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PHARMACY features 4
DEMAND FOR OTC MEDICINES CONTINUES TO RISE The UK over-the-counter pharmaceutical market benefits from an ageing population and changes in the healthcare system. by Kitty Zhang
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PHARMACEUTICAL POLYMORPHS AND COCRYSTALS: IS THE SAME ALWAYS THE SAME? The recent addition of polymorphs and cocrystals to the EMA guidelines regarding classification of materials as new active substances or otherwise has inspired the formulation of a brief clarification detailing the fine line between what is equivalent and what is not, in the context of pharmaceutical polymorphs and cocrystals. by Liana Vella-Zarb
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MANIPULATING DOSAGE FORMS FOR CHILDREN: UNDERSTANDING AND IMPROVING PRACTICE Manipulation of adult medicines is frequently used to provide paediatric doses. The guideline Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals was produced and emphasises the lack of evidence around manipulation whilst suggesting good practices that might reduce potential risks. by Roberta Richey, Utpal Shah, Matthew Peak, Jean Craig, Jim Ford, Catrin Barker, Tony Nunn and Mark Turner
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PROTECTING MEDICAL RECORD DATA The healthcare industry, valued at $3 trillion, has become an increasingly valuable target for cyber thieves, and in some cases, a much easier target to attack, due to their often less than adequate investment in cyber security. What is it about the healthcare industry that has captured the cyber criminal’s interest in the last few years? by Lauren Sporck
regulars 3 17 18 20
EDITORIAL COMMENT NEWS FROM THE EIPG REGULATORY REVIEW EVENTS
ISSUE 27 • DECEMBER 2015 www.industrialpharmacy.eu www.eipg.eu
associate editors
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December 2015 ISSN 1759-202X
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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
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Cover photo: OTC medicines (see Demand for OTC medicines continues to rise on page 4)
european INDUSTRIAL PHARMACY December 2015
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editorial An interested party Influencing the evolution of EU regulations and guidelines concerning standards of quality, safety and efficacy of medicinal products is one of the main objectives of the EIPG. This activity has always been performed regularly since the foundation of our group, relying on the contribution of our members. A considerable number of documents have been generated over the years and, nowadays, one can easily find the latest EIPG position papers on our website. There is no doubt that one of our points of strength is the presence of a very large number of members with varying experience in all fields where an industrial pharmacist can be employed, allowing us to call on a multiple competency support. It was in order to build on this solid foundation that 2 years ago – at the 2014 General Assembly in Sofia – Special Interest Groups (SIGs) were set up with the aim of facilitating the communication and collection of opinions on specific topics among our members. In spite of the general consensus of all delegations to this initiative, we still have to make some additional organisational efforts in order for these groups to be adequately productive, as it is not always so easy to stimulate and maintain a constant participation of delegates in this activity, which is based exclusively on the exchange of written communications. Nevertheless, we always try to express the EIPG opinion on the most important issues, mainly focusing on the technical papers under consultation, which are published by the European Medicines Agency (EMA) or the Commission, requiring
comments from the so-called “interested parties”. In fact, the EIPG is fully recognised as a professional European association entitled to communicate the position of industrial pharmacists, like other pharmaceutical groups representing professionals and entrepreneurs operating in the pharmaceutical area. In the last few years, the EIPG has been regularly invited to attend the annual meeting of the Interested Parties organised by the GMP/GDP (good manufacturing/distribution practice) Inspectors Working Group of the EMA, where we have the opportunity to be informed about the work in progress on the GMP/GDP guidance and to make our voice directly heard on the most critical issues. At the meeting this November, the EIPG made a presentation on Regulation No. 536/2014, noting the elements missing from Annex 13 on GMPs and emphasising the importance of quality risk management in setting up the appropriate technical agreements between the sponsor and the manufacturer of samples for clinical trials (see News from the EIPG for a report of last month's meeting). With the contribution of all our members through the coordination of each country delegate, we look forward to keeping the EIPG actively present in the pharmaceutical arena as a standing interested party.
Piero Iamartino Vice-President Technical and Professional Development
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
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DEMAND FOR OTC MEDICINES CONTINUES TO RISE by Kitty Zhang
T
he market for over-the-counter (OTC) pharmaceuticals in the UK has been growing in recent years, driven by the country’s increasingly ageing population, cuts to public healthcare spending, and a rise in National Health Service (NHS) prescription charges. The OTC medicines market has also benefitted from the emergence of the Internet and social media platforms in the past two decades, which have enabled patients and health consumers to more easily acquire medical information and purchase OTC pharmaceutical products. Kitty Zhang joined Key Note in 2010, and works as Key Note’s Senior Business Analyst. She specialises in the following areas: healthcare, energy, utility, agriculture and chemistry.
According to government figures, over the last three decades, the median age of the UK population (the age at which half the population is younger and half the population is older) increased from 35.4 years in 1985 to 40 years in 2014. The UK’s ageing population is expected to continue to grow and, by 2035, the number of people aged 65 and over is predicted to account for 23% of the total UK population. An ageing population is creating unprecedented demand for health products and services. Based on data from IRI, the UK’s OTC pharmaceuticals market grew by an estimated 9.2% in value between 2010/2011 and 2014/2015. The largest sector is analgesics, which made up 21.5% of the total OTC pharmaceutical sales in 2014/2015, followed by skincare treatment (19.4%), cough, cold and sore-throat remedies (17.8%), and gastro-intestinal remedies (9.6%), with the remaining 31.7% accounted for by other OTC products, such as vitamins and minerals and smoking cessation products (see Figure 1).
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year ending February 2015, compared with moderate growth rates of 1.1% and 1.7%, in the years ending February 2013 and 2014, respectively. Demand for analgesics is mainly driven by seasonal sales, as well as price discounts and promotional offers by retailers. Adult oral analgesics comprise the largest subsector within the analgesics market, accounting for 61.9% of total sales in 2015. An estimated two-thirds of the adult population purchase an analgesic every year and oral analgesics are the most popular choice. Skincare treatment
The market for skincare treatment is diverse and covers a wide range of
products for different treatment purposes, including those for foot care and anti-fungal treatment, dry skin treatment, medicated skincare, antiseptic creams/liquids/spray, cold sore treatment, scalp and cystitis treatment, and adult infestation treatment. Foot care is the largest subsector within the skincare treatment market and demand for these products has been rising, driven by the UK’s ageing population and rising obesity rates, as well as increased awareness of products regarding foot-related problems, such as dry cracked feet. Cough, cold and sore throat remedies
Demand for cough, cold and sore throat remedies is influenced by seasons and weather conditions. Cold viruses survive better in winter months due to low humidity, while the lining of the nose also gets drier in winter, thus becoming more vulnerable to cold and flu viruses. Sales of cough, cold and sore-throat remedies witnessed double digit growth during winters of 2012/2013 and 2014/2015 when flu virus circulated at the highest level. By sector, cold and flu decongestants are the largest subsector, accounting for more than half (52.5%) of the total sales of this sector in 2015, followed by medicated confectionery (25.7%) and cough liquids (21.8%). Gastro-intestinal remedies
Sales of gastro-intestinal remedies increased by a moderate 5.7% between 2010/2011 and 2014/2015, fuelled by increasingly healthconscious consumers and improved eating habits. Indigestion remedies Figure 1: The UK OTC pharmaceuticals market by sector share of sales, year ending February 2015 (Source: IRI).
Analgesics Skincare treatment Coughs, cold and sore throat remedies
Analgesics
Gastro-intestinal remedies
Retail sales of analgesics witnessed a dramatic increase of 8.3% in the
Other
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DEMAND FOR OTC MEDICINES CONTINUES TO RISE
continued
are the most used type of gastrointestinal remedies, making up nearly half (49.5%) of total sales of gastro-intestinal remedies in 2015, followed by anti-diarrhoea remedies (19.7%) and laxatives (19.1%). The remaining 11.7% was accounted for by remedies for stomach upsets, irritable bowel syndrome (IBS) and travel sickness. Other OTC products
Sales of other OTC products – including vitamins and minerals, smoking cessation products, nutritional foods, hay fever remedies, eye care treatment, sleeping aids and stress aids – experienced consistent growth over the past 3 years, with vitamins and minerals representing the largest subsector within the other OTC pharmaceutical products sector, followed by nutritional foods, smoking cessation products and hay fever remedies. In recent years, the Government has introduced national initiatives to increase uptake of OTC medicines and help to make better use of NHS resources. In 2010, the Self Care Campaign was launched, bringing together key stakeholders in the UK, including professionals from the NHS Alliance, the Royal College of Nursing, the Proprietary Association of Great Britain and the National Association of Primary Care. The Self Care Forum was created the following year to help organise and raise awareness of Self Care Week. The Forum produces a series of fact sheets for minor illnesses, such as eczema, back pain and heartburn, to help doctors and patients discuss issues surrounding self care during consultation. Changes in the healthcare system in the UK in the past few years have had strong implications for pharmaceutical companies and the demand for OTC pharmaceuticals. As in many other developed nations, the recent economic downturn has led to a fall in healthcare expenditure in the UK. Government figures reveal that UK healthcare expenditure grew by an annual average of 8.1% between
1997 and 2009; however, the rate of growth slowed significantly from 2010 onwards as the Government’s austerity measures started to bite. The NHS in England has been instructed to make efficiency savings of up to £20 billion between 2010 and 2015, while at the same time dealing with the demographic pressure of a growing and ageing population. Indeed, between 2010 and 2013, growth in healthcare expenditure slowed to an average annual increase of just 2%. Changes in the healthcare system have led to greater rationing of services and increased waiting times for patients, as well as a diminished ability across the NHS to provide care. General practitioners (GPs), which are often the first point of contact for patients, are under increasing pressure from rising patient demand combined with NHS funding cuts. According to data published by Deloitte, 8.4% of NHS budgets were spent on GP services in 2012/2013, down from 10.3% in 2004/2005. Over the same period, the number of patient consultations in England increased. GP services are struggling to meet the needs of increasing numbers of patients demanding appointments and there are mounting concerns that overstretched GP services have resulted in accident and emergency units coming under strain as patients fail to get appointments at surgeries. Meanwhile, prescription charges in England have risen dramatically in recent years: the cost of an NHS prescription charge in England has
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increased from £7.20 per item in 2010 to £8.20 per item in 2015. The OTC pharmaceuticals market has benefitted from the rise in prescription charges in England in recent years, as OTC pharmaceuticals are often cheaper. The OTC market is highly competitive and the market in the UK is dominated by a small number of multinational companies. These companies often have established brands that are well known and trusted by consumers. Examples include: Rennie, for heartburn and indigestion, produced by German healthcare company Bayer; Beechams Cough & Cold and Panadol by GlaxoSmithKline; and Voltarol pain relief and Nicotinell, by Swiss company Novartis. All of these companies have large operations in other countries. There have been major changes in the competitive structure of the OTC market in recent years. The year 2014 saw two of the world’s top pharmaceutical companies, GlaxoSmithKline and Novartis, enter a consumer healthcare joint venture and combine their OTC businesses. In the same year, Bayer announced it agreed to acquire the consumer care division of Merck & Co for $14.2 billion. The UK’s growing population over the next few decades will help to drive demand for all consumer goods, including OTC pharmaceutical products. Economic growth will help to restore consumer confidence and increase expenditure on all consumer goods, including OTC pharmaceuticals.
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PHARMACEUTICAL POLYMORPHS AND COCRYSTALS: IS THE SAME ALWAYS THE SAME? by Liana Vella-Zarb
T
he recent addition of polymorphs and cocrystals to the European Medicines Agency (EMA) guidelines regarding classification of materials as new active substances or otherwise has inspired the formulation of a brief clarification detailing the fine line between what is equivalent and what is not, in the context of pharmaceutical polymorphs and cocrystals. Dr Liana Vella-Zarb is currently a lecturer in solid state chemistry at the University of Malta. Her research interests lie in crystal structure determination using X-ray powder diffraction techniques, as well as in crystal structure prediction and crystal engineering of materials, specifically those that are of relevance in a pharmaceutical or cultural heritage context.
The physical properties of a crystalline material are, in great part, dictated by the three dimensional arrangement of its constituent atoms. In the case of pharmaceuticals, most of which are administered in crystalline form, the crystal geometry of the active ingredient and its excipients directly affect the drug’s bioavailability, and consequently its activity and toxicity1. As new molecular materials are being developed, the characterisation of their solid state properties is shifting the concepts on which we base our understanding of their crystallisation. Instead of a molecule having a unique crystal structure, it often appears as if the number of known solid forms, or polymorphs, is proportional to the time and money spent investigating the compound2. The term ‘polymorphism’ is used to describe the existence of a substance in more than one crystalline form. Organic molecular crystals often display multiple polymorphs and pseudopolymorphs (solvates and hydrates). There is a close relationship between the unique crystal structure
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of a compound and its properties, such that different polymorphic structures of a material often have different physical, chemical, biological and pharmaceutical properties. The unexpected appearance of novel crystalline forms in a pharmaceutical context can be a scientific, industrial, or commercial disaster. The case of the protease inhibitor ritonavir (Norvir® ), Abbott Laboratories’ anti-HIV drug, is a high-profile example of polymorphs exhibiting different properties. The drug was formulated and marketed as an encapsulated solution in ethanol and water. However, a new crystal form appeared in 1998, first at a production plant in North Chicago, then at a plant in Italy. Ritonavir was the victim of a lateappearing polymorph with different solubility properties3, a case which was not the only one of its kind to hit the pharma industry. Another practical example is paracetamol; form I can only be formulated as a suspension and was the commercially available form until the discovery of form II, which undergoes plastic deformation and is suitable for direct compression,
thus making it potentially advantageous to the pharmaceutical industry as it lends itself to the manufacture of tablets, if its production in bulk is feasible4. The appearance of different polymorphic forms can be attributed to both kinetic and thermodynamic parameters. Polymorphs tend to convert from less stable to more stable forms, the rate of conversion depending mainly on the required activation energy and the differences in free energies between the two forms. The relative stability of these crystals as a function of conditions and the ability to produce a desired polymorph on demand are areas of great current interest. In some systems, one polymorph is the stable form at all temperatures (monotropic) while in other systems the stable form varies with temperature (enantiotropic). In addition, many organic systems display multiple metastable polymorphs. In the ideal thermodynamic case, each polymorph is stable over its own individual range of temperatures and pressures and, when that range is exceeded, it changes into a new polymorph. These interconversions are reversible and occur at a fixed transition temperature analogous to the melting and freezing points, which separate the solid and liquid states. In actual practice, however, several polymorphs may coexist at the same temperature and pressure, in which case only one of them is thermodynamically stable. In this case, the other polymorphs are said to be “kinetically metastable”. The Gibbs free-energy values of the various polymorphs define the depth of each energy minimum and determine which of the various coexisting polymorphs is the thermodynamically stable form5. Thus, knowledge of the thermodynamic stability is important for the selection of the appropriate polymorph for pharmaceutical and chemical development, and one of the goals of pharmaceutical manufacturers is to develop the most thermodynamically stable polymorph to ensure bioavailability of the product over its shelf-life.
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PHARMACEUTICAL POLYMORPHS AND COCRYSTALS: IS THE SAME ALWAYS THE SAME?
Figure 1: Molecular structure of the cocrystallisation of piracetam and gentisic acid as published by Vishweshwar et al 16,17. C, H, N, O atoms are in black, grey, blue and red, respectively. (Program used to create the picture: H. Putz, K. Brandenburg, DIAMOND, Program for X-ray structure analysis, Crystal Impact GbR, Bonn, Germany, 2012).
Over the past few decades, ever since the ritonavir disaster hit the headlines3, the influence of polymorphism on dissolution kinetics and bioavailability has been a hot topic also from a regulatory point of view. It has been shown how different crystal forms of drug substances exhibit different physical properties, including photostability6–8, compressibility, flow rate, and solubility, as well as differences in their solid state chemistry relating to stability and bioavailability. For these reasons, it is essential for regulatory bodies to pay close attention to such differences so as to ensure that polymorphic differences, if present, are borne in mind during the design stages via the tailoring of formulation and process conditions to ascertain physical and chemical stability of the product over the intended shelf-life, as well as product bioavailability/ bioequivalence. Cocrystals are crystalline materials made up of two or more different molecular entities that are synthesised with the aim of altering the physical properties of their constituents without the need to
make or break any chemical bonds. Their synthesis is based on the formation of supramolecular synthons that leads to a variation in the three-dimensional arrangement of their components, leading to a change in one or more physical properties. There has been a steady increase in the number of pharmaceutical cocrystals reported in the literature over the past few years, and a quick search in the Cambridge Crystallographic Database9 yielded more than 1505 excluding ethylacetate solvates. While some do have improved physical properties when compared to the active pharmaceutical ingredient (API) alone10–13, others are interesting from a purely crystallographic perspective. While the inclusion of polymorphs and cocrystals in the recent EMA notice is undoubtedly a step in the right direction, there are some aspects that need clarification. Although many polymorphs do differ morphologically, some may have the same crystal morphology but still be different crystallographic forms. Differences in crystal packing and lattice energies may result in a different solubility profile which will
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continued
inevitably cause differences in the drug’s bioavailability. Therefore, control of the crystal form in formulation is essential if the quality of the drug product is to be ascertained. In some instances, different polymorphic forms do result in comparable bioavailability, but this is not always the case. The impact of polymorphism on formulation bioequivalence, as well as on other factors such as photostability5, which might necessitate different packaging, must not be overlooked. Classification of polymorphs as having identical pharmacological action based solely upon their chemical structure does not give due consideration to the pharmacokinetic aspects affected by the material’s variation in physical properties. Prior to the marketing of a drug, applicants must quantify any crystal form impurity14,15, as high levels of polymorphic contaminants with differing physical properties would have an impact on the final efficacy of the drug. In the case of cocrystals, it is assumed that the API and a coformer are present in their neutral states (thereby classifying them as pharmaceutical cocrystals rather than salts). Their status as cocrystals implies stoichiometric amounts of their consituents, whereby alteration of such stoichiometries would imply differing physical properties. Specification of these stoichiometries, along with assurance of complete dissociation of the API from its coformer, should be required. If one is to classify cocrystals or polymorphs of a drug as the same active substance, one must first understand the implications this has upon developers and patients alike, and set limits to this generic definition. Two substances may be classified as “the same” in terms of pharmaceutical activity, but have very different physical properties that would make one form much more bioavailable than the other, or make one compressible into tablets as opposed to the other, which can only be marketed in liquid form. It is
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PHARMACEUTICAL POLYMORPHS AND COCRYSTALS: IS THE SAME ALWAYS THE SAME?
important to distinguish between substances that exert the same pharmaceutical activity but are otherwise very different. Much effort goes into the improvement of physical properties of materials, not just in a pharmaceutical setting, but also in food, construction, materials, and agriculture scenarios. Classifying compounds as the same regardless of the physical properties they exhibit is a dangerous practice that could result in patenting and patentability issues in the best instance, not to mention the potential to market sub-par drug products without any legal implications.
References 1
2
Almarsson O, Peterson ML, Zaworotko M. The A to Z of pharmaceutical cocrystals: a decade of fast-moving new science and patents. Pharm Pat Analyst 2012;1(3):313–327. McCrone WC. In: Physics and Chemistry of the Organic Solid State; Fox D, Labes MM and Weissberger A, Eds. London, UK: Interscience Publishers; 1965, Volume 2, pp. 725-767.
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Bauer J, Spanton S, Henry R, et al. Ritonavir: an extraordinary example of conformational polymorphism. Pharm Res 2001;18:859–866. 4 Nichols G, Frampton CS. Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution. J Pharm Sci 1998;87:684–693. 5 Bernstein J. Polymorphism in Molecular Crystals. New York, NY, USA: Oxford University Press; 2002. 6 Matsuda Y, Akazawa R, Teraoka R, Otsuka MJ. Pharmaceutical evaluation of carbamazepine modifications: comparative study for photostability of carbamazepine polymorphs by using Fourier-transformed reflection-absorption infrared spectroscopy and colorimetric measurement. J Pharm Pharmacol 1994;46:162–167. 7 Byrn SR, Pfeiffer RR, Stowell JG. SolidState Chemistry of Drugs, 2nd Edition. West Lafayette, IN, USA: SSCI, Inc.; 1999, p. 205. 8 Kiss A, Repasi J, Salamon Z, et al. Solid state investigation of mefloquine hydrochloride. J Pharm Biomed Anal 1994;12:889–893. 9 Cambridge Crystallographic Data Centre. www.ccdc.cam.ac.uk 10 Reddy LS, Bethune SJ, Kampf JW, Rodríguez-Hornedo N. Cocrystals and salts of gabapentin: pH dependent cocrystal stability and solubility. Cryst Growth Des 2009;9(1):378–385.
Expert Guidance on Industrial Pharma Microbiology Edited by Geoff Hanlon and Tim Sandle
Industrial Pharmaceutical Microbiology: Standards and Controls provides clear, practical and up‐to‐date guidance for handling virtually every compliance and operational challenge associated with pharmaceutical microbiology. Expert Advice
In over 600 pages and 25 chapters a team of twenty four international authorities answer all your questions concerning regulatory expectations in areas such as microbiological audits, rapid microbiological methods, conducting risk assessments, both proactive in terms of minimising contamination, and reactive in terms of addressing microbial data deviation; and also ensuring that processes meet “quality by design” principles. International Applications
Connect instantly with regulations and current best practices on everything from disinfectants to sterility testing; environmental monitoring to hazard analysis; and from pharmaceutical processes to biological indicators. All of this is developed from an international perspective, where different regulations are compared and contrasted together with insightful commentary as to best practices.
11 Harriss
BI, Vella-Zarb L, Evans IR. Furosemide cocrystals: structures, hydrogen bonding, and implications for properties. Cryst Growth Des 2014;14(2):783–791. 12 Tao Q, Chen J-M, Ma L, Lu T-B. Phenazopyridine cocrystal and salts that exhibit enhanced solubility and stability. Cryst Growth Des 2012;12(6):3144–3152. 13 Grossjohann C, Serrano DR, Paluch KJ, et al. Polymorphism in sulfadimidine/4aminosalicylic acid cocrystals: solid-state characterization and physicochemical properties. J Pharm Sci 2015;104(4):1385–1398. 14 Vitez IM. Utilization of DSC for Pharmaceutical crystal form quantitation. J Therm Anal Calorimetry 2004;78:33–45. 15 Yamada H, Masuda K, Ishige T, et al. Potential of synchrotron X-ray powder diffractometry for detection and quantification of small amounts of crystalline drug substances in pharmaceutical tablets. J Pharm Biomed Anal 2011;56(2):448–453. 16 Vishweshwar JA, McMahon ML, Peterson MB, et al. Crystal engineering of pharmaceutical co-crystals from polymorphic active pharmaceutical ingredients. Chem Commun (Camb) 2005;September 28(36):4601–4603. 17 Bruno IJ, Cole JC, Edgington PR, et al. New software for searching the Cambridge Structural Database and visualizing crystal structures. Acta Cryst 2002;B58:389-397.
This new second edition is an excellent reference work for those working in industrial pharmaceutical microbiology. It covers all aspects of this complex subject with contributions from many leading figures in the field and is highly recommended European Journal of Parenteral and Pharmaceutical Sciences
rial cal t s u Ind aceuti y og rm Pha crobiol ontrols Mi dards & C Stan
continued
This book is essential for every pharmaceutical laboratory: scientific, topical and practical. Pharmig
ors Edit lon Han f f o Ge Sandle Tim
5 201
ion edit
order online at www.euromedcommunications.com Or contact the publishers: email: publisher@euromedcommunications.com; Tel: +44 (0)1428 752222; Fax: +44 (0)1428 752223.
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MANIPULATING DOSAGE FORMS FOR CHILDREN: UNDERSTANDING AND IMPROVING PRACTICE by Roberta Richey, Utpal Shah, Matthew Peak, Jean Craig, Jim Ford, Catrin Barker, Tony Nunn and Mark Turner
L
ack of authorised age-appropriate formulations can make it difficult to administer medicines to children. Manipulation of dosage forms, although outside licensing requirements is undertaken by carers to achieve the required dose. A free to access guideline Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals was produced following a systematic review, observations of clinical practice, and questionnaires surveying manipulations and professionals’ experiences and views. Concerns about the accuracy of the dose achieved following manipulations and a lack of practice guidance were highlighted. This paper summarises some of this guideline and draws attention to the lack of evidence around manipulation processes. The guideline aims to provide guidance on avoiding manipulations (where possible), dosage form specific guidance where unavoidable and highlights medicines that should not be manipulated. The guideline also draws attention to the regulatory bodies and the pharmaceutical industry of the need to provide their known data for the benefit of children. Background
Manipulation of any medicinal product is not without risk. For instance, modifying the dosage form just before administration may result in an inaccurate or poorly reproducible dose, altered product efficacy, or medication error1. Many medicines given to children are dosage forms designed and authorised for adults (e.g. tablets and capsules), and manipulated just before administration in an attempt to deliver the desired dose2. The magnitude of the dose required, throughout childhood can vary up to 100-fold3 and often is a proportion of the dose in the marketed product4. Manipulations include cutting, breaking or splitting
of tablets, suppositories or transdermal patches into smaller segments, dispersing whole tablets into liquids to take a proportional dose, crushing tablets or opening capsules and mixing the resultant powder with liquid and taking proportions of enemas or nebuliser contents. Any manipulation should raise concerns about the resultant dose accuracy5, stability, and bioavailability of the active pharmaceutical ingredient (API)6. The quality and performance of a medicine is assured only if used in accordance with the marketing authorisation. Manipulation is, therefore, an uncontrolled practice which remains essential if children, especially in hospital, are to receive
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the required dose. Older medicines are often used for children who were not included in the original product licence or marketing authorisation (e.g. the intended patient age group and intended route of administration). These medicines are often more suited to adults than children. Manipulation of adult medicines with the aim of achieving the required paediatric doses is commonly acknowledged among professionals as a widespread practice, but poorly evidenced in the literature. Even when ageappropriate formulations are marketed, the need for manipulation will remain, as formulation development is not able to take account of all the possible circumstances of administration. We were commissioned by the National Institute for Health Research (NIHR) to develop guidelines on manipulation of medicines for children. Observation of clinical practice, a questionnairebased survey and a systematic review were used to collect data to construct draft guidelines that were finalised following reviews by a guideline committee and are available7. This article summarises the development and content of these guidelines. Study protocols
A structured, undisguised, observational study of dosage form manipulations in paediatric inpatient areas was conducted at three sites; a large regional children’s hospital, a regional specialist neonatal unit and a district general hospital8. Three hundred and ten manipulations were identified (Table 1), 54 of which were observed. To provide a national context, paediatric nurses across the UK were surveyed via a questionnaire8. Five hundred and sixty questionnaires were distributed with 153 returned (Table 1). Respondents reported 189 manipulations that met the inclusion criteria to be considered. Four databases were searched for the systematic review; International
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MANIPULATING DOSAGE FORMS FOR CHILDREN: UNDERSTANDING AND IMPROVING PRACTICE
Table 1: Summary of data used to construct guidelines Observational Use noted in Dosage form study: procedures questionnaire identifieda (%/153)a Tablet 191 59 (38.6%) Capsule 4 13 (8.5%) Sachets 30 2 (1.3%)
42 Nil Nil
Liquids for oral administration Nebuliser solutions Intravenous injection
0
0 (0%)
Nil
4 65
22 (14.4%) 19 (12.4%)
Nil Nil
Transdermal patches Suppository Enemas
10 6 0
20 (13.1%) 15 (9.8%) 6 (3.9%)
Nil 1 Nil
a b
Most frequent medicines 40+ Loperamide, melatonin, oseltamivir Vigabatrin, morphine sulphate (MST), Gaviscon (compound alginate), Movicol (macrogol 3350) n/a Ipratropium bromide Omeprazole, phenobarbitone, ranitidine, midazolam Hyoscine hydrobromide Paracetamol, diclofenac, glycerine Phosphate enema
Data taken from Richey et al.8 Data taken from Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals7
Pharmaceutical Abstracts (IPA), PubMed, CINAHL and EMBASE, using the protocol of Richey et al 9. The findings have recently been updated (unpublished data) without finding significant developments to those reported in the guideline. Observation and survey results
Of the 310 recorded manipulations, 62% involved tablets8, 21% were intravenous drugs and 10% were sachets. Of 40 manipulations of tablet observed, 25 were splitting, 12 aqueous dispersion, and one each involved crushing, breaking by hand and splitting followed by dispersion in liquid and measurement of a proportion of the liquid to provide the dose. Three of the 25 tablet manipulations were repeated due to crumbling or uneven splitting. Visible powder was generated during nine of these manipulations. One tablet manipulation was due to child preference over the taste of an available liquid. Questionnaire responses8 confirmed that the common tablet manipulations were splitting, crushing or dispersing in water and giving a proportion (used by >50% respondents). The predominant method reported to split tablets was with a tablet splitter. The
10
Systematic review papersb
continued
predominant proportions of dose taken for non-intravenous (IV) administration were ¼, ½, or ¾ of the dosage form prior to manipulation; however, doses equivalent to, e.g. 1%, 7%, 19% and 80% content were also reported. Observations of manipulation of other dosage forms are also summarised in Table 1. Over 50% of respondents reported that the sole reason for manipulation was that there was ‘no suitable preparation or strength available’. Other reasons given were patient preference and usual practice. Concerns with the dose accuracy achieved by manipulation was reported by 35% of respondents. Major risks of
manipulation are summarised in Table 2. Systematic review
No studies identified the resultant bioavailability following manipulation of tablets to obtain a proportion of the original dose, but two studies indicated no significant changes in bioavailability following the administration of crushed sustained-release tablets. Where sustained-release tablets were split and administered, no significant changes to bioavailability and peak plasma concentrations were recorded. Seven studies halved tablets and used adapted pharmacopoeia criteria for assessment; no
Table 2: Risks of manipulationa Patient – Delivery of inaccurate and/or non-reproducible doses – Altered efficacy of the product (e.g. sub-therapeutic doses) – Increased adverse events Product – Alteration to the integrity of the dosage is untested, possibly resulting in altered pharmaceutical, pharmacokinetic and pharmacological properties and stability – Contamination Person performing – Exposure to the API or excipients into the atmosphere the manipulation potentially causing sensitisation or inhalation of powder Environment – Release of APIs – Release of antimicrobials, and their use in sub-therapeutic doses may predispose drug resistance a
Data taken from Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals7
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Table 3: Questions to be considered before manipulation is undertakena Is a more appropriate formulation available? What is the acceptable dose range for a particular patient/medical condition? Is the commercial product suitable for such a manipulation? Is there evidence that the manipulation can be performed adequately and reproducibly? Is drug stability maintained? Are there indications that manipulation may not provide dose accuracy (e.g. tablet crumbling)? Is there a risk of an adverse event if a 20% over-dose or under-dose is given? Has the manipulation been performed previously? Is the manipulation usual practice and been approved by a pharmacist? b Data taken from Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals7
pharmacopoeial specifications for subdivided tablets existed at the time these studies were published. Such specifications are now included in the British Pharmacopoeia 201610 for scored tablets. Results varied with one study finding that up to 75% of halved and quartered tablets were outside ±15% of the desired weight. Several methods of splitting tablets were evidenced including manual splitting and the use of tablet splitters, razor blades, kitchen knives and scissors. No one method was ranked as consistently the best or worse technique. Halved irregularly shaped tablets did not meet the weight specification. Importantly, halving scored tablets did not always produce halves that met specified criteria. Dispersible tablets can also yield inconsistent doses when doses are withdrawn from different depths of the container11. Table 1 also indicates that only one other publication, investigating suppositories, was identified as being helpful in informing the guideline development.
the point of care. A guideline development group consisting of healthcare professionals, research, academic, formulation and pharmaceutical quality control experts and parent representatives reviewed the presented evidence and developed the guideline. It describes options available to avoid manipulation, but when manipulation is unavoidable provides readily accessible, easy to read guidance for delivering appropriate and reproducible medicine doses to neonatal and paediatric patients. The guideline is intended for use by healthcare professionals working in UK hospitals in neonatal and paediatric in-patient settings and its use should increase the numbers of babies and children who get the prescribed dose. Additionally, it provides a risk assessment tool for use at ward level to minimise risk to the product, patient, operator and environment. Finally, the guideline informs professions, regulators and the public of best practice and potential risks associated with manipulation of medicines.
Guideline development and purpose
Summary of guideline recommendations
The three data sets summarised above were used to draft the guidelines which covered the manipulation of medicines to deliver appropriate, reproducible doses to paediatric patients where no suitable product is available at
The guideline has not been reproduced in its entirety in this paper. Primarily, dosage forms which are appropriate to the age and ability of the patient, of appropriate strength and licensed should be procured where possible; however, it
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continued
may be necessary to procure unlicensed special formulations or imported medicines to meet this need. Consideration should also be given to rounding the dose to an available product strength or convenient measurable volume, to whether an alternative dosage form can be used or whether an alternative medicine within the same therapeutic class can be substituted. If this is impossible, the questions raised in Table 3 must be answered prior to healthcare professionals undertaking any manipulation. The aim is to avoid manipulating medicines wherever possible. Simple guidelines include the following.
• Do not manipulate medicines
with a narrow therapeutic index.
• Never manipulate hazardous
medicines outside a controlled environment.
• Do not manipulate medicines which are modified release dosage forms unless specific information from the manufacturer or pharmacist permits manipulation.
• Any manipulation should be
undertaken immediately prior to administration.
• As the effects of a manipulated
product may differ from those described for the nonmanipulated product, careful monitoring of the patient is recommended particularly after administration of the first dose.
If a manipulation is considered necessary, further information may be required to ensure this is carried out safely and as accurately as possible. Suggested practices are given in Table 4. Any new manipulation in an acute situation should be reported to pharmacy at the earliest opportunity and a risk management process implemented. The future
In 2007, legislation13 was introduced in Europe to provide impetus into the development of appropriate
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MANIPULATING DOSAGE FORMS FOR CHILDREN: UNDERSTANDING AND IMPROVING PRACTICE
medicines for children. Eight years later, it will be some time before the influence of this legislation and campaign strategy is realised. Children will always require alternative administration strategies for medicines when they cannot manage the authorised dosage form even though it has been
deemed ‘age appropriate’14. An understanding of the current, imperfect situation must be recognised by regulators and the pharmaceutical industry. All must recognise the following:
• the lack of evidence relating to the manipulation of medicines
continued
for the purposes of achieving a suitable dose; • the research findings within the guidelines and be prepared to support practitioners in their requests for information around manipulations of medicines; • that children may require a range of doses that require
Table 4: Some suggested practicesa Tablets – Where patient preference requires manipulation, the implications should be discussed with the patient, parents or carers – Tablets should be split using a tablet splitter in preference to dispersing or crushing – Dispersion in liquid should be used only if there is knowledge of the dispersibility or solubility of the API, and formulation characteristics – Scored tablets should be split along the score-line, with the score-line uppermost – Do not split tablets into less than ¼ segments – Visually assess the segments to establish if they appear equal in size Capsule – Unless designed as a sprinkle formulation, do not open capsules to take a proportion of their contents without consulting a pharmacist – Do not disperse the contents and take a proportion without knowledge of the solubility characteristics of the drug – Dispersion in liquid should be used only if there is knowledge of the dispersibility or solubility of the API, and formulation characteristics – Avoid removing the contents from liquid-filled capsules, but where necessary withdraw the required volume into a syringe when the fill volume is known Sachets – Do not disperse the contents and take a proportion without knowledge of the solubility characteristics of the drug Liquids for oral – Volumes of <5mL should be administered using an oral syringe administration – If volumes <0.1mL are required, they should be diluted to ensure that a volume can be measured accurately – Prepare single doses: diluted liquids should not be stored for future use – The chosen diluent should be compatible with the medicinal product Nebuliser solutions – Withdraw the required dose volume from the vial into the syringe and add to the nebuliser chamber – To avoid inadvertent IV administration, nebuliser solutions should be drawn up and added to the nebuliser chamber in one uninterrupted operation – Any diluent should be added to the chamber and the solution mixed using a suitable, preferably sterile, device IV and sub– The National Patient Safety Agency 2012 advises that certain injectable therapy manipulations are cutaneous undertaken in a pharmacy injections – Consult local/hospital IV guidelines prior to any manipulation – The chosen diluent must be compatible with the injectable product – The measurement of volumes of <0.1mL should be avoided (with the exception of insulin) but, if required, the dose should be measured after appropriate dilution. The diluent should not be added to the syringe containing the drug. Mix the active drug and diluent and withdraw the required volume into a separate syringe Transdermal – Check the product’s release characteristics with the pharmacy department as different brands of the same patches API may have different release characteristics and may not be equivalent – Do not manipulate reservoir transdermal patches – Where a proportion of a matrix patch is required, cut along the full thickness of the patch to produce symmetrical segments – Do not cut patches into more than four segments Suppository – Consult with pharmacy whether drug distribution is homogenous – Cut suppositories from tip to base using a scalpel blade – Assess the suppository segments to establish equality in size Enema – Withdraw the proportion of the enema which is not required from the container using a syringe and needle and discard – Administer the remainder of the enema from the original container – If the enema nozzle is unsuitable for administration, the required dose should be withdrawn and administered via a suitable rectal tube a
12
Data taken from Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals7
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manipulation of ‘adult’ medicines;
• that manipulation is being
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undertaken, despite its inadequacies for the paediatric population;
• that carers would not have to
manipulate if age-appropriate dosage forms were more generally available.
The full guideline is now published and freely available for health professionals7 and presents results from independent research commissioned by the NIHR under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0807-13260). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. References 1
2
3
4
5
6
7
8
9
Ernest TB, Elder DP, Martini LG, et al. Developing paediatric medicines: identifying the needs and recognizing the challenges. J Pharm Pharmacol 2007;59:1043–1055. Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ 2000;320(7227):79–82. Rocchi F, Tomasi P. The development of medicines for children. Pharmacol Res 2011;64:169–175. Standing JF, Tuleu C. Paediatric formulations – getting to the heart of the problem. Int J Pharmaceut 2005;300:56–66. Kayitare E, Vervaet C, Ntawukulilyayo JD, et al. Development of fixed dose combination tablets containing zidovudine and lamivudine for paediatric applications. Int J Pharmaceut 2009;370:41–46. Quinzler R, Gasse C, Scheider A, et al. The frequency of inappropriate tablet splitting in primary care. Eur J Clin Pharmacol 2006;62:1065–1073. Barker C (Chair), Nunn T, Turner M, et al. Manipulation of Drugs Required in Children (MODRIC): A Guide for Health Professionals. Commissioned by NIHR RfPB Programme. www.alderhey.nhs.uk/wpcontent/uploads/MODRIC_Guideline_FU LL-DOCUMENT.pdf. Richey RH, Shah UU, Peak M, et al. Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence. BMC Pediatrics 2013;13:81. doi: 10.1186/14712431/13/81. Richey RH, Craig JV, Shah UU, et al. The manipulation of drugs to obtain the
11
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required dose: systematic review. J Adv Nursing 2012;68:2103–2112. Medicines and Healthcare Products Regulation Agency. Subdivision of tablets. In: British Pharmacopoeia Volume III, Formulated Preparations > General Products > Tablets > Production. London, UK: MHRA; 2016 Broadhurst EC, Ford JL, Nunn AJ, et al. Dose uniformity of samples prepared from dispersible aspirin tablets for paediatric use. Eur J Hosp Pharm Sci 2008;14:27–31. National Patient Safety Alert 20, Promoting safer use of injectable medicines, Reference number 0434, Central Alert System (CAS) reference NPSA/2007/20, Issue Date: March 2007
13
14
continued
Regulation (EC) no 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Official Journal of the European Union 2006;L 378:1–19. European Medicines Agency. EMA/CHMP/QWP/805880/2012 Rev. 2.Guideline on pharmaceutical development of medicines for paediatric use. Brussels, Belgium: EMA; 1 August 2013. Available at www.ema.europa.eu/docs/en_GB/docum ent_library/Scientific_guideline/2013/07/ WC500147002.pdf [accessed 27 November 2015].
Roberta Richey works in national clinical guideline development for the National Institute for Health and Care Excellence. She was a Research Associate at Alder Hey Children’s NHS Foundation Trust. Utpal Shah was formerly post-doctoral formulation research fellow for the NIHR Medicines for Children Research Network supporting clinical study groups in issues surrounding age-appropriate formulations and clinical trial supplies for investigator and industry led paediatric trials. He was also Research Associate at Alder Hey Children’s NHS Foundation Trust and Liverpool John Moores University where he was involved in pharmaceutics projects and the development and conduct of numerous national and multinational paediatric formulation research studies. Matthew Peak is Director of Research at Alder Hey Children’s NHS Foundation Trust and Clinical Lead for NIHR Clinical Research Network: Children in the NW Coast. He has extensive experience in the design and delivery of both basic science and applied research studies in child health, including medicines use and optimisation. Along with Mark Turner, he leads the Liverpool Paediatric Medicines Research Unit which is a joint initiative between Alder Hey and Liverpool Women’s NHS Foundation Trust and Liverpool John Moores University. Jean Craig previously worked as a Paediatric Nurse at Alder Hey Children’s NHS Foundation Trust and as a Research Associate in the Evidence Based Child Health Unit, University of Liverpool, undertaking systematic reviews and contributing to development of national evidence-based guidelines. Her PhD included systematic review methodological research. She now works as a Research Adviser with the NIHR Research Design Service and as a Senior Research Associate in the School of Medicine, University of East Anglia. Jim Ford is Emeritus Professor in Pharmaceutics at the School of Pharmacy and Biomolecular Sciences at Liverpool John Moores University. He gained his PhD in Solid Dispersions in 1980 and spent 34 years working in academia becoming Director of the School. He has published over 250 papers on topics including solid dispersions, controlled release matrices, thermal analysis and paediatric medicines. Catrin Barker was appointed Chief Pharmacist at Alder Hey Children’s NHS Foundation Trust in 2012. She has spent 30 years working in paediatric pharmacy practice and has specific interests in clinical pharmacy practice, medicines information and implementation and delivery of paediatric research. She has several publications in the area of paediatric clinical pharmacy practice. Tony Nunn was Clinical Director of Pharmacy at Alder Hey Children’s NHS Trust until 2011. He has honorary positions at Liverpool John Moores University and University of Liverpool and continues to work with various organisations to get ‘better medicines for children’. Mark Turner is a Neonatal Consultant at Liverpool Women’s NHS Foundation Trust and Senior Lecturer in Neonatology at the University of Liverpool. Mark currently chairs the European Network of Paediatric Research at the EMA (Enpr-EMA).
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PROTECTING MEDICAL RECORD DATA by Lauren Sporck
A
fter a slew of data breaches in 2014, the FBI warned the healthcare industry that cyber-criminals would be directing more attention their way in 20151. The healthcare industry, valued at $3 trillion, has become an increasingly valuable target for cyber thieves and, in some cases, a much easier target to attack due to their often less than adequate investment in cyber security. What is it about the healthcare industry that has captured the cyber criminals’ interest in the last few years2? Lauren assists in OPSWAT’s research and content development; her editorial background includes writing for Urbanspoon and Optify. She received her Bachelor's degree in Business from the University of Washington.
Overview of data breaches in 2014
At the end of each year, the Identity Theft Resource Center (ITRC) produces a data breach report showing the total number of data breaches and records stolen for each industry3. The data is taken from credible sources, including the Attorney General’s website, and includes data breaches that occurred in the year of the report or breaches that were made public in the year of the report. 2014 was a big year for data breaches in general, with a total of 761 breaches, amounting in 83,176,279 exposed records. The following industries were included in the report.
• Credit/Financial (5.5%) • Business (32.7%) • Education (7.6%) • Government/Military (11.8%) • Healthcare (42.3%) Of the industries represented, the healthcare industry had the highest number of total breaches in 2014: 322 out of a total of 761 breaches. In terms of the total amount of records stolen or compromised by breaches in 2014, the business
14
sector had the highest at 65,896,115, followed by the healthcare industry at 8,255,247 records4. It might be surprising that the banking industry only had 1,185,492 records stolen, especially when considering how frequently credit card fraud makes the news. It’s not often that you hear about someone who had their medical record stolen. Unfortunately, stolen medical record data is not usually reported in a timely manner; often taking years before someone discovers that the data has been compromised. Unlike stolen medical records, stolen credit card information is usually reported rather quickly, due to banks’ monitoring for suspicious account activity. Comparing medical records to credit card data
In order to understand why the healthcare industry is such a big target for cyber-criminals, you have to understand the value of a stolen medical record. Personal banking information is still valuable to the average cyber thief, but it doesn’t have nearly as high a payout as that of a medical record. Reuters placed a value on stolen medical
information that is 10 times more than that of credit card data5. According to data collected from monitoring exchanges on the black market, the director of threat intelligence at PhishLabs estimates the value of stolen medical information to be around $10 per record, and that is on the low end of black market prices. Some sources claim that they can be sold for as much as $60 to $70 per record. In the ITRC report mentioned above, of 322 reported breaches for the healthcare industry, 289 breaches resulted in confirmed quantities for the number of records stolen. The average amount of records stolen per known breach was about 28,564. If each medical record is assumed to be worth a minimum of $10, then the average payout for cyber-criminals from each breach would be at least $285,640, and that is considered to be a conservative estimate. If a record were assumed to be worth around $60–$70, then the average payout would be over $1.7 million per breach6. Credit card data on the other hand is worth around $1 per record, so cyber-criminals would have to steal at least 10 times as many banking records to realise similar profits. Medical records sell at a high price because they contain personal data such as names, addresses, social security numbers, birth dates, billing information, among other information. This information is used by cyber-criminals to create fake IDs that can be used to buy drugs that can be resold later, or to file false insurance claims using patient data7. Industry spending on cyber security
Hospitals are often easier targets for cyber-crime because they lack the proper cyber security defenses8. Healthcare spending for cyber security is known to be low, compared to other regulated industries. In a 2012 report released by the Ponemon Institute, the healthcare industry listed a lack of funds as one of the main obstacles preventing them from taking the proper steps towards better data
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security practices9. ABI Research recently reported estimates that worldwide healthcare spending on cyber security will be around $10 billion by 202010. This only amounts to about 10% of the amount spent on cyber security by the critical infrastructure industry. By comparison, the financial industry is expected to spend $9.5 billion in 2015 alone12. We know how much cybercriminals stand to gain from a healthcare industry data breach, but how much do these data breaches cost the companies who are affected? With the average cost of a data breach for a company in the healthcare industry of about $2 million over a 2-year period12, the case for investing in additional cyber security defenses becomes clearer. The problem with BYOD
One of the biggest concerns facing the healthcare industry is the increased adoption of “bring your own device” (BYOD) by medical professionals. According to a recent report, 88% of healthcare organisations said they permitted employees and other medical staff to use personal devices for work purposes13. More than half of those same organisations claimed they did not have visibility to the security status of those BYOD devices. If organisations are not certain of the security of a device, how can they effectively protect any patient data contained therein? Although many healthcare organisations allow medical staff to use personal devices for work purposes, their IT departments do not adequately support that use14. There seems to be some sort of disconnect between the Electronic Medical Record (EMR) tools that are chosen by the IT department and the willingness of medical professionals to use those tools. In a study recently released by Spyglass Consulting, 70% of physicians interviewed claimed that their IT department wasn’t making adequate progress towards supporting mobile computing and
continued
communication requirements. This statistic is alarming as 96% of those same physicians claim to be using their personal smartphone for clinical communication purposes. Inefficient support of physician’s mobile devices results in communication issues, which in turn leads to higher costs created by communication delays. The healthcare industry clearly needs to find a way to integrate BYOD trends without compromising the security of devices. Solutions for preventing future breaches
With healthcare industry data breaches predicted to have increased in 2015, organisations must take the proper precautions to avoid hefty fines resulting from federal Health Insurance Portability and Accountability Act (HIPAA) violations. Multi-scanning technology
As a requirement for the HIPAA, installing an antivirus product is an important layer of protection. By choosing multi-scanning, organisations reduce the risk of that malware entering their network; what one antivirus engine doesn’t detect another often will. Document sanitisation capabilities are also useful, allowing users to prevent infections by advanced threats and/or zero-day attacks by converting potentially dangerous file types to remove embedded malware.
containerisation, but the issue is largely unaddressed for desktops and laptops. Improved email security
A phishing attack is believed to be the cause of the recent Anthem breach, where stolen employee credentials were used to gain access to a secure network. In order to avoid this type of attack, the healthcare industry must invest in the proper email security software. Industry-wide spending on cyber security remains low, despite the fact that healthcare is the largest target for cyber-criminals. If organisations in the healthcare sector want to reduce their risk of cyber-attack, they have to reevaluate their views on security. Too often, investment in cyber security occurs after a breach has already taken place and patient data has already been compromised. If organisations find the right security tools they can protect patient data while addressing organisation-wide communication issues, saving the valuable time of medical staff and avoiding the potential loss of millions in data-breach recovery costs. References 1
2
Protection of endpoints
If devices connecting to a hospital’s internal network cannot be confirmed as secure, how can organisations expect to avoid a possible data breach? Proper host checking and monitoring of endpoint security status is imperative as more physicians adopt BYOD practices. This endpoint visibility challenge is unique and difficult to address while still maintaining the spirit of BYOD policies. Some MDM (Mobile Device Management) products have addressed this using techniques like
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3
4
5
Finkle J. Exclusive: FBI warns healthcare sector vulnerable to cyber attacks. New York, NY, USA: Thomson Reuters; 23 April 2014. Available at: www.reuters.com/article/2014/04/23/uscybersecurity-healthcare-fbi-exclusividUSBREA3M1Q920140423 [Accessed 5 March 2015]. Orcutt M. “2015 Could be the year of the hospital hack. MIT Technology Review; 23 December 2014. Available at: www.technologyreview.com/news/533631 /2015-could-be-the-year-of-the-hospitalhack/ [Accessed 5 March, 2015]. Identity Theft Resource Center. 2014 Data Breach Stats. San Diego, CA, USA: ITRC; 27 August 2015. Available at: www.idtheftcenter.org/images/breach/ITR C_Breach_Stats_Report_2014.pdf [Accessed 5 March, 2015]. Identity Theft Resource Center. 2014 Data Breach Category Summary. San Diego, CA, USA: ITRC; 23 December 2014. Available at: www.idtheftcenter.org/images/breach/ITR CBreachStatsReportSummary2014.pd [Accessed 5 March, 2015]. Waugh R. Healthcare data worth ten times price of credit card data. Bratislava,
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6
7
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Slovakia: ESET; 25 September 2014. Available at: www.welivesecurity.com/2014/09/25/healt hcare-security/ [Accessed 5 March, 2015]. Van Cleave K. Anthem highlights desireability of stolen health records. New York, NY, USA: CBS; 5 February 2015. Available at: www.cbsnews.com/news/do-hackershave-your-health-records/ [Accessed 5 March, 2015]. Humer C. Your medical record is worth more to hackers than your credit card. New York, NY, USA: Thomson Reuters; 24 September 2014. Available at: www.reuters.com/article/2014/09/24/uscybersecurity-hospitalsidUSKCN0HJ21I20140924 [Accessed 5 March, 2015]. Murphy T. Health records are easy targets for hackers. Columbus, OH, USA: The Columbus Dispatch; 15 February 2015; Available at: www.dispatch.com/content/stories/busine
continued
ss/2015/02/15/health-care-records-areeasy-targets-forhackers.html?utm_content=12155422&ut m_medium=social&utm_source=linkedin [Accessed 5 March, 2015]. 9 Ponemon Institute. 2012 Cost of Cyber Crime Study. Traverse City, MI USA: Ponemon Institute; October 2012. Available at: www.ponemon.org/local/upload/file/2012 _US_Cost_of_Cyber_Crime_Study_FINAL 6%20.pdf [Accessed 5 March, 2015]. 10 ABI Research. Healthcare cybersecurity a massive concern as spending set to reach only US $10 billion by 2020. London, UK: ABI Research. Available at: www.abiresearch.com/press/healthcarecybersecurity-a-massive-concern-as-spen/ [Accessed 5 March, 2015]. 11 Cybersecurity Ventures. Cybersecurity Market Report. Menlo Park CA, USA: Cyber Security Ventures. Available at: http://cybersecurityventures.com/cybers ecurity-market-report-q2-2015/
[Accessed 5 March, 2015]. Institute. Fourth Annual Benchmark Study on Patient Privacy & Data Security. Traverse City, MI USA: Ponemon Institute; March 2014. Available at: www.privacyrights.org/sites/privacyrights.or g/files/ID%20Experts%204th%20Annual%2 0Patient%20Privacy%20&%20Data%20Secu rity%20Report%20FINAL.pdf. [Accessed 5 March, 2015]. 13 Weisbaum H. Heath care system’s $5.6 billion security problem. Engelwood Cliffs, NJ, USA: CNBC; 12 March 2014. Available at: www.cnbc.com/id/101488137 [Accessed 5 March, 2015]. 14 Comstock J. Report: Most physicians use BYOD smartphones, but lack support from hospital IT. MobiHealthnews 14 January 2015. Available at: http://mobihealthnews.com/39718/report -most-physicians-use-byod-smartphonesbut-lack-support-from-hospital-it/ [Accessed 5 March, 2015]. 12 Ponemon
PharmacoVigilance Revıew PharmacoVigilance Revıew Supporting the safe use of medicines and medical devices
Managing Reference Safety Information The EU centralised application from a pharmacovigilance and risk management prospective
Journal on drug safety issues Editor – Rob Begnett
Post-authorisation aggregate safety reporting: the new PSUR
This quarterly journal provides informed comment and analysis of international pharmaceutical regulations relating to the safe use of medicines and medicinal devices. It also carries reviews of current methods of pharmacovigilance. New European pharmacovigilance legislation – an adequate response to current challenges?
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news from the EIPG Bureau meeting
A Bureau meeting is to be held on 15/16 January 2016. Anyone wishing to raise a subject concerning the EIPG should write to Jane Nicholson (jane@nicholj.plus.com). Reminder – nominations for the EIPG Emerging Industrial Pharmacist Award
Nominations for the 2016 award should be submitted by any EIPG Full Member no later than 1 January to a member of the Bureau or to Jane Nicholson (jane@nicholj.plus.com). The purpose of this award is to recognise significant intellectual contributions by emerging industrial pharmacists within EIPG that promote state of the art in industrial pharmacy and the pharmaceutical sciences. At the time of nomination, the nominee should be a person who is within 10 years of having started a career in industrial pharmacy. European Pharmaceutical Students Association (EPSA)
Claude Farrugia (Vice-President Communications) was invited by EPSA to attend their Autumn Assembly in Malta, where he delivered a presentation on the formulation of protein based drugs. The next joint EPSA/EIPG Webinar will be held at the beginning of February and will be on the subject of Pharmaceutical Marketing. The EPSA executive would like to encourage industrial pharmacists working in marketing to participate in the discussion. Medicines shortages
Claude Farrugia and Jane Nicholson have both been appointed to the Management Committee of the COST (International Cooperation and Specific Organisations Participation) Project on Medicines Shortages. The project will commence during the second quarter of 2016 and aims to improve the sharing of research and evidence about the problem of medicines shortages in Europe. European Medicines Agency and Interested Parties Meeting
EIPG comments on the proposed GMP (good manufacturing practice) and GCP (good clinical practice) inspection
procedures for investigational medicinal products (IMPs) were submitted to the European Commission (see EIPG website) and presented at the Interested Parties Meeting held at the European Medicines Agency in November. Piero Iamartino (Vice-President Technical and Professional Development), Jane Nicholson and Mounir Rizovsky (VAPI/ UPIP Belgium) represented EIPG at this meeting. The future work plan of the Inspectors' Working Group (IWG) was presented by the IWG and discussed with the industry representatives: GMP Annex 1 – Sterile Products
There has been substantial feedback on the need to revise the Concept Paper and a draft revision of the Annex is to be distributed for public consultation during 2016. This will take account of the revised European Pharmacopoeia Monograph for Water for Injection. A preliminary guidance will be published in the form of Q&As during 2016. GMP Annex 13 and IMPs
As a result of Regulation 536/2014, a minor update is required. However, the European Commission has advised that for legal reasons this cannot take the form of an Annex, hence the draft which has been published for consultation. There was concern expressed by all industry representatives that GMP fragmentation will lead to confusion and misunderstanding by staff in companies. Industry would like to see a single, common approach to GMPs that continues to focus on the ‘what to do’. Annexes on specific operations should identify additional hazards to control without repeating the principles. This could be supported by ‘how to do/best practice’ documents and standards outside the regulatory framework. An analysis of the practical impact of the Clinical Trial Regulation on GMP inspection-related activities will be undertaken by the IWG in 2016.
GMP Annex 21 – Importation
This document is intended to clarify the expectations for importers and to ensure that third country manufacture is carried out in accordance with GMP standards equivalent to those in force in the EU. Following comments received on the concept paper, drafting has been initiated and the aim is to publish for public consultation during 2016. Other GMP-related activities
The European Commission plans to create specific GMP guidelines for “Advanced Therapy Medicinal Products” and held a targeted consultation this year. The IWG will continue to engage on this topic. Lack of harmonisation
Various industry examples of inconsistencies with interpretation amongst national GMP inspectors were discussed. Industry would like to see a greater focus on science and risk. In particular, industry representatives felt that there appears to be a lack of appreciation of the relationship between hazard and risk and an enhanced understanding would benefit both industry and regulators. There have been problems with revised Chapter 5 of Eudralex Volume 4 since active pharmaceutical ingredient (API) producers have been asked to disclose details of suppliers of API starting materials and this appears to be a contradiction to other guidance documents. It was noted that the IWG will continue to devote a significant proportion of its resources to harmonisation and European Medicines Agency members will continue to run workshops, and attend meetings and case studies as well as producing advice in publications. A brief update on the Shortages Workshop was made and it was noted that a training document is freely
available on the International Society for Pharmaceutical Engineering website.
GMP Annex 17 – Real Time Release
An updated draft has been published and the aim is to finalise during 2016.
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Jane Nicholson, Executive Director EIPG jane@nicholj.plus.com
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regulatory review The current review period has seen a number of changes in the regulation of medicines and regulatory guidance in the EU, International markets and the USA
USA Entities considering whether to register as outsourcing facilities
The Food and Drug Administration (FDA) has received questions about whether entities engaged in various types of activities, such as compounding only non-sterile drugs or only repackaging biological products, should register as an outsourcing facility. The FDA has issued guidance to answer such questions and to provide additional information about the regulatory impact of registering as an outsourcing facility. Endotoxin Testing Recommendations for Single-
are also applicable to detection of other visible defects that may affect container integrity or cosmetic appearance of the product.
Use Intraocular Ophthalmic Devices
Toxic Anterior Segment Syndrome (TASS) has been associated with single-use intraocular ophthalmic devices (IODs) and single-use intraocular ophthalmic surgical instruments/accessories that are contaminated with endotoxins. This guidance document provides recommendations for endotoxin limits as well as endotoxin testing to manufacturers and other entities involved in submitting premarket applications or premarket notification submissions for IODs to mitigate future outbreaks of TASS.
Europe Annex 16 – Certification by a Qualified Person and Batch Release
This Annex has been revised to reflect the globalisation of the pharmaceutical supply chains and the introduction of new quality control strategies. The revision includes the prevention of the entry into the legal supply chain of falsified medicinal products. It also implements International Conference on Harmonisation (ICH) Q8, Q9 and Q10 plus interpretation documents, e.g. the manufacturing and importation authorisation interpretation document. Areas where the interpretation by Member States has not been consistent have been clarified. The Annex becomes operational on 15 April 2016.
United States Pharmacpeia (USP) Visual Inspection of Injections (USP Pharmacopoeial Forum 41(6) In-Process Revision: <1790>)
The General Chapters–Dosage Forms Expert Committee proposes this new chapter to provide guidance on the inspection of injectable drug products for visible particles. The methods discussed
Clean Air and Containment Review The journal to enhance your knowledge of cleanroom, clean air and containment technology
Clean Air an Containmend t Review
• Learn about different aspects of these technologies from clearly written articles by experts
ISSN 2042-326 8 Issue 6 | Apri l 2011
• Keep up to date on standards with regular updates by standards committee members • Read about innovations
Measuremen t of air velo cities Settle plate s in unidirectiona l airflow The ISO calib ration stan dard for particle counters: a user’s com ments Biological safety operator prote cabinets: ction tests on narrow cabin ets Zoned ultra clean air operating theatres
• Understand the jargon • Become an expert yourself
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european INDUSTRIAL PHARMACY December 2015
• Issue 27
REGULATORY REVIEW
New EU guidance to speed up development of antibiotics
The European Medicines Agency has released a draft guideline which provides guidance for the conduct of robust analyses to facilitate and speed up the development of new antibiotics, in particular those targeting multi-drug resistant bacteria. Medical devices – proposal for a regulation of the European Parliament and of the Council
Following on from the Poly Implant Prothèse breast implant scandal, this revised proposal would, if adopted, amend Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009. Implementing Act on Principles and Guidelines on GMP for Medicinal Products for Human Use
The purpose of this consultation is to collect views, evidence and information from stakeholders to help the European Commission develop its thinking in this area.
continued
published and revised ICH and EU guidelines. CEP (Certificate of Suitability) applicants should ensure compliance with these new requirements. Failure to do so could result in the application being considered deficient. Medicines and Healthcare Products Regulatory Agency (MHRA) advises the Cell Therapy Catapult on emerging clinical grade induced pluripotent stem cells bank regulation
Using induced pluripotent stem cells (iPS) is an exciting new development, which sees medicine go beyond its traditional boundaries. iPS cells are developed by taking specialised adult dividing cells (e.g. skin cells) and ‘reprogramming’ them back to stem cells. These stem cells are considered to be ‘pluripotent’, meaning that they can be used to make any type of cell in the body. The MHRA provided advice on a wide variety of novel issues faced by the organisation.
CEP – Content of the Dossier for Chemical Purity and Microbiological Quality
TxCell manufacturing facility in Besançon shut down following inspection by the French ANSM
This new guidance is applicable immediately. It takes account of the increased requirements of newly
A non-compliance report has been published in the Eudra GMP database for this facility. The action
taken is suspension of manufacturing/release and distribution, including suspension of distribution of released batches. There were 22 deficiencies observed, including seven major deficiencies. (This serves as a reminder that EU regulatory authorities will not hesitate to take action against manufacturers when serious GMP deficiencies are noted at inspection – MH.)
International WHO Guidance on Good Data and Record Management Practice
This guidance consolidates existing principles and gives further detailed illustrative implementation guidance. Additionally, it gives guidance as to what these requirements mean in practice and what should be demonstrably implemented to achieve compliance. 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@euromedcommunications.com
CALL FOR ARTICLES Dear Colleague We hope you enjoy the European Industrial Pharmacy and find it both useful and informative. We are currently seeking new articles for future issues of the journal and would like to invite you to contribute an article or review paper on any aspect of industrial pharmacy to the journal. All issues of European Industrial Pharmacy are indexed by both Scopus and Embase and thus are available through the listings for any other industrial pharmacist internationally. Please contact the Managing Editor, Sue Briggs (suze.briggs@sky.com) for further information or submissions.
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events JANUARY 2016 19–21 January 2016 – Brussels, Belgium 6th Annual Clinical Trial Supply Europe www.clinicalsupplyeurope.com 19–21 January 2016 – London, UK Festival of Genomics www.festivalofgenomicslondon.com 20–21 January 2016 – London, UK Pharmaceutical Microbiology 2016 www.pharma-microbiology.com 24–27 January 2016 – Arlington, VA, USA IFPAC-2016: International Forum & Exhibition Process Analytical Technology…Quality by Design www.ifpacglobal.org 25–28 January 2016 – Frankfurt, Germany 15th Annual Cool Chain Temperature Controlled Logistics Europe www.coolchaineurope.com 26–27 January 2016 – Washington, DC, USA CBI’s 13th Annual Pharmaceutical Compliance Congress www.cbinet.com 28–29 January 2016 – Alexandria, VA, USA 11th Summit on Biosimilars www.cbinet.com
FEBRUARY 10–11 February 2016 – Barcelona, Spain World Generic Medicines Congress Europe 2016 www.healthnetworkcommunicatio ns.com 10–11 February 2016 – Barcelona, Spain Biosimilar Drug Development World Europe 2016 www.healthnetworkcommunicatio ns.com
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11–12 February 2016 – Basel, Switzerland Targeted Drug Delivery http://pharma.flemingeurope.com /targeted-drug-delivery 22–24 February 2016 – Munich, Germany Software Design for Medical Devices Europe www.sdmdeurope.com 23–24 February 2016 – Berlin, Germany Pharmaceutical Microbiology www.pda.org 23–24 February 2016 – London, UK Early Clinical Development www.informa-ls.com 25–26 February 2016 – Manchester, UK 11th Annual Biomarkers Congress www.biomarkers-congress.com 29 February–1 March 2016 – Arlington, TX, USA 2016 ISPE 25th Aseptic Conference www.ispe.org 29 February–3 March 2016 – Toronto, Ontario, Canada 4th Annual Cold Chain Management & Temperature Control Summit www.coldchainpharm.com 29 February–3 March 2016 – Munich, Germany Disposable Solutions for Biomanufacturing www.disposablebiomanufacturing. com
MARCH 7–9 March 2016 – Frankfurt, Germany 2016 European Annual Conference www.ispe.org 7–9 March 2016 – Madrid, Spain 8th International Conference and Exhibition on Pharmaceutics and Novel Drug Delivery Systems http://novel-drugdeliverysystems.pharmaceuticalconferences .com
7–10 March 2016 – Athens, GA, USA 40th International Good Manufacturing Practices Conference www.georgiacenter.uga.edu/ugahotel/conferencesevents/register/internationalmanufacturing-practices-2016 9–10 March 2016 – London, UK Clinical Outsourcing & Partnering World Europe 2016 www.healthnetworkcommunicatio ns.com 13–16 March 2016 – San Antonio, TX, USA 2016 PDA Annual Meeting www.pda.org 16–18 March 2016 – Vienna, Austria 21st Congress of the EAHP www.eahp.eu 17 March 2016 – London, UK JPAG Annual General Meeting www.jpag.org
APRIL 4–7 April 2016 – Glasgow, UK 10th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology www.worldmeeting.org 11–12 April 2016 – Ware, UK APS Industrial Insights 2016 www.apsgb.co.uk 12–13 April 2016 – Venice, Italy Parenteral Packaging www.pda.org 12–13 April 2016 – Dusseldorf, Germany 2016 Pharma Congress: Production and Technology www.pharma-kongress.com 17–21 April 2016 – Phoenix, AZ, USA RDD 2016 www.rddonline.com 19–20 April 2016 – Chicago, IL, USA 12th Annual Medical Device Compliance Congress www.cbinet.com
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