in the Pharmaceutical Industry and that unfortunately is no longer the case and for that matter is simply following the evolutionary curve which the Automotive, Power and Steel Industries experienced over the last three decades. I draw parallels between the state of the Pharmaceutical Industry and that of the EIPG when I first became President. The EIPG was losing membership and, to be frank, was not as influential as it once had been. I believe today, with a growing membership, a clear strategy, a healthy budget and a constitution that is fit for purpose for the modern Pharmaceutical Industry, the EIPG has evolved into a vibrant and influential lobbying group for the Industrial Pharmacist! More importantly, the EIPG has evolved at the right time to provide support for Industrial Pharmacists against this backdrop of change and obvious anxiety. I believe it is these changes and the fact that as a professional body we are passionate about helping Industrial Pharmacists that our membership and our influence have grown. I mention people but the fact is any organisation can only deliver through its people. I once heard a senior executive state that ‘people are the only capital resource that can decide not to turn up for work the next morning’.

european INDUSTRIAL PHARMACY March 2013

I have been blessed in that the EIPG has some very talented and dedicated people behind the scenes and these are: Mrs Jane Nicholson – Executive Director (UK) Mr Piero Imartino – Vice President (Italy) Mr Jean Pierre Paccioni – Vice President (France) Ms Valerie Lacamoire – Vice President (France) Dr Claude Farrugia – Vice President (Malta) These marvellous individuals have made the EIPG a powerful and successful organisation. I would like to thank them all dearly. I note that with the London 2012 Olympic Games, there was overwhelming appreciation of the volunteers and their spirit. I have calculated that over my tenure as President during the last seven years – all the above people have dedicated around 35 to 40 days of their own personal and family time to make the EIPG a successful body for its members and for the pharmaceutical profession. That is why this editorial is dedicated to our long suffering wives or partners who put up with our absences over the many weekends away from home as we volunteers try to drive professional bodies such as the EIPG. I also would like to thank Joe Ridge and the Euromed team for supplying such a high quality and very informative Journal and one which we are all very proud to have sponsored and contributed towards. Finally, I would like to thank all of you for your continued support and enthusiasm for the EIPG and, more importantly, reading this journal, our articles, our guidance documents and access our website (www.eipg.eu), which houses all this information for you. Best wishes for your futures

Gino Professor Gino Martini FRPharmS, MBA. Professor of Pharmaceutical Innovation and Co-Director of Rainbow Medical Engineering.

• Issue 16

GENERICS UPTAKE IN EUROPE – THE IMPACT OF PRICING AND REIMBURSEMENT POLICIES Introduction In the EU, Member States are free to develop their national – and regional – pharmaceutical policies in the field of pricing and reimbursement. This is permitted so long as they comply with overall EU provisions, such as the Transparency Directive, formal procedural aspects such as deadlines or a transparent publication policy. Despite EU harmonisation of marketing authorisations, EU Member States can freely design their pharmaceutical pricing and reimbursement framework, thus opting for more market control and/or promoting competition with regard to generics and other pharmaceutical products. All European countries are facing growing pharmaceutical expenditure, particularly in public expenditure given that Europe has a comparatively higher coverage of publicly funded health care compared to the rest of the world. For example, two thirds of European pharmaceutical expenditure is funded by a third party payer such as social health insurance, despite individual countries varying in the share of public funded medicines. Public pharmaceutical expenditure in the outpatient sector increased in EU countries by 76% between 2000 and 2009 (median: 53%; lowest value: 21%; highest value: 243%). Aggravating the situation further, the global financial crisis has forced several European countries to introduce short-term rigid costcontainment measures. With limited budgets, European countries view generics as a policy option that enables savings to be made and which can then be used for funding high-cost medicines. As stated in the European Commission’s Communication on a Renewed Vision of the Pharmaceutical Sector: ‘[m]any Member States recognise that generic medicines play an important role in helping to limit their healthcare expenditure in their

reimbursement and prescribing practices. Competition with offpatent products enables sustainable treatment of more patients with less financial resources. The generated savings create financial headroom for innovative medicines’. Different European countries vary in the size of the pharmaceutical market occupied by generic medicines, with high shares apparent for several central and eastern European countries, Germany, The Netherlands and UK. Figure 1 also shows that some countries, while starting at a lower point, have succeeded in increasing their generics markets in recent years. This article provides: first, an up-todate picture of the pharmaceutical pricing and reimbursement policies aimed at promoting generics uptake, and second, a discussion of the possible impact of different generics policies on the generics market. Information was achieved through direct contact with representatives of the competent public authorities responsible for pharmaceutical pricing and reimbursement. Results

Pricing and reimbursement policies are an essential part of a

pharmaceutical system. Such policies might be individually designed for different groups of medicines such as innovative medicines, hospital medicines and/or generics. In terms of pricing, a country may allow free pricing for (some) medicines, i.e. the manufacturer may freely decide on the price, or the authorities can regulate medicine prices according to various price setting methodologies and criteria. In most European countries manufacturer prices (ex-factory prices) are directly regulated by the State. However, in a few countries (Cyprus – for imported medicines, Denmark, Finland, Latvia, The Netherlands, Norway, Poland, Sweden and UK) the ex-factory price is indirectly regulated. For example, in Nordic countries, the relevant authorities approve a maximum wholesale price; and in the UK, the Pharmaceutical Pricing Regulation Scheme controls the maximum profit of companies. At the manufacturer level, most countries surveyed control medicine prices only for reimbursable medicines–whose costs are at least partially covered by the national health services or social health insurance. Five countries apply price regulation to all medicines, whereas Denmark and Germany are typically defined as ‘free pricing countries’. However, even these countries have long-operated price controls on reimbursable off-patent products. Additionally, ongoing reform in Germany has introduced a kind of price control for new medicines. In summary, a major feature of price control is reimbursement status: reimbursable medicines tend to be subject to state price control whereas non-reimbursable medicines are allowed free pricing. The same applies to reimbursable versus non-reimbursable generics. At the distribution stages (wholesale and pharmacy), the scope of medicines price control is broader: several countries regulate the remuneration for distributors, usually in the form of maximum linear, or regressive, mark-ups. A few other countries only regulate the

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GENERICS UPTAKE IN EUROPE

continued

medicines is at a lower rate. Criteria for inclusion on a positive list include cost-effectiveness, medical need and therapeutic value – in particular, the relative effectiveness in the case of medicines with no new, but added therapeutic value. Another consideration is the estimated budget impact – in central and eastern European countries. Reference price system

distribution mark-up of reimbursable medicines; including generics. Price and reimbursement

A common method for determining medicine prices is external price referencing–international price comparison. In 25 of the 29 countries surveyed, competent authorities check medicines prices in other countries when setting and/or negotiating a price. Only Denmark, Sweden and UK do not apply external price referencing, while Germany is just beginning to consider medicine prices elsewhere with regard to certain new medicines. Generic price link

External price referencing is typically limited, however, to original products. The most common pricing procedure applied to generic medicines is internal price referencing. This is the practice of using the price(s) of identical or similar products in a country when setting a price. Sixteen countries surveyed required generics – and other ‘follower products’ – to be priced at a certain percentage lower than the originators–a policy called ‘generic price linkage’, see Table 1. Austria

and Estonia, for example, specify that not only the first ‘follower’, but also all additional followers and the original products are required to lower their price. Since 2005, Norway has used the ‘stepped price model’ (Trinnprismodellen) to incrementally reduce the price of a medicine according to predefined rates, depending on sales volumes. The first reduction occurs after a medicine has lost patent protection. Key elements of pharmaceutical reimbursement systems are reference price systems and reimbursement lists – positive lists for medicines eligible for reimbursement and negative lists specifying products explicitly excluded from reimbursement. Positive lists are in place in 26 of the surveyed countries (all but Germany, Spain, UK), whereas negative lists are only used in Germany, Hungary, Spain, and UK. Third party payers do not automatically cover the full costs of medicines from the positive lists. Full reimbursement of eligible medicines only occurs in seven countries – Austria, Germany, Ireland, Italy, Malta (only for eligible cronic conditions), The Netherlands and UK, while elsewhere reimbursement for several

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A reference price system is a major policy option for the promotion of generics uptake. This entails clustering identical or similar products into so-called reference groups. Each cluster has a maximum reimbursement amount (reference price) to be covered by the thirdparty payer. The patient must pay the difference between this reference price and the actual pharmacy retail price, in addition to any other co-payments. Twenty-two of the countries surveyed have a reference price system, 13 of which specify clusters containing medicines with the same active ingredient. Most countries define the reference prices around or below the average price of generics, or at the lowest price in the cluster. Generics

In addition to these pricing and reimbursement policies, European countries also employ specific demand-side measures to promote the use of generics, targeting prescribers, pharmacists and the public. For example, 23 countries surveyed use generics substitution (mandatory in six countries); while 24 countries use international nonproprietary name (INN) prescribing (mandatory in five countries). Public information campaigns often focus on generics with the goal of raising awareness and building trust and/or explaining a specific generics policy. Discussion

This survey of generics policies and pharmaceutical pricing and reimbursement shows that European pharmaceutical systems have a strong linkage between

GENERICS UPTAKE IN EUROPE

pricing and reimbursement, and that some policies are only relevant for reimbursable medicines. As a result, only those generics that are eligible for reimbursement are covered by specific regulations such as price control. In contrast, non-reimbursable generics do not fall within the scope of price control. In addition, generics are specifically targeted by policies aimed at enhancing their use and saving money – for public payers. The potential for costcontainment can be seen in the prices of generics which may be set at a lower level (generic price linkage), and via competition from the arrival of new generics on the market. The latter also leads to lower prices of other generics and the originator. Both strategies, partially in parallel, occur in the countries surveyed, and add to a growing body of reports about different generics pricing policies including mixed approaches. Policymakers tend to take a broad view of generics. Several countries promote the use of not just generics but also ‘non-expensive’ products. These may include copyproducts, parallel imported medicines, for example, in Denmark or Germany, and even less expensive original products (as in Belgium). Countries vary as to the necessary price difference between a generic medicine, or other follower products, and the originator. Questions may arise over whether higher price differences are possible, and by how much, and whether lower prices might be achieved for generics through policies other than the generic price linkage. Countries, which do not explicitly require generics to be priced at a certain percentage lower still report considerable price differences, for example, The Netherlands and Slovakia. This they attribute to market competition, for instance, supported by tendering mechanisms in the outpatient sector. In addition, according to a literature review, while generic price

continued

linkages and price regulation did succeed in lowering generic medicine prices to a certain point, there were indications for a higher potential for savings which might be triggered by free-price competition in the generics market. Demand-side measures

A widely-used approach to promote generics in European countries is the introduction of demand-side measures, notably generics substitution and INN prescribing. Ten countries in the survey combined these two measures. A few countries have either one or other in place. The choice of just one of the policies could be due to its appearing sufficient for achieving the expected results. (In the UK, with a high rate of INN prescribing and a comparatively high generics market share, the government decided against the introduction of generics substitution planned for 2010 following a public consultation). A common combination, however, is generics substitution or INN prescribing together with a reference price system – seen in 20 countries. In combination, these two tools appear to positively influence each othe. Among the countries surveyed, only one country (Austria) lacks all three of the aforementioned policies. Its generics market shares are comparably low, but are now on the increase following the introduction of a generics price linkage policy. It is important to highlight not only the quantity of measures, but also the quality of their implementation. Stringent implementation of a few measures

can produce the desired effects. For instance, Sweden produced a high generics market share even after abolishing the reference price system, perhaps because another system of clustering similar medicines already existed, as well as mandatory generics substitution . Norway’s stepped price model, introduced in 2005, has increased the market share for generics from 31.8% of the volume of the outpatient market in 2005 to 38.4% in 2007, see Figure 1. Norway has thus ‘ensured that prices for generics have fallen’. But in the context of Norway’s overall pricing policies, the introduction of a pricing regime linked to prices in other European countries, and the design of their external price referencing, had a moderating effect on the Norwegian price level in general. The level of enforcement also affects the success of new measures

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GENERICS UPTAKE IN EUROPE

to promote generics use and control prices. Policy measures, such as generics substitution and/or INN prescribing, might be implemented on a voluntary or a mandatory basis. A voluntary implementation occurs in the majority of countries surveyed, but some, for example, Lithuania and Slovakia, have changed their legislation and made INN prescribing obligatory. This mandatory implementation of a policy has proved successful at increasing generics uptake, for example, in Sweden. Incentives for stakeholders

Besides mandatory enforcement (possibly accompanied by financial sanctions), incentives for stakeholders can also be an issue. In The Netherlands, a financial incentive was in place for years allowing pharmacists to retain one third of the difference between the price of the medicine and the reference price if they dispensed a medicine below the reference price. This incentive appears to have contributed to an increase in the generics market share, but interestingly, after the abolition of the measure in 2005, the generics substitution rate continued to stay at a high level and even rose (42% in volume of total market in 2005, 56% in 2009, see Figure 1). Some experts feel that the continuing high substitution rate is attributable to a positive attitude that has developed among Dutch pharmacists. Another example is a pilot project in Austria, in which patients of a small sickness fund were charged a lower prescription fee if they obtained a generic instead of a brand-name medication. As a result, the patients asked for the generics and the share of generics prescriptions rose. These examples suggest that in addition to formal mechanisms, such as punishing sanctions or encouraging incentives, a ‘generics culture’, i.e. a positive attitude and trust in generics (and biosimilars), may contribute significantly to an increased use of generics. We recommend the development of

continued

such a culture, using strategies that target all stakeholders, including patients. Finally, the organisation of a reference price system is another trigger for generics uptake. Twentytwo of the European countries surveyed have a reference price system; 13 of these organise the reference groups at the Anatomic Therapeutic Chemical classification level 5, in other words, clustering of medicines with the same active ingredient. This is the easiest way to manage the system and probably an appropriate starting point when introducing such a policy. However, care should be taken over the definition of a cluster: a very narrow cluster can result in some patients re-allocating their demand away from the reference group to an alternative non-patent medicine, with the consequent loss of potential savings . Such ‘reallocation of demand’ has been observed, to some extent, in a few European countries, for example, France and Italy. Another relevant parameter in the design of a reference price system is the fixed reimbursement amount, i.e. the so-called reference price. In mature high-volume generics markets such as in Poland, a higher reimbursement amount might be advisable for a brief period, to provide incentives for generics manufacturers to enter the market. A lower reference price generally results in higher savings. In this respect, Portugal, which initially set the reference price at that of the highest priced generics in the reference group, decided in 2010 to reset the price to the average of the five lowest priced medicine. In future it will be useful to examine the impact of this decision on the generics market shares. Furthermore, in five other European countries: Belgium, Estonia, Latvia, Lithuania and Spain; the methodology regarding the calculation of the reference price was changed in 2010 and 2011, apparently for costcontainment reasons, because these countries were strongly hit by the global financial crisis.

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Conclusion

European pharmaceutical systems use several different types of pricing and reimbursement policies for medicines including reimbursable medicines. Generics, if deemed reimbursable, are subject to the same policies. In addition, many countries have implemented specific measures to promote generics uptake, including demand-side measures targeting prescribers, pharmacists and, less frequently, patients. Usually, a mix of policies is employed. The design of these measures can significantly influence generics uptake and the degree of public savings. However, the difficulties in enforcing these measures should be addressed. Creating a ‘generics culture’, i.e. an environment which is positive towards generics, appears to support other policy measures. For patients

Several European countries aim to increase generics uptake. This allows offering medicines at lower prices for the sake of patients who have to pay out-of-pocket and/or to co-pay. In the case of publicly funded medicines it also offers savings for the healthcare system and thus provides financial headroom for funding innovation, therefore, increasing both accessibility and affordability to patients. Evidence about generics policies helps not only the policymakers to reach their aims but also the patients by benefiting from improved accessibility and affordability.

This article is derived from the original paper by Vogler S. The impact of pharmaceutical pricing on generics uptake, implementation of policy options on generics in 29 European countries – an overview. Generics and Biosimilars Initiative Journal (GaBI Journal) 2012;1(2):93-100. With permission of the publishers, Pro Pharma Communications International. A full list of references is published within the original paper.

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particulates in finished parenteral drug products.

IMPROVING THE QUALITY OF INJECTABLES

History and background on foreign particulate matter

by minimising and controlling sources of particulates originating from primary packaging components by Mike Schaefers

articulate matter is a key indicator of quality for injectable drug products. An undissolved particle, other than gas bubbles, unintentionally present in a drug product solution is defined in United States Pharmacopeia (USP) as foreign particulate matter1. Particulates are considered to be a broad category of material that can be intrinsic to the drug product or extrinsic, which may result from the manufacturing process. Mike Schaefers is Vice President, Marketing Europe, West Pharmaceutical Services, Inc.

Concerns for patient safety have been recognised relative to particulates in parenteral drug products as early as 1940, when pulmonary emboli in animal models were traced to cotton fibres. Particles ingranulomas and thrombi in the lungs of children, and pulmonary arterial lesions in infants, were observed after administration of intravenous fluids dating back to 19552,3. The current USP limit for particulate matter was instituted in 19954,5 and was derived from knowledge based on process capability and methods employed in 1970, which does not reflect the quality concerns for today’s drug products. USP methods

The USP methods were initially developed for visible particulates and primarily intended for small molecule drug products. Data mining over a five-year period at the FDA Office of Generic Drugs suggests that the acceptance limits could be lowered, thus increasing drug safety without placing excessive burden on the industry6. Within the biopharmaceutical industry, understanding the generation of particulate matter less

than 10µm is important since data seem to support the immunogenic effect of smaller particulates. The clinical consequences of injected particulate matter continue to be discovered and test methods improved with the intent to find the materials responsible for the particle(s), understand them and make improvements in order to alleviate drug product contamination. The desired goal of zero defects drives continuous process improvement; however, it is not a workable acceptance criterion for visible particulate matter because of current packaging components and processing capabilities7. Regulatory expectations for foreign particulate limits continue to evolve and the value of vision inspection systems for elastomeric primary components is shown to mitigate the risk of

The USP recognised that parenterals should not be contaminated with particulates as early as 1936 and subsequently required a test to indicate solution clarity to show products were “substantially free” from particles. The USP was revised in 1949 due to concerns for contamination. Each injection, in the final container, was to be subjected to visual inspection for clarity of solution. From 1955 through 1970 the USP provided guidance about visual inspection of injections with a philosophical requirement for a “zero-defect quality” for foreign matter. The standards were indefinite and subjective; if the nature of the container permitted, it should be inspected and rejected if there were evidence of contamination. In 1995, the USP revised the term “substantially free” to “essentially free” and included a grading system. Test methods for counting particles continually improved through collaborative investigation and method revision. Through the Pharmacopoeial Discussion Group, the United States, Europe and Japan have harmonised methods, definitions and limits8. In the current USP monograph, <788> Particulate Matter in Injections, two testing procedures are specified: Method 1: Light Obscuration Particle Count Test and Method 2: Microscopic Particle Count Test. Limits for particles are listed in Table 1. Since USP <788>, there have been many changes in drug product formulations such as vaccines, oncology products, nanoparticles, microspheres and liposomes, which

Table 1: Limits for particles Method 1 Light Obscuration

Method 2 Membrane Microscopy

Volume

≥ 10µm

≥ 25µm

≥ 10µm

≥ 25µm

<100mL

6000 per container

600 per container

3000 per container

300 per container

>100mL

25 per mL

3 per mL

12 per mL

2 per mL

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continued

such as the ingredients in the drug product, processing equipment, environment or the container closure system. Manufacturers of sterile drug products should consider a means to reduce or exclude particulate matter and container closure defects in products11. Inspection of elastomeric closures to reduce particles in finished pharmaceuticals Figure 1: Probability of detection with increasing particle size.

have presented challenges for detecting, counting and profiling particles. USP methods may not be applicable for preparations with reduced clarity or increased viscosity, such as emulsions, colloids and liposomes. In addition, particulates as big as red blood cells (~7µm) going through capillaries (510µm) could cause problems. There is a need for sensitive methods with tighter particulate specifications9. The current USP methods are not necessarily optimal for any particular formula or dosage form; different techniques are needed for different size ranges and sensitivity. Figure 1 illustrates the probability of detection with increasing particle size10. USP <788> represents a standardised approach that can provide reasonable monitoring of the particle load in the final product form, but when foreign particles are present, even within regulated limits, additional information about their nature and possible origin involves a complete program for the control and monitoring of particulate matter. Regulatory expectations for foreign and particulate matter in finished drug products

Manufacturers of drug products are confronted with increasing quality standards to produce defect-free products, reduce process/product variation and minimise product rejects. Parenteral drug products intended for injection must meet

requirements set forth in USP, but there are still concerns for the risk to patient safety (i.e. phlebitis, occlusions, thrombi, immunogenic/antigenic reactions) and challenges with methodology. Process control based on testing final product is not consistent with modern GMP expectations. The underlying and most important consideration is the level of quality built into the product. The best visual inspection strategy remains probabilistic in regard to defect removal; the only real assurance is provided by a process that generates extremely low numbers of defects. Strategies for continuous improvement would involve mitigation of risk for contamination of finished drug product through upstream controls. Particulate matter in finished pharmaceuticals can come from multiple sources

Packaged drug products can contain particles originating from elastomeric closures due to the closure environment, manufacturing process and handling. Reducing the particulate load of the elastomeric closure will minimise the risk for undetected particles in finished pharmaceuticals and product rejects. The added value to high-quality components is twofold: greater assurance for patient safety and cost savings resulting from fewer rejects. Preparation and inspection of elastomeric closures for use with a drug product when performed upstream at the closure manufacturer can alleviate concerns of particles originating from these components. Evidence of this has been demonstrated through studies using high-quality Westar® Ready-to-Use and EnvisionTM automated vision inspected components compared to standard components. The results demonstrated improvements in the overall quality of the elastomeric

Implementation of vision inspection

Figure 2: Results of finished drug product before and after the Envision process.

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continued

specification for cleanroom standards. Reducing contact with particles at the appropriate time is a proactive approach to manufacturing quality components. EnvisionTM automated vision inspection process for components

Vision inspection machines are programmed to distinguish a quality component from a defective component. Typically, multiple cameras that use bright and diffused illumination are used to detect defects. These defects include stains, tool marks, foreign matter and rubber inclusions embedded or protruding from the elastomer surface. The processing and capability for automated vision inspection systems relies on the preparation of the closure and qualification of the equipment relative to the intended outcome. The Envision automated inspection process occurs after the pharmaceutical washing step is completed in the ready-forsterilisation process (Figure 4).The end result is a washed product that meets specified limits for bacterial endotoxin, particulate matter and bioburden. After the ready-to-sterilise process, stoppers are unloaded from the washer in an ISO 5 (Class 100) cleanroom. The elastomeric components are then loaded into the vision inspection equipment, inspected and packaged in sterilisable bags or rapid transfer port bags. Bags of product are removed from the vision inspection machine, sealed and labelled in the ISO 5 cleanroom. Depending on defined need, the sealed and

Visual inspection in the manufacturing process

component, leading to reduced rejection of the final drug product (Figure 2). Strategies to enhance the quality of component manufacturing

The manufacture and preparation of elastomeric components involves multiple steps that include moulding, trimming, sterilising, inspection, packing and shipping, all of which can impact particle load. An inspection process is a critical aspect to reducing particulates because it verifies specified quality and rejects components that do not meet criteria. Furthermore, the rejected components are examined to provide feedback to the closure manufacturing process for areas of improvement. Qualified inspection systems also can detect defective closures that can potentially impact the filling capacity or sealing of the container closure system, compromising the integrity of a sterile drug product.

As the volume of the inspection process increases, so does the data to create effective libraries. Statistical analysis and characterisation of each type of defect allows component manufacturers to gain an enhanced understanding of the defects that occur. Advances with inspection equipment along with a substantial library of defects will differentiate artifacts from defects and provide knowledge to improve processes at the beginning of the manufacturing cycle and prevent recurrence of a particular defect. The goal of manufacturing quality components is not just to monitor for defects but to understand the potential for particle generation. The manufacturing environment and the flow should be designed to minimise exposure to particles consistent with expectations for finished pharmaceuticals. Exposure to particles decreases exponentially in an ISO 5 cleanroom compared to room air. Table 2 gives the ISO

Table 2: ISO specification for clean room standards

Class ISO

Clean Room Standards – maximum particles µm3 ≥0.1µm

≥0.2µm

≥0.3µm

≥0.5µm

≥1µm

Equivalent ≥5µm

100,000

23,700

10,200

3,520

832

Class 100

1,000,000

237,000

102,000

35,200

8,320

293

Class 1000

352,000

83,200

2,930

Class 10,000

3,520,000

832,000

29,300

Class 100,000

35,200,000

8,320,000

293,000

Room Air

european INDUSTRIAL PHARMACY March 2013

• Issue 16

IMPROVING THE QUALITY OF INJECTABLE DRUG PRODUCTS

continued

Figure 4: Envision inspection process flow.

bagged products are either placed in cartons for shipping or sent to be sterilised outside the ISO 5 environment. The ISO 5 environment is controlled and monitored for particles in the range of 0.1-5µm per cubic metre to reduce potential for particulates. Defect library

To test the reliability of the inspection process, a capability study is performed. For the purpose of the study, a defect library is created to aid in the programming and testing of the machine. The library can be populated based on extrinsic and intrinsic particulate sources and can be customised for specific purposes. Defects used to challenge a vision inspection machine may include hair, fibre, loose particulate contamination, embedded and adhered foreign material, moulding defects and cosmetic defects. The goal is to obtain enough defects per component to establish a representative defect reference to be included in the library. This assures that the vision inspection machine is consistently detecting specific defects that were created for reference. The greater the knowledge base, the better the detectability of defects. To perform capability testing, component sample sets from the defect library consisting of known accepted product and known rejected product are run through the

provide a finished drug product that efficiently and effectively meets the needs of the patient.

vision inspection machine. The defects are used to optimise the vision software and challenge the vision system. Finally, the rates of acceptance and rejection are determined for each component and defect category. After capability testing is performed, the defect library is used to verify that the vision inspection machine can detect the standard defects appropriately.

USP 34 General Chapter<788>Particulate Matter in Injections, United States Pharmacopeia, Rockville, MD, 2011.

von Glahn WC, Hall JW. Am J Pathol 1949;25:575-84.

Bruening EJ. Virchow Arch 1955;327:460-79.

Conclusion

Sarrut S, Nezelof C. Press Med 1960; 68:375-7.

Garvan JM, Gunner BW. Med J Austr 1963;50:140-5.

Pillari B, Microbiology Team Leader OGD, FDA. Review of PF 30.6 Particulate Contaminants of Sterile Injectable Drugs and Limits Set by USP General Chapter <788>, USP Workshop on Particle Size:Particle Detection and Measurement, Rockville, MD, December 8, 2010.

Madsen RE, Cherris RT, Shabushnig JG, Hunt DG. Visible Particulates in Injections – A History and a Proposal to Revise USP General Chapter Injections <1> Pharmacopeial Forum Vol. 35(5) [Sept.–Oct. 2009].

Ibid. Madsen RE., Cherris RT, Shabushnig JG, Hunt DG.

Ibid. Pillari B, Microbiology Team Leader OGD, FDA.

Manufacturing efficiencies benefit suppliers and manufacturers, and ultimately help to ensure adequate supplies of needed drug products reach the market. High-quality elastomeric components enable upstream controls to reduce particles and rejection of finished pharmaceuticals. Elastomeric closures for parenteral products, including serum stoppers, lyophilisation stoppers and syringe pistons, can be verified for quality to meet stringent standards using automated vision machines that are designed to examine the external quality attributes of elastomer components. Qualification of an inspection process is critical to ensure reliable detection and understanding of defects, and the knowledge will create multiple opportunities for preventative action and continuous improvements. The ultimate goal for a component manufacturer is to build a relationship with the pharmaceutical manufacturer to

References

10 Aldrich

S, Historical Perspective and Current Chapters Review, USP Workshop on Particle Size: Particle Detection and Measurement, Rockville, MD, December 8, 2010.

11 Langille

S, Senior Microbiology Reviewer, OPS,FDA, Particulate Matter in Parenteral Drug Products: A Regulatory Perspective, PDA Visual Inspection Forum, Rockville, MD, October 3, 2011.

Envision and Westar are trademarks or registered trademarks of West Pharmaceutical Services, Inc. in the United States and other jurisdictions.

european INDUSTRIAL PHARMACY March 2013

• Issue 16

THE FUTURE OF PHARMA? SPECIATION, SEX AND DEATH by Brian D Smith

apply to industries. We’re all familiar with evolutionary theory as a tool biologists use to explain how ecosystems change, but it is in fact a general theory for describing the behaviour of any complex, adaptive system. Ecosystems and industries differ only in details; the general principles are the same. Speciation

aving published a 3-year research project and an 80,000 word book on the subject, I am often asked, by pharma executives too impatient to read the whole story, “So, in a nutshell, what is the future of Pharma?” Hiding my amusement that such a huge subject can be compressed into a sound bite, my usual reply is: “Speciation, sex and death”. Of course, my slightly flippant answer begets a puzzled look so, if you have the patience, here is a slightly fuller version. Brian D Smith is adjunct professor at SDA Bocconi, Italy and visiting research fellow at the Open University Business School in the UK. He also runs www.pragmedic.com , a specialist consultancy. He welcomes comments and questions at brian.smith@pragmedic.com. His book,” The Future of Pharma: Evolutionary threats and opportunities”, was reviewed in the September 2011 issue of Industrial Pharmacist.

Most people connected to the industry agree that we are in the midst of massive, once in a century change. Patent cliffs, R&D productivity, market access and emerging markets are just some of the huge, strategic issues that everyone sees are converging to reshape the industry. Despite this, no-one has (until now) painted the big, over-arching picture of how pharma will look in, say 10 or 20 years. The economic and social importance of the pharmaceutical industry means that this is too big

and too important a question to be left to speculation. So, if we want to predict the future on any sort of scientific basis, as opposed to merely speculating, we need a robust explanation of how complex adaptive systems like the pharmaceutical industry change over time. Fortunately, Darwin gave us an explanation of how complex, adaptive biological systems evolve and, in more recent years, management scientists have developed evolutionary theory to

Apply evolutionary theory to pharma and it predicts that business models will adapt to fit the changes in the market environment by a process called adaptive radiation. More specifically it predicts that the three present “species” of pharmaceutical company – big pharma, speciality pharma and generics, will become extinct and be succeeded by about seven new species of business model, each one superbly adapted to a particular sub-habitat of the pharmaceutical market (Table 1). Just as different kinds of mammals have different traits, then different kinds of pharmaceutical company will have different kinds of capabilities. Details of these are spelled out in the book, but as a general point it is worth noting that these new business models will both look very different from each other and also very different from today’s companies. So that’s the speciation part. We should expect to see more types of business models than we have today and some of them will be barely recognisable as pharmaceutical companies. Sex

It is worth stressing here that I am not using evolution as a metaphor

Table 1. Seven distinct new species of business model

The Future of Pharma ● ● ● ● ● ● ●

The monster imitator – ultra efficient operations and patent busters The Genii-spotting viable markets and developing new products The Trust manager-brand management and branded proposition development The Disease manager-develop and manage therapies and programmes around chronic disease more effectively than the state The Lifestyle manager-focus on preventative healthcare Value pickers-focus on specific clinical niche areas The Health concierge-focus on supplying superior healthcare for minor conditions compared to the state.

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THE FUTURE OF PHARMA?

for what is happening in the industry; I am saying that the changes in pharma are not like evolution, they are evolution. And the biological comparison goes a lot further. Those companies that survive (and most won’t, because the research suggests that speciation will be accompanied by mass extinction of older, less well adapted models), will do so by acquiring new DNA and new traits or, in corporate terms, new capabilities. Some of these will be obvious whilst others are less so. For example, most industry leaders can see that it is essential to develop value propositions that appeal to payers as well as patients and prescribers. Less obviously, the ability to work in a virtual network structure of development, manufacturing and marketing partners will become very important as firms “dis-integrate”. Firms will acquire these new capabilities from other firms, sometimes by acquisition and merger, sometimes via consultants and business schools. This capability acquisition is analogous to the swapping of DNA between organisms and is the business equivalent of sex, so that is the second part of change.

continued

Firms that fail to acquire new capability “genes” will fail to adapt to the market changes wrought by technology, demographics, globalisation, economics and politics. And as Darwin famously said, it is not the strongest of the species, nor the most intelligent, that survives. It is the one that is the most adaptable to change. In other words, companies that persist in thinking narrowly in terms of “industry best practice” are likely to be out-evolved by their more promiscuous cousins. Timeline

Once pharmaceutical executives have grasped the basic ideas of industry evolution, they inevitably ask for some idea of the timeline. It is impossible to answer this question without introducing more evolutionary theory, in this case the concept of punctuated equilibrium. This idea suggests that evolutionary systems do not change steadily. Instead, they have long periods of stasis with little apparent change then sudden period of very fast change. What this means is that executives cannot wait until they are sure change is happening and then react because by then it is too late. It seems likely, however, that the industry is entering one of those periods of rapid change.

Death

And the death part? Well, most pharmaceutical companies are poor at acquiring capabilities from outside of the industry. By and large, they prefer to swap genes within the industry pool. Academics have a term for this – mimetic isomorphism – and it is the equivalent of having sex with your cousin, with similarly poor results.

What to do?

So what should the leaders of the pharma companies be doing? Well, at the risk of over-simplification, there appears to be a three-step process to making sure that your firm is not one of the majority that will become extinct. Firstly, understand what the future environment will look like.

Evolutionists call this the fitness landscape and the future fitness landscape for pharma, which consists of about 11 new ecological niches, is described in detail in the book. Second, decide which niche or niches you want to occupy. As in biology, new species thrive when they dominate a niche and fail when they try to straddle across several niches. The choice of niche is difficult but important and straddling seems to be the quickest route to extinction. Finally, having decided which niche to dominate, the company will have to develop or acquire the capabilities needed to thrive there. As we have discussed, such capability acquisition is unlikely to come from incestuous industry best practice. The key to it will be the understanding that capabilities come in three flavours: Core, such as getting regulatory approval, that merely gets you into a market; Differentiation, such as segmentation, that allows you to compete and Dynamic, such as insight creation, that enable strategic change. Summary

In summary, we know that the industry will evolve in the same way as a biological system. This will result in speciation into a baffling array of different business models and the death of companies who cling onto old business models. But even companies who try to change will succumb to extinction unless they do it wisely, making hard choices about what they want to become and avoiding the temptation to straddle and be incestuous.

Visit the website: www.industrialpharmacy.eu for PharmaTV and Quality by Design videos, Regulatory Review, Financial Pharma News and other current items concerning Industrial Pharmacy

www.industrialpharmacy.eu

european INDUSTRIAL PHARMACY March 2013

• Issue 16

WORKING TOWARDS A STANDARDISED IDENTIFICATION SOLUTION by Peter Belden

he security of the pharmaceutical supply chain is an issue of growing concern, with recent reports addressing its vulnerability to counterfeiting. The complexity of the European supply chain is one of the key factors of this counterfeiting pandemic, with millions of medicine packs being moved around the EU annually. Aside from this, fragmentation has resulted in decreased transparency in the supply chain and increased difficulties to track and trace medicines, leading to significant threat from counterfeiting. As a key source of income for the European economy, it is essential that the supply chain remains safe and free from counterfeits. Peter Belden is SVP of Global Commercial Services, AndersonBrecon

A significant stumbling block within the industry remains the lack of a unified, single-source pan-European or indeed global database where scanned bar codes on drug packaging can be verified at point of dispense. At some time in the future the pharmaceutical industry, regulatory bodies, clinicians and retailers will need to join forces to overcome this. The wider impacts of counterfeiting

Pharmaceutical counterfeiting can place serious burdens on the economy. National governments face increased economic pressures such as increased law enforcement costs, loss of foreign investments and an increased possibility of untoward public health incidents. Not only does the practice of counterfeiting place pressures on the economy, it also puts lives at risk. With many counterfeit drugs containing very little or none of the active ingredient, often incorrect ingredients, and potential toxins, they can lead to further illness and even fatalities. A proven history of fatalities as a result of counterfeit

drugs include the deaths of over 500 children after ingesting paracetamol containing a renal toxin1. Unfortunately, this is one of many cases over the last decade which have seen counterfeit products leading to death, with developing countries being particularly vulnerable. Regulatory outlook

The decreased transparency of the supply chain and the growing number of counterfeit products making it into the supply chain has encouraged a number of regulatory bodies to introduce further requirements governing the identification and traceability of pharmaceutical products. The European Medicines Agency states that it will be focusing upon tackling counterfeits, with measures from its 2011 Directive on Falsified Medicines required to be implemented by EU member states from January 2013 2. This legislation aims to make it significantly more difficult for counterfeits to release false medicines into the market by using enhanced safety features on prescription drugs, closely

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supervising manufacturing activities and clamping down on internet sales. Current coding & identification of medicines in Europe

A large majority of the counterfeiting problem lies with the fact that there is currently no standardised system or recognised industry standard for the identification and coding of pharmaceutical products in Europe. As a result, many EU countries are proposing and developing individual coding systems, further adding to the fragmentation problem. Whilst pharmaceutical coding was initially used predominantly for logistical purposes such as the management of trade flows, many national authorities have now adopted coding systems for public health reasons. While many European countries now have systems to track and trace pharmaceutical products, these all vary in terms of the contents of the code through to the physical placement of the code. This fragmentation is further adding to the growing problems faced by Europe as a result of pharmaceutical counterfeiting. The move to serialisation

As a growing amount of industry guidelines stipulate the need for more stringent measures in the battle against imitation drugs, more and more pharmaceutical companies are implementing track and trace processes into their products. Although the pharmaceutical industry has not yet established a centralised and regulated database for serialisation, it is fully aware that a move into serialised products is essential to ensure the safety of the supply chain. A significant stumbling block to true serialisation and therefore security, remains with the lack of a unified, single-source pan-European or indeed global database where scanned bar codes can be verified at point of dispense. At some point in the future the pharmaceutical industry, regulatory bodies, clinicians

WORKING TOWARDS A STANDARDISED IDENTIFICATION SOLUTION

and retailers will need to join forces to overcome this. As the battle against counterfeiting remains high on the agenda within the pharmaceutical industry, serialisation is no longer just an ‘if’ or ‘when’, but a key requirement for many companies. Choosing the correct supplier/partner

It is essential that when completing any serialisation project, both supplier and client form a complementary partnership. It is important that a supplier is chosen who has the right equipment to facilitate its partners’ needs throughout a project. We believe that there are a number of aspects that must be taken into account when choosing a partner: 1. Suppliers must be fully in tune with the needs and goals of the client project. 2. Suppliers must possess all the correct equipment. 3. Both parties must be fully aligned with the brief and task in hand. Key benefits/costs

Ultimately, the number one aim of serialisation is to protect the pharmaceutical supply chain and hence the patients. Whilst patient safety is the number one concern, it is also worth noting the various business and economic benefits that can be reaped from the practice. A counterfeit pharmaceutical product, in many cases, can cause a brand reputation to be tarnished, leading to reduced revenue and market share. Serialisation can lead to less pharmaceutical product returns, recalls and defects and, in turn, reduced revenue losses. In line with this, secure and traceable products are much more appealing to customers. References 1

Newton PN. Counterfeit anti-infective medicines. Lancet Inf Dis 2006;602-613. European Medicines Agency. July 2011 Directive. Available at: www.ema.europa.eu/ema/index.jsp?curl= pages/special topics/general/general_content_000186.js p&mid=WC0b01ac058002d4e8

continued

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european INDUSTRIAL PHARMACY March 2013

• Issue 16

TRAINING – doing it wrong! Michael Anisfeld

ithout question the need for staff training is an essential element to attain quality, and as such is a GMP prerequisite in every GMP code world-wide. The EU GMPs (in section 2) states that “All personnel should be aware of the principles of Good Manufacturing Practice that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs”. The US cGMPs (in 21CFR211.25) states that “training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them”. Mr. Anisfeld is a consultant on worldwide GMPs and can be contacted at Globepharm Consulting (e-mail: manisfeld@globepharm.org). © Copyright, Globepharm Consulting, Inc. 2013

But these requirements, while stating the bare essentials, leave lots of questions to be answered. For example in the USA, training shall be by a “qualified individual” – what makes a “qualified individual? Is this a training professional (perhaps an ex-teacher) who knows the theory and practice of teaching (perhaps only to grade school children, which is very different from teaching adults) but who does not know anything of the technology being discussed; or is this a technical person who knows the technology inside and out, but who cannot get a message across. In thirty years of attempting to get an answer to this question I have gotten nowhere! Basics

I suppose that we need to start at the basics. What is the task that the person is being hired to perform? Amazing to me how many professionals in the pharmaceutical industry either do not have a job description; or they know that one exists but they have never seen it; or over the years the job that they were hired to perform has gradually morphed into a different job with different responsibilities, but no updating of the job description has

ever happened.. A proper job description needs to be in place, and approved, in order to interview a potential candidate – consider it the quality acceptance criteria which if not met would result in the candidate not being hired. If you do not have a job description, then how as a manager can you objectively evaluate a potential candidate? And if you have a job description, then you need to also ask the question – when hired how will the candidate be expected to work to fulfill the expectations and requirements of the task? The answer to that has to be that there are standard operating procedures (SOPs) in place defining how work needs to be performed in order to fulfill the tasks described on the job description. So before we begin any ideas of training, we need in place a job description and a set of SOPs for the job incumbent to be trained in – often termed the job description/SOP matrix. Every job needs a job description, a list of SOPs which when mastered means the incumbent can effectively perform the task, and of that total list of job fulfillment SOPs a sub-list of core SOPs that must first be mastered in order for the job incumbent to be allowed to work

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• Issue 16

under supervision. Core SOPs can be as mundane for a laboratory analyst, or for a weighing operator, as “data recording”, “performing calculations”, and “understanding what an out-of-specification result is” (and yes, they happen in manufacturing too!) There are two hiring scenarios that reflect themselves in training – the new hire that joins the company from school or college, and the new hire that joins the company from another company. The new hire from school or college is relatively easy to train, they have no previous knowledge or expectations – they are a blank slate. Harder to train are new hires whose heritage is another pharmaceutical company or they have come from an allied industry such as the chemical industry where the degree of exactitude we expect is not as stressed. Either way, a new hire with previous industry experience represents two challenges – the challenge of undoing her prior work habits, and the challenge of training her to work to our company’s methods, a very different training exercise. GMP and OJT

According to the regulations, there are two types of training requirements – GMP training and On-The-Job training (OJT). OJT is relatively the easier of the two. OJT requires that the worker understand, and work to, the SOPs, the batch record instructions and other company documents that define how a job is to be performed. GMP training is more difficult and perhaps more nebulous. It requires the worker to understand the concepts, philosophy, regulations and implementation of GMP by the authorities. If a worker does not understand the “why” behind the GMP requirements, then the GMP training has failed. Why is the use of “whiteout” unacceptable? Why cannot quarantined raw material be used in production? (When I audit the effectiveness of training I always ask workers these questions – amazing how often I get a blank stare as a response). Teaching the philosophy

TRAINING – DOING IT WRONG!

continued

Business people watching an online training demonstration.

of, and engendering a mindset of “quality”, after all that is what GMPs are about. It is extremely difficult and why all GMP codes world-wide require such training to be provided and frequently repeated. Repeats

For reasons that I have never understood, many companies regard repeat GMP training as being a literal word-for-word repeat of the induction GMP training provided, and this to be performed annually. In many companies, staff dread these sessions in ultimate boredom but sit through them as a relief from the routine everyday activities of production, packaging or lab work. Nothing is more boring than hearing the same presentation year after year after year (does this sound familiar?). And, again, for reasons that I have never understood many companies have an annual GMP training day for all staff. Actually it is usually not a full day, but typically 1, 2 or 4 (very occasionally 6) hours depending on production or laboratory constraints. Typically vice president and director level management always seem to find a reason why they are too important, too busy, too educated, too erudite (pick any reason) to attend – even though the

GMPs explicitly require their attendance. Actually this is a western world, primarily an arrogant US management, cultural issue. I am frequently invited by Japanese companies to present GMP training to Management Committees, and to Boards of Directors; the exact people who need GMP training to understand the impact of their financial and strategic decisions on the company’s quality image, reputation and regulatory compliance posture. Regular training

Assume for a moment that I am the world’s greatest lecturer (which, of course, I am!), and you are the world’s greatest student (which, of course, you are!); repeated studies have shown that two weeks after a training session I present to you, for any task in any industry, you will remember only about 10% of the training delivered (and although repeatedly asked, I will not shorten the training session to cover just the 10% most important points – why, because then you’ll only remember 10% of that). Think for a second – what is the job of the army? To defend the nation. How does it do that? By training soldiers in, among other things, how to shoot a rifle. Are soldiers trained to shoot once a

year? Of course not. They are trained and drilled in the actions and reactions that they need to perform every day, in rain or sunshine, day and night, when they are fresh and when they are bonetired. The army cannot wait for a soldier to be fired on by an enemy, and only then have the soldier start thinking about what action he needs to take – actions need to be instinctive and ingrained. And so it is in the manufacture of pharmaceuticals. Far, far, better than a once-a-year GMP training day, is every week to have a “GMP Moment”, actually every week to have a 15 – 20 minute departmental GMP session. Each week pick a different topic relevant to the department to discuss. For example, go over complaints received in the last quarter and how they can be traced to the department’s actions. Review an FDA Warning Letter issued to another company, and discuss whether your department might be guilty of the same types of action, or inaction. Review new SOPs issued that week of impact to the department, etc. etc. Small dose repetitive training beats once a year mammoth sessions hands down for training effectiveness.

Continued on page 20

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• Issue 16

COST VERSUS QUALITY – the real price you could pay for ‘budget’ PV by Steve Proudlove

Introduction In any business, reputations are hard to build and easy to destroy. Mistakes in pharmacovigilance can ruin the names of products, manufacturers and – in some cases – result in QPPVs and company executives facing prosecution in the criminal courts. It may therefore be a false economy to choose PV services based on cost rather than quality. Steve Proudlove graduated from Cambridge University with a degree in pharmacology and began work in clinical trial and post-marketing pharmacovigilance with Roche. He then moved to Medis Limited and gained valuable experience in regulatory affairs and helped develop pharmacovigilance processes for a variety of generic medicines throughout the EU. Steve, who has nine years’ experience covering all areas of pharmacovigilance work including acting as a QPPV, joined Panacea Pharma Projects in 2009 as Head of Pharmacovigilance.

In the current economic climate it is understandable that all businesses are looking to cut costs – and pharmaceutical manufacturers are no different. Economic realities dictate that every area of the business needs to be scrutinised to make sure that it is cost effective and efficient. However, there are parts of the pharmaceutical industry where cutting costs may become a false economy and when the risks posed by reducing expenditure far outweigh the financial benefits. One such area is in pharmacovigilance (PV). Usually large global companies can afford to do all their PV inhouse, while small and medium sized companies often find it more cost effective to outsource. From the perspective of a Marketing Authorisation Holder’s (MAH) finance director, PV can seem a necessary evil. It can involve significant expenditure and yet there is no direct financial return for the MAH. It is true that PV can seem costly, but this is because it is a highly specialised field and requires employment of a Qualified Person for Pharmacovigilance (QPPV), a physician, a team of case processors, safety reviewers, and all

these staff must receive regular training to ensure they are up-todate on the latest developments in their products’ safety profiles or any changes in legislation or guidance. Ultimately some expenditure on PV is essential. It is a legal requirement and, although it is not a profit-making activity, it can save the company money if done correctly. Failed regulatory inspections can result in re-inspections (and each inspection costs money and time), hefty fines and possibly even restriction or revocation of licenses. Selecting a PV company can be very daunting and time consuming as there are many companies to choose from. Meeting representatives from all of these companies takes time and can become confusing as they all promise “the best service”. But it is worth doing your research to ensure you hire the right people for your company. Balance

Of course, not every company can afford to pay for the most expensive PV services on the market and the most expensive PV service on offer is not necessarily the best or most appropriate for a particular MAH.

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Obviously, a balance has to be struck between quality and cost effectiveness but in all matters concerning PV, priority must be given to the quality of the work being provided. There is no point trying to cut corners because at inspection time the company will be scrutinised and all failings will be discovered. In such a scenario the very least that can be expected is that the company emerges with a damaged reputation. At worst, the company can be shut down. There are PV service providers who can cut costs drastically by hiring staff in locations where salaries and overheads are cheaper. However, this can present new difficulties for the MAH in overcoming written and spoken language barriers, cultural issues and time-zone differences. The need for face-to-face communication can result in regular expensive and time-consuming business trips. These are very real issues that MAHs should consider carefully in making decisions about PV service providers. Good communication between the MAH and PV provider and a focus on quality are essential and any obstacles to these are potential sources of problems. Of course, there are undeniable financial advantages in seeking PV service providers overseas. Panacea, for example, is able to offer cost savings by being based on the Isle of Man where tax rates are much lower than other jurisdictions such as the UK. But as the Isle of Man falls into the regulatory remit of the UK MHRA, Panacea cannot sacrifice any of its high quality standards or this would be recognised very quickly. Financial costs

When an MAH has established that the services provided by a PV company are of the required standard (ideally by auditing them), they must examine the financial costs. Some PV companies offer charges at an hourly rate for their work. At first glance this ‘pay as you go’ type of arrangement can seem like a good deal. The MAH will only pay for work as and when it is required and this can give the

COST VERSUS QUALITY

continued

to build and easy to destroy – and in the context of employing PV service providers this is even more important. If you are an MAH faced with choosing a PV provider, then it is the reputation of the provider that should always be a major consideration in your final choice. Ask around – contact other companies who have worked with PV providers. Request past inspection reports from the authorities and do an audit before committing to anything. Even once you have signed with a provider, it would be good practice to audit them regularly, even if you have to pay another company to do it, as

MHRA Purple Guide – Good Pharmacovigilance Practice Guide.

Induction

Regulations

Videos

All companies have some type of induction GMP training for new employees. Unfortunately when exactly that training is provided, many times depends on the type of new employee you are. Hired for permanent work, then you typically receive GMP training during your few days on-site; hired as a temporary worker, then your GMP training might be provided during the first week, the first month, the first quarter, or perhaps never – a situation which, from a product quality perspective I have never understood. My children deserve the best quality medication your company makes, regardless of whether it was packaged by a permanent or temporary worker. Induction GMP training ranges from the brilliant, where concepts are explained and examples of the impact of non-GMP compliant practices on patients are elaborated on, to the abysmal where the regulations are read in a monotone and each worker is provided with a pocket copy of the GMPs. (Conflict of interest note: in a former life, in my many years as a book publisher I made a fortune selling copies of “pocket GMPs”, knowing full well, that once distributed to staff, they were hardly ever looked at again!).

Trying to sell GMP compliance to staff because “the regulations say we must” is like me trying to get my teenage son, a new driver, to obey the speed limit because “the regulations say you must drive slowly on residential streets” – a waste of time. Unless people understand the logic of regulations, the “why” of the regulations, it is an abstraction and will never become a way of life. I finally taught my son to obey the speed limit by having him volunteer at a hospital emergency room over a Christmas weekend where all the drunk and speeding drivers were being treated for wounds and injuries. The concept of death is not real to a teenager; the concept of becoming a paraplegic if they do not obey the traffic regulations is very real – and seeing the victims drove the point home. Same with GMP training – it needs to be designed to push whatever button is relevant to the worker, analyst, manager, vice president and board director (for whom I tailor GMP courses with data on the financial impact of non-quality that affected the company in the past year, and how GMP compliance could have dramatically, and positively, impacted the company’s bottom line).

Actually the biggest training crime is the “talking head” GMP training session. Several companies I know have video recorded their boring GMP training into a 2 or 4-hour unedited video. New hires, or annual repeat trainees, need to sit through this – nobody to ask questions to, just watching the monotone talking head, and afterwards signing a form that they had been through induction/repeat GMP training. If you think that the original training was boring and ineffective, watching the video is guaranteed to induce torpor, and retention of points made drop to perhaps 1 – 2%. What a stultifying training, and what a tragic introduction to the company for a new hire! And many times commercially sourced videos are not a lot better (but management feels better as they have paid a fortune for these tapes, and the authorities never quibble with commercial training tapes, so by definition they must be good!). There are lots of things wrong with GMP training, as performed by many pharmaceutical companies today. Yes, the regulatory requirements of the GMPs have been fulfilled, but what a waste of time and effort. And what a waste of an opportunity!

impression that it offers a good way of keeping PV expenditure under control. However, with the amount of work involved in PV, paying for the hourly rate can very quickly escalate out of control. A good way of dealing with this is to negotiate a capped price up front based on the estimated work-load so there is a pre-determined maximum sum payable for the services. This must be flexible in exceptional circumstances but at least gives the MAH some protection against spiralling costs. Reputation at stake

In any business, reputations are hard

you have to be sure the provider is doing the job you are paying them to do to the standard you expect. It may seem old fashioned, but word of mouth and personal recommendation from valued and trusted business contacts are as important as ever in making your final decision. Further reading: Volume 9a of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use – September 2008.

TRAINING – DOING IT WRONG! continued from page 18

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regulatory review Review of developments in the regulation of medicines and regulatory guidance in the Eeu, International markets and the USA

by Malcolm Holmes

United States of America cGMP Requirements for Combination Products – Final Rule

This final rule effective July 22, 2013 is intended to clarify which CGMP requirements apply when drugs, devices, and biological products are combined to create combination products. FDA seeks listing under EU Falsified Medicines Directive

The FDA’s Listing Request sends a clear and strong message that recognition of equivalent scientificallybased standards better protects the public. Inspection of speciality compounding pharmacies

Following the meningitis outbreak last fall that was linked to tainted drugs FDA has launched an inspection campaign of large specialty pharmacies.

Europe Guideline – setting health based limits for risk identification in the manufacture of different medicinal products in shared facilities

The potential for cross contamination becomes a concern when different medicinal products are produced in shared facilities. Active Substances (AS) as a cross-contaminant may pose a risk to the patient and should be restricted to a level that can be considered safe for all populations. A threshold value (permitted daily exposure (PDE) or threshold of toxicological concern (TTC) should be the result of a structured scientific evaluation of all available pharmacological and toxicological data. Where scientific data does not

support threshold values for safety or, where the risk cannot be adequately controlled, dedicated facilities are require. This document is published for comment by 30 June 2013. Guideline – porcine trypsin used in the manufacture of human biological medicinal products

DNA sequences of porcine circovirus (PCV) attributed to the porcine trypsin used have been found (2010) in a live attenuated rotavirus vaccine. As a result EMA requires the MA holder/ Applicant for such products to have sufficient information on the trypsin to allow a comprehensive risk assessment and provide a sufficient data package to the competent authority for assessment. This should include a description of testing methods/stage at which virus testing is performed/ sensitivity of virus tests/reports validating virus reduction steps.

●

Ch 5 – Production

Changes have been made to: – Sections 17-20 – prevention of crosscontamination – Sections 26 to 28 – qualification of suppliers/supply chain traceability/ legal obligation of manufacturing authorisation holders to ensure GMP for active substances – Section 33 – clarifies and harmonises expectations regarding the testing of starting materials – Section 68 introduces guidance on notification of restrictions in supply. ●

Ch 6 Quality Control

A new section on technical transfer of testing methods and other items such as OOS results ●

Ch 8 Complaints, Quality Defects and Product Recalls

Quality Risk Management principles to be applied when investigating quality defects/complaints/making decisions in relation to product recalls etc.

Task Force for the Falsified Medicines Directive

Framework for a close collaboration with Israel

The Heads of Medicines Agencies (HMA) state that, approximately 300 sites may require inspection to prevent AS and therefore finished product shortages. EU level availability of resources for such inspections is limited (25 sites by the end of June 2013)

The agreement (ACAA) recognises Israel’s industrial standards as equivalent to European standards. It includes the mutual recognition of the conclusions of GMP inspections/ manufacturing and import authorisations/certification of conformity without rechecking at import/official-control-authority batch release (OCABR)

Guidelines on Good Distribution Practice (GDP) of Medicinal Products for Human Use

The revised guideline proposes appropriate tools for wholesale distributors/the international pharmaceutical logistic business to conduct their activities and to prevent falsified medicines from entering the legal supply chain.

EU GMP Guide Revisions to EU GMP Chapters 3, 5, 6 & 8

Comments are invited on these guidelines by 18 July 2013 ●

Ch 3 – Premises and equipment

The only change is to section 6 as part of the improved guidance on prevention of cross-contamination

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MHRA MHRA launches an ‘Innovation Office’

Developers of novel technologies or products are often unsure which UK or European regulations apply. The ‘Innovation Office’ will give them the help they need to understand the regulatory requirements and pathway for progressing their novel product or approach. For further information on these and other topics we suggest you refer to the websites of relevant regulatory bodies and to current and past editions of “GMP Review News” published by Euromed Communications. To subscribe to this monthly news service contact info@euromed.com

news from the EIPG Bureau

During their January meeting, the Bureau considered the current status of the Professional Qualifications Directive and the latest draft of the EIPG Internal Rules following review by the lawyers in the French Order of Pharmacists. The plans for the General Assembly were finalised. The outcome of teleconferences with our sister associations PGEU (community) and EAHP (hospital) were discussed. It was agreed to raise the issue of Medicines Shortages with the European policy agenda and Gino Martini has been asked to be a “respondent” at the European Public Health Alliance meeting on Access to Medicines in the European Parliament on 16th May.

successfully submitted to the European Commission/EACEA and we await the outcome. European Commission

Our comments on the time needed to phase in the Black Symbol identifying medicinal products subject to additional monitoring were sent to SANCO. Cold Chain Transport Recommendations

The Conseil Central B of the Ordre National des Pharmaciens has published its "Recommendations concerning the transport of health care products under controlled temperature (5°C +/–3°C)". An English translation of the document is available on the EIPG website (www.eipg.eu) under “Guides and Codes”

Education

The PHAR-IN bid with the EAFP (academics) on “Competences for industrial pharmacy practice in biotechnology” has been

EIPG. Discussions included the hospital pharmacists concerns over the anti-counterfeiting legislation, inter-professional communication, specialisations in pharmacy and the root causes of medicines shortages. Their proposed European Summit was outlined which aims to produce “best practice” statements for various aspects of hospital pharmacy including production and distribution of medicines. European Pharmacy Students Association(EPSA)

The February meeting of EPSA entitled “Access to Medicines” was held in the European Parliament. Rizovsky Mounir (VAPI/UPIP) represented EIPG at the meeting and gave a presentation on Medicine Shortages. His report of the meeting is given below.

European Hospital Pharmacists’ Congress (EAHP)

Jane Nicholson attended EAHP round table meetings on behalf of

Jane Nicholson (jane@nicholj.plus.com)

EIPG invited to EPSA Annual Reception on “Health Inequalities – Access to Medicines” EU parliament – Brussels, 21st Feb 2013 The EPSA annual reception is one of the events of excellence held every late February/early March in the European Parliament in Brussels. During this reception, the point of view of EIPG concerning drug shortages in EU countries was shared and discussed with the students. Most of them will work in pharmaceutical companies in the near future, probably as Qualified Persons. We had the opportunity to exchange with representatives from EPF (European patients forum), The European Association of Pharmaceutical Full-Line Wholesalers (GIRP), European Association of Hospital Pharmacists (EAHP), Pharmaceutical Group of the European Union (PGEU) and EFPIA. As the EIPG is a professional organisation of pharmacists employed in pharmaceutical

companies of the European Union we tried to focus on the role of the pharmacist working in the pharmaceutical industry. EMA Reflection Paper

The Qualified Person is highly concerned by the drug shortage mitigation problem. In November 2012 the EMA published a reflection paper on medicinal product supply shortages caused by Good Manufacturing Practice Compliance problems which underlines the role of key persons within companies. GMP compliance problems which could have an impact on supply to patients, cannot always be predicted and is often the result of multiple problems at multiple levels from manufacturing until final delivery to the patient. This can include regulatory and or national legislation

The European Pharmaceutical Students' Association (EPSA) was established in 1978 and represents today around 120000 pharmacy students though its 33 members associations.

changes. However, it is the responsibility of the Marketing Authorisation holder to ensure appropriate and continued availability of medicinal products for human use to meet the needs of patients in accordance with Article 81 of DIR 2001/83. The problem of drug shortage could lead to a change in the prescribed product and the use of an unfamiliar alternative could often lead to a failure to treat and poorer patients outcomes1. The EMA reflection paper clearly covers the drug shortages problem

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related to GMP compliance problems as there could be many other reasons such as the single source strategy by purchasers, fewer manufacturers, low level of contingency stocks, parallel trade, downward pressure on generic prices, complexity of outsourcing operations. But it should be kept in mind that each situation is unique and requires a multi-disciplinary team of experts. Drug shortage mitigation is more and more a concern for both, pharmaceutical companies but also the regulator at national and EU level. In that way, 3 important points have been identified (see Table 1), adapted from EMA reflection paper) Globalisation

Moreover, pharmaceutical companies operate in a globalised world which continues to increase in importance day after day. The existence of extended manufacture, linked to a complex supply chain increases the risk of a shortage. Indeed, as we increase the number of those involved in the drug supply chain it seems logical that a deficiency in one of those could lead to a shortage. Another point is that the sources of API for life-saving drugs is wholly located in uncertain political and regulatory systems. Consolidation of manufacturing operations, leading to very few manufacturing sites supplying at a global level, is also one of the identified points of drug shortages within EU countries. Approach to drug shortages as globally speaking the industry has to

be more and more proactive rather than reactive to the drug shortage problem. As an example, EIPG highlighted the role of the QP in the management of this type of problem which has been identified as increasing day by day. Duties of the QP are mentioned in Art 51 of DIR 2001/83. Also, Art 23a of this Direction states that “The holder shall also notify the competent authority if the product ceases to be placed on the market of the Member State, either temporarily or permanently. Such notification shall, otherwise than in exceptional circumstances, be made no less than 2 months before the interruption in the placing on the market of the product. In the EU, the Qualified Person is very often the first contact point with health authorities.” Considering those points and the globally changing environment of pharmaceutical companies, it is obvious that the QP has to be more and more implicated in managing and mitigating the risk of drug shortage in two ways: internally (upper management) and externally (health authorities); These could be achieved by a risk management approach. EIPG position

The EIPG position on European drug shortage was presented to this EPSA annual Reception and can be summarised as follows: The ability to maintain adequate levels of supply should be subject to a balanced product-by-product risk analysis based on "available alternative therapies and the type of

Table 1. Results of drug shortages

disease". It is of huge importance that security stocks for "sensitive and essential medicines" are made available. The risk management approach has been identified as the best way to mitigate the risk by identifying drug alternatives. However, we have to keep in mind that not only “sensitive medicines” are facing shortage problems. Active pharmaceutical ingredient (API) manufacturers inspected and approved by PIC/S including the FDA should be automatically recognised within the European Union. This type of initiative should minimise the time taken to find an alternative API manufacturer. Last but not least, essential early discussions with local health authorities should occur as soon as a potential risk of shortages has been identified, followed by a smooth method of fast communication between all players concerned in the provision of healthcare as mentioned above, by highlighting the role of the Qualified Person. Conclusion

In conclusion, working in a highly regulated environment such as pharmaceuticals is very challenging but is also a guarantee of quality and supply for the patients. The trust we make in drugs distributed within EU has to be maintained at its highest level even if the environment is changing at a global level. Risk management, better communication and international co-operation between industry, patients, health authorities and healthcare representatives are the key success factors to avoid drug shortages. Rizovsky Mounir Rizovsky Mounir graduated in industrial pharmacy in Ucl, Belgium, School of Pharmacy. He works at SGS Belgium in the regulatory affairs post marketing department as associate and QP.

References: 1

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SMP Medication Safety Alert, Special Issue Drug shortages: National Survey Reveals High Level Of Frustration, Low Level Of Safety, September 23, 2010 issue.

AN INDUSTRY CAREER FOR A YOUNG PHARMACIST by João da Silva Duarte As U2 once sang, many things in life move in mysterious ways. Recently I’ve found that is surely the case when it comes to careers: I’d never believe during my graduation day if someone would tell me I’d be working as a regulatory intelligence professional in France one year and a half later. João da Silva Duarte is a Regulatory Intelligence & Policy Manager at H. Lundbeck A/S

So, how did it happen exactly?

Some years ago, during my Pharmacy course in the University of Lisbon, I started understanding that there was certainly more than lectures and exams before graduation. There should be something students could develop in advance, in order to be more prepared for the tough job market ahead. That’s when I started becoming more and more involved in students’ associations: after being active in the local level, I decided to accept the challenge to become active for two years in the European Pharmaceutical Students’ Association (EPSA) in the fields of Public Health and Pharmacy Education. This experience in EPSA was essential for me to be involved in policymaking activities, know the biggest pharmaceutical stakeholders and understand their role in the EU, knowledge which was fundamental later on. It was actually in 2011, during my mandate as EPSA’s Vice President of Education that I got in touch with EIPG for the first time: EPSA was developing the biggest event of the year in Lisbon related to the new Pharmacovigilance legislation and we’d like to have the industrial pharmacists’ view on how it would impact the work of companies

and how it would ensure an enhanced public health in EU. We were glad to have Ms. Cláudia Bicho as EIPG representative in the event, which was highly praised, and to engage once again with EIPG, a long-lasting partner of EPSA. While working for EPSA in my last mandate, I managed to enter the pharmaceutical industry still as a student, working as a scientific assistant for Medac GmbH’s affiliate in Portugal. I had a truly scientific work and started to develop a passion for regulatory affairs. However, I also started to understand the lack of opportunities in the field of drug development in Portugal and set my mind to find opportunities abroad, especially the ones that could potentiate that passion for regulatory affairs. That’s when I decided to apply for the Traineeship program of the European Medicines Agency (EMA) and, fortunately, in October 2011 I began my international career with them as a regulatory professional. Being in such an organisation as the EMA gave me not only an enriching training experience but also a privileged perspective on the importance of drug regulation in Europe. I had the chance to interact with many regulators and learn from their own experience, while building

my professional foundations in this important area of drug development. However, at the end of my traineeship, a question lingered in my mind: where to go next? I had the passion, a handful of regulatory knowledge to put in practice and an intense desire to participate actively in the drug development process for innovative medicines. After looking for some opportunities, I noticed a role in regulatory intelligence and policy in Lundbeck, based in Paris. I had only heard about the concept of regulatory intelligence through professionals of the area but I felt it was the ideal role for me. I used all my knowledge and experience gathered through EPSA and EMA to convince Lundbeck that, even though I was still a young pharmacist, I had the skills and passion needed for the task. Fortunately I was chosen for the role and couldn’t be happier right now: I support the development of innovative medicines and I have a constant urge to learn on the job and to develop even more. I’m sure that my early work in EPSA was truly indispensable for this big career step abroad due to the soft skills it provided me and the number of opportunities I had to truly understand the importance of drug development in Europe. I shall always live and work with these during my path towards professional competence.

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events MAY

JUNE

14-15 May 2013 – Budapest, Hungary Bioavailability, Bioequivalence, Dissolution and Biowaivers www.Informals.com/filter/manufacturing

3-6 June 2013 – Berlin, Germany 4th Virus & TSE Safety Forum www.pda.org

14-15 May 2013 – Brussels, Belgium Filing Variations www.Informals.com/filter/manufacturing

5 June 2013 – London, UK Innovation in the development and regulation of biopharmaceuticals www.mhra.gov.uk 12-13 June 2013 – London, UK Company Core Data Sheets www.informa-ls.com/CCDS

15-16 May 2013 – Amsterdam, The Netherlands 2nd Annual Open Innovation in Pharmaceutical R&D www.pharma.flemingeurope.com 16 May 2013 – London, UK New Approaches in Bio-analysis and Analytical Toxicology www.jpag.org20-21 May 2013 – London, UK ADC Summit 2013 www.adcsummit.com 21-23 May 2013 – St Petersburg, Russia Russian Pharmaceutical Forum www.adamsmithconferences/sector/ pharmaceuticals 21-24 May 2013 – Berlin, Germany Respiratory Drug Delivery, Europe 2013 www.rddonline.com/rddeurope2013

14 June 2013 – London, UK 4th Annual Cleanrooms Conference – Energy Management in Cleanrooms www.bsigroup.com 18-19 June 2013 – Singapore World Orphan Drug Congress www.terrapinn.com/orphan 19-20 June 2013 – Barnard Castle, UK Good Engineering Practice www.honeyman.co.uk 19-20 June 2013 – Prague, Czech Republic Filing Variations www.Informals.com/filter/manufacturing 19-21 June 2013 – London, UK Dissolution testing for the pharmaceutical industry www.rpharms.com/courses/dissol ution-testing.asp

23-27 June 2013 – Madrid, Spain 8th International Dendrimer Symposium www.ids-8.com 23-27 June 2013 – Boston, USA 49th Annual Meeting of DIA www.diapubs-digital.org24-26 June 2013 – Uppsala, Sweden 5th World Conference on Drug Absorption, Transport and Delivery www.eufeps.org 24-26 June 2013 – London, UK Global Pharmaceutical Contract Manufacturing www.gpcmevent.com 25-26 June 2013 – Florence, Italy Advanced Therapy Medicinal Products www.pda.org

JULY 4 July 2013 – London, UK Meeting Stability Challenges www.jpag.org

AUGUST/SEPTEMBER 31 August – 5 September 2013 – Dublin, Ireland World Congress of Pharmacy and Pharmaceutical Sciences www.fip.org/dublin2013

Clean Air and Containment Review The journal to enhance your knowledge of cleanroom, clean air and containment technology • • • • •

Learn about different aspects of these technologies from clearly written articles by experts Keep up to date on standards with regular updates by standards committee members Read about innovations Understand the jargon To subscribe, or for more information including Become an expert yourself contents lists for all previous issues, visit www.cleanairandcontainment.com

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