Page 1

european INDUSTRIAL

PHARMACY FEATURES 4

WICKED PROBLEMS The technique of General Morphological Analysis provides a virtual model for complex, apparently insoluble “wicked problems” that are normally difficult to define and structure. by Nassir Hussain and Tom Ritchey

8

TOWARDS A EUROPEAN PATENT LITIGATION SOLUTION Intellectual property protection is now harmonised throughout most of Europe but there is still disagreement in setting up a central court to deal with infringements. by Gareth Williams and Graham Burnett-Hall

11

14

19

ACHIEVING CLEANLINESS IN MEDICAL ENGINEERING Modern cleaning processes for medical instruments, devices and implants are described and discussed. by Doris Schulz

THE CHALLENGES OF BACTERIOPHAGE THERAPY Bacteriophages should now be considered as possible alternatives to antibiotics providing that technical and non-technical problems can be overcome. by Alexander Sulakvelidze INNOVATION – SCIENCE OR ART? Willingness to Innovate is a key factor in the development of a successful drug discovery unit. by Robert Bates and Anna Bruns

REGULARS 3

EDITORIAL COMMENT

23

REGULATORY REVIEW

21

24 26

27

BOOK REVIEWS

PHARMACEUTICAL FORUM NEWS FROM THE EIPG EVENTS

ISSUE 10 • SEPTEMBER 2011 www.industrialpharmacy.eu www.eipg.eu


Associate Editors Belgium: Kristina Bindus, Bart de Greef Bulgaria: Valentina Belcheva

european INDUSTRIAL

PHARMACY Issue 10 September 2011 ISSN 1759-202X

Czech Republic: Ales Franc Denmark: Marie Fog

EDITOR Joe Ridge, MRPharmS

Finland: Anni Svala

PRODUCTION Dave Johnson

France: Jean-Pierre Paccioni

SUBSCRIPTIONS Jill Monk EDITORIAL BOARD Michael Anisfeld Michael Gamlen Linda Hakes John Jolley

Germany: Armin Hoffmann Great Britain: Shilpa Gohil Greece: Margarita Efthymiopoulou

European Industrial Pharmacy is published four times a year by: Euromed Communications Ltd Passfield Business Centre, Lynchborough Road, Passfield, Liphook, Hampshire GU30 7SB

Hungary: Georgina Gal Ireland: Anna O’Mahony Italy: Piero Iamartino

Tel: +44 (0)1428 752222 Fax: +44 (0)1428 752223 Email: info@euromedcommunications.com www.industrialpharmacy.eu Annual subscription rate £65

Latvia: Inta Saprovska Malta: Claude Farrugia Netherlands: Florentine Nieuwmeyer

european INDUSTRIAL

PHARMACY discussion group:

Portugal: Luis Baiao, Sofia Guimas

www.pharmweb.net/gmp.html

Spain: Emma Fernández Sweden: Pär Tellner Switzerland: Stephan Buchmann, Valter Gianesello

Views expressed in European Industrial Pharmacy are those of the contributors and not necessarily endorsed by the Publisher, Editor, Editorial Board, or by our corporate sponsors who accept no liability for the consequences of any inaccurate or misleading information ©2011 Euromed Communications Ltd

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

2

Cover photo: Canulas cleaned by the CO2 snow jet process (see page 13)

european INDUSTRIAL PHARMACY • Issue 10 September 2011


EDITORIAL COMMENT Dear Colleagues This editorial is slightly different in that I will be writing this editorial no longer as a pure Industrial Pharmacist but as an Academic, in my case as Professor of Pharmaceutical Innovation at King's College London. I will be the first example of an Industrial-Teaching practitioner in the UK. It is perhaps synchronicity occurring but this edition of the journal covers a book review I composed on 'The Future of Pharma' written by Professor Brian D Smith who is a former Industrial Chemist but now a leading Academic at the OUBS and SDA Boccini and consultant adviser for a number of corporations. Perhaps it was findings in Professor Smith's research which spurred this change in direction for me, who knows? But what is known is that innovation or productivity within the Pharma sector is at an all time low! In very simple terms the Pharma Industry is only about twothirds as productive as it once was, when measured in new drug approvals. It is clear when you read Professor Smith's book or at least my review and, from your personal experiences in your own company, that Pharma is going through

change. We all know this but it is the RATE OF CHANGE which is unprecedented and we are now seeing companies undertake various defensive strategies or business models in order to overcome the productivity gap. In the UK, the Government is keen to forge closer links between Academia and Industry and are in the progress of establishing Technology Innovation Centres (TICs) in order to jump-start innovation and creativity. This TIC model is based upon the German model of the Fraunhofer Institutes where there is great emphasis on applied research in order to translate ideas from paper to product. What relevance is this to Industrial Pharmacy you may ask? Well, my view is that there will be a wide variety of business models in operation which will require a multi-skilled workforce in order to deliver new medicines or novel therapies/healthcare programmes. Clearly, Pharmacists with their multi-disciplinary background and training, can and should play active roles in the Future of Pharma. Thus, it is imperative that Associations such as the EIPG, FIP and the various national

associations continue to work together to encourage more Pharmacists to enter Industry and also to provide mentoring and career advice to experienced Pharmacists on opportunities for development and to 'think outside the box'. Providing mentoring and career advice to Industrial Pharmacists and Pharmacists in general will be my main focus as I enter my last 24 months as President of EIPG. Without a succession plan we are nothing! Please enjoy the current edition of the Journal and please do not hesitate to contact me or contact the EIPG on www.eipg.eu. We look forward to hearing from you.

Best wishes

Dr Gino Martini FRPharms EIPG President

gmp-review news

free news service for gmp revıew subscribers

Monthly news service will keep you up-to-date on new developments in GMP and associated regulations. gmp-review news will be sent by email only to current gmp revıew subscribers.

Subscribers should contact subs@euromedcommunications.com to register european INDUSTRIAL PHARMACY • Issue 10 September 2011

3


WICKED PROBLEMS

Achieving clarity in complex pharmaceutical problems: from innovation to policy formulation

by Nasir Hussain and Tom Ritchey

I

n pharmaceutical and healthcare planning sectors, a modelling environment must interrelate diverse issues such as technology development, national policy directives, organisational structure, public perception, ethical issues and educational requirements. Furthermore, it should be able to take account of global forces shaping healthcare and novel emergent business models. Analysing such complex socio-technical systems presents a number of problems. Firstly, many of the variables involved are not readily quantifiable, containing strong social, political and cognitive dimensions. Secondly, the uncertainties inherent in complex problems are in principle non-reducible, and often cannot be fully described or delineated. Compounding this is the extreme connectivity of socio-technical systems that results in elements within the problem complex being inextricably linked to each other. What might seem to be the most marginal of factors can, under the right circumstances, become an overwhelming force of change (the socalled butterfly effect). In short, traditional quantitative methods, mathematical modelling and simulation simply do not suffice to tackle such complex issues which have been termed ‘wicked problems’. Wicked problems

Relatively unknown in the pharmaceutical sector, the term ‘wicked problem’ is transdisciplinary, cited principally in public planning, policy formulation and socio-political arenas. It describes a state of extreme complexity defined by criteria listed in Table 1.

Although sounding a touch comical, wicked problems are neither ‘evil’ in the traditional sense, or indeed even ‘problems’ as no stable problem statements have actually been defined. For this reason, Russell Ackoff in his book ‘Redesigning the Future’ used the equivalent term unstructured reality to describe such ‘social messes’. More recently, the uncertainties embedded within such conundrums have been (in)famously termed ‘unknown unknowns’ and the unintended consequences of ill-thought out decisions highlighted in the Freakonomics series of publications. In short, wicked problems are ill-defined, ambiguous, and associated with strong moral, political and professional issues. As they are strongly stakeholder dependent, there is often little consensus about what the problem is, let alone how to resolve it. Examples in the healthcare sector include end-of-life decisions, assessing the cost-benefit ratio for new drug approvals, the difficulty of integrating vast amount of disparate data into any meaningful outcome and the types of emerging business models for the pharmaceutical-governmental-private payer complex. As an alternative to mathematical modelling and other ‘hard’ operational research methods, a number of nonquantified problem structuring methods (PSMs) have been developed during the past 40 years. One such method, Morphological Analysis, enables multidimensional problems to be analysed, structured and displayed in two dimensions. Modelling wicked problems with morphological analysis

The kneejerk reaction that often befalls regulators, senior executives and politicians in tackling complex issues is most aptly summed up by Michael Pidd:

Table 1: The five principal criteria of a wicked problem as proposed by Rittel and Webber (1973). Nasir Hussain, PhD and Tom Ritchey, PhD are Founding Partners of Strategy Foresight, London, UK. email: hussain@strategyforesight.org

4

Continually developing and mutating (no stable problem statement) Full of ambiguities, contradictions and circular causality Strongly stakeholder orientated Associated with strong political, moral and professional issues Reactive: the problem complex fights back european INDUSTRIAL PHARMACY • Issue 10 September 2011


W I C K E D PR O B L E M S ( C o n t . ) “one of the greatest mistakes that can be made when dealing with a mess is to carve of off part of the mess, treat it as a problem and then solve it as a puzzle – ignoring its link with other aspects of the mess.” And while one is busy solving the puzzle, the mess is still mutating – retrofitting the solution to the puzzle merely puts it into another state of flux. PSMs engage stakeholders of the wicked problem expressly at the level of the mess – this requires experienced independent facilitation to map the boundary conditions of the problem complex, as well as managing strongly held opinions and beliefs of the participants. When dealing with complex planning problems, PSMs such as Morphological Analysis offer a number of distinct advantages. PSMs must be able to: ●

Accommodate multiple alternative perspectives to deal with uncertainties Facilitate a process of collective creativity amongst the stakeholders to develop shared concepts, terminology and

ownership of the problem formulation Generate, in real time, a visual representation of the problem space for the systematic and transparent group exploration of a solution space Focus on relationships between discrete alternatives Concentrate on possibility rather than probability.

Morphological analysis is fully attuned to meeting these criteria as it is an objective method for structuring and analysing wicked problems that are naturally nonquantifiable, contain ineradicable uncertainties and cannot be causally simulated or modelled in a meaningful way. Computerised in the mid-90s, Morphological Analysis made it possible to create non-quantified multi-dimensional inference models that endeavoured to represent the total problem space, and as many of the potential solutions as possible. This, in itself, went a long way in satisfying the first – seemingly incredible – criterion concerning wicked problems: ‘in order to

a)

describe a wicked problem in sufficient detail, one has to develop an exhaustive inventory for all the conceivable solutions” ahead of time. In complex, dynamic, planning problems, the concern is with form over function i.e. forming the hyperspace, the extreme boundary conditions to encompass the possibilities (and even absurdities) before developing any strategies. These possibilities arise from the interaction of the various states within multiple dimensions – a three dimensional typological construction and its equivalent morphological field is shown in Figure 1. Typologies of greater dimensions can be represented by placing the dimensions as columns beside each other as shown in Figure 2. In 1995, the Swedish Defence Research Agency developed a dedicated, highly flexible, workshop orientated computer support for Morphological Analysis that could incorporate multiple dimensions and millions of constructed configurations. What took researchers months to construct and model can now be done in

Figure 1: Visually, a typology uses the (Cartesian) dimensions of a physical space to represent its dimensions – however this ends at three (a). Extra dimensions can be embedded as hyperspaces but visually this is not particularly appealing, prone to errors and merely adds another layer of complexity to an already complex situation. The equivalent 3D typological format can easily be represented as 3columnar morphological table (b).

P (1)

P (2)

P (3)

P12

P22

P32

P11

P13 P14 b) eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

P15

P21 P23 P24

P31 P33

P25

5


W I C K E D PR O B L E M S ( C o n t . )

Figure 2: An 8-dimensional morphological field developed for the Swedish National Rescue Services on evaluating preparedness for chemical accidents, accidental or deliberate, for different municipalities. One possible configuration (out of 57,600) is shown – cells shaded in red are inputs while blue cells represent possible responses. Each and every pair of cells shown in the configuration below is mutually compatible. Any single contradictory pair knocks out the entire string (e.g. ‘standard routine for general case’ and the top three response cells are not highlighted as this was deemed contradiction in terms by the subject-matter specialist working group). matter of few days provided that facilitated, interactive group workshops are conducted.

Morphological analysis for the pharmaceutical and healthcare sectors

PSMs are uniquely equipped to model complexities and uncertainties that healthcare professionals, scientists and administrators face in healthcare systems planning, policy formulation and regulatory issues. Figure 2 displays an 8-dimensional morphological field developed for the Swedish National Rescue Services for dealing with chemical accidents. This relatively small problem space of 57,600 possible configurations (fields of up to 105 to 106 configurations are frequently encountered) is an example of an input-output inference model that

6

can be adapted for a variety of situations e.g. dealing with drug recalls, drug interactions, and Quality by Design issues. To give decision support, the group must be facilitated to conduct a Cross Consistency Assessment, which is a pairwise comparison of every pair in the multi-dimensional field as shown in Figure 3. Analytical, empirical and occasionally normative “contradictions” between any two states results in the removal of any and all “strings” that contain that contradiction: the example shown in Figure 2 displays a configuration that is entirely internally consistent i.e. every pair can co-exist as determined by the working group. This reduces the entire problem space to a workable solution or design space – up to 99% of the

configurations in the problem space can be removed to yield an interactive inference model in which any dimension or multiple dimensions can be selected as input and any others as output. This resulting “design space” allows for exploring scenarios, testing assumptions and interventions and identifying unintended consequences – the principal considerations for engaging a wicked problem in the first instance.

Concluding remarks

The earliest known publication citing the use of Morphological Analysis for healthcare systems planning dates to the 70s in the design and evaluation of healthcare provision for a large metropolis. Here the authors stated that “modern day healthcare has become a highly complex system, having numerous components

european INDUSTRIAL PHARMACY • Issue 10 September 2011


W I C K E D PR O B L E M S ( C o n t . ) whose relationships are generally not well understood.” They further cited problems that included i) the types of care rendered ii) access to healthcare for different populations iii) utilisation of scarce manpower and iv) structuring and evaluating the consequences of incentives in the health sector – does this sound familiar? In the current economic environment of austerity measures (a wicked problem in itself, particularly what to do with banker’s bonuses) where the healthcare and pharmaceutical sectors are expected to “innovate with less”, the industry is already in the midst of a wicked problem (the patent cliff) that has been brewing for at least a decade before the recent financial crash. Receding drug pipelines, increased regulatory scrutiny, governmental pricing pressures, the rise of patient advocacy groups and how to (bio)ethically integrate emerging

technologies are all but a few symptoms of the ‘Kondratiev winter’, the trough of the supereconomic cycle, in which we find ourselves. A new line of questioning is needed in these post-normal times, defined as a line of enquiry “where facts are uncertain, values are in dispute, stakes are high and decisions urgent.” Causal modelling, such as Bayesian Belief Networks, when applicable, can and should be used as an aid to judgement. However at a certain level of complexity i.e. social, political, cognitive processes, judgments must often be used – and worked with – more or less directly. PSMs such as Morphological Analysis allow judgmental processes to be placed on a sound methodological basis, with a digital audit trail, to give decision makers systematic support in identifying a consensual framework for engaging with their complex problems.

Further Reading Ackoff RL. Redesigning the future: a systems approach to societal problems. New York: John Wiley and Sons; 1974 Funtowicz SO, Ravetz JR. Uncertainty, complexity and post-normal science. Environ. Toxicol. Chem. 1994; 13: 1881-1885. Levitt SD, Dubner SJ. Freakonomics. New Work: Harper Collins; 2005 Mingers J, Rosenhead J. Problem structuring methods in action. Eur. J. Oper. Res. 2004; 152: 530-554 Pidd M. Tools for thinking: modelling in management science. 2nd ed. Chichester: John Wiley and Sons; 2003 Ritchey T. Problem structuring using computeraided morphological analysis. J. Oper. Res. Soc. 2006; 57; 792-801 Rittel H, Webber M. Dilemmas in a general theory of planning. Policy Sci 1973; 4: 155-159 Turley RE, Richardson WC, Hansen JV. Morphological analysis for healthcare system planning. Socio. Econ. Plan. Sci. 1975; 9: 83-88 Zwicky F. Discovery, invention, research – through the morphological approach. Toronto, Macmillan Company; 1969

Figure 3: In the Cross Consistency Matrix (denoted by the C toggle), all conditions under each dimension in the morphological field of Figure 2 are pitted against each other, pairwise. As each pair of conditions is examined, a judgement is made, as to whether or not, or to what extent, the pair can coexist. It is important to note that there is no reference here to direction or causality, but only to mutual consistency. This approach allows a typical problem space to be reduced up to 99%

eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

7


TOWARDS A EUROPEAN PATENT LITIGATION SYSTEM by Gareth Williams and Graham Burnett-Hall

E

fforts to establish a single European patent system have seen both progress and setback in the first half of 2011. Such a system has the potential to provide protection for pharmaceutical and other products across the entirety of the EU, with recourse to one central court system should patents be infringed or attacked. Pharmaceutical companies depend on their patent portfolios to protect their product pipelines, with any gaps in protection leaving them vulnerable to competitors, generic or otherwise. With Europe being the second largest pharmaceutical market in the world, robust protection of drugs and medicines is extremely important. However, the current system’s fractured and complex nature leaves many companies with incomplete and partial protection. Unlike other areas of intellectual property, such as trade marks, patents in Europe can currently only be obtained and enforced on a national basis, country by country, albeit through a central application system administered by the European Patent Office (EPO). The EPO examines applications and, if approved, patents are granted in whichever European countries the applicant chooses, with multiple national patents referred to as a ‘bundle’. While other patent-dependent industries, such as engineering, may file applications for patents only in countries where they have a definite market for their product, pharmaceutical companies prefer to file more widely. All European countries provide a potential market for pharmaceutical products and this strategy prevents companies’ competitors from gaining a European foothold. High costs

Gareth Williams is a patent attorney and Graham BurnettHall is a solicitor at Marks & Clerk UK.

8

The fragmented application process incurs higher costs than in territories like the US where one patent covers an entire major market. For example, according to

the EU, a bundle of patents covering all 27 EU member states costs €32,000, compared to the €1,850 for a US patent. A major component of the expense is the cost of translating the patent applications into the official languages of the different countries, although the London Agreement (2000) went some way to lessen the effect by eliminating the need for translation in certain countries. In the previous €32,000 figure, translation costs counted for €23,000. Increased costs result in some companies questioning the value of seeking protection in all European countries but incomplete protection can have commercially and financially damaging consequences. It is known that in the US, generic products already capture a large share of prescriptions dispensed (44%) and market sales (50%).1 Generic prices at launch are on average 25 per cent lower than the originator brand price, falling to one fifth of the initial generic price as more generics enter the market.2 While similar figures are not available for Europe, the patchy protection system leaves originator brands even more vulnerable than in the US. Enforcement

The system for protecting and enforcing patents is, on the whole, kept separate from that of granting them. As patents only exist at a national level, when they are infringed or questioned, cases are dealt with in individual national courts. Consequently, enforcement of patents across Europe has been inconsistent and unpredictable. A decision by one court may have some persuasive influence on the courts in other countries but it is not binding on them. Patent law is harmonised to some extent within Europe but this does not prevent inconsistent decisions being given from time to time. EPO decisions are also not able to bring about judicial consistency throughout Europe. Although decisions of the Boards of Appeal of the EPO are authoritative, they are not binding and decisions of the national courts can and do differ. One recent example is Human Genome Sciences v Eli Lilly & Co. In August 2005, HGS was awarded a patent for the nucleotide and amino-acid sequence of a novel member of the TNF ligand super-

european INDUSTRIAL PHARMACY • Issue 10 September 2011


TOWARDS A EUROPEAN PATENT LITI GATION SYSTEM (C on t.) family, the polypeptide neutrokinealpha. Eli Lilly sought to revoke HGS’s patent on grounds including failure to disclose an industrial application for the invention. Whereas the Technical Board of Appeal of the EPO upheld the patent with more limited claims than those originally granted, the English and Welsh Court of Appeal revoked the patent altogether, fully conscious that its decision was contrary to that of the EPO. The decision of the UK Supreme Court is now keenly awaited. The uncertainty which arises from not knowing if patent infringement and validity decisions in one territory will be replicated in another leads to higher costs for pharmaceutical companies. Organisations are forced to rely on local legal representation in each country where their product is marketed. While countries like the UK, Germany and the Netherlands have judges experienced in patent disputes, other countries lack such judges, leading to increased uncertainty when it comes to litigation in those markets. Harmonisation

The current system, although far from ideal, is the fruit of many decades’ work to harmonise intellectual property protection in Europe. Much is owed to the EPO, as well as the European Patent Convention (EPC), which served to establish it. Signed in 1973 by seven countries, the EPC standardised much of the patent law and the EPO has since become responsible for assessing and administering applications for European patents potentially valid in all EPO member states. A non-EU body, since its inception it has grown to include 38 member states, including all major European markets, with Serbia becoming the most recent full member in October 2010 (see Table 1). Other landmarks for standardisation include the Strasbourg Convention,

and even the failed unitary patent project, the Community Patent Convention, which sought to establish a single patent for all the Community but which failed to be ratified by sufficient states. The London Agreement, signed in 2000, achieved significant cost reductions for patent applications by eliminating the need for translations to national languages at various stages of patent applications for signatory states (currently 16 of the 38 EPO members). While previous efforts have been commendable, the principal objective has always been a single Europe-wide patent enforced in a European court system. Following a decade-long stalemate over language issues, the last eight months have seen a great deal of activity in Brussels and Luxembourg. Previous attempts at establishing such a system have failed, primarily due to objections over the planned language regime. States such as Spain and Italy have challenged any plan which excludes their national languages from the working languages of the proposed system. Such stances are reflected in their refusal to participate in the London Agreement. At the end of 2010, 12 of the remaining 25 EU member states expressed their desire to the Commission to go ahead with plans for the EU patent, through a procedure known as ‘enhanced cooperation’. The procedure allows a group of member states to pursue an area of integration without the consent or participation of all 27. Subsequently, all 25 remaining states joined the proposal. The proposed patent system would require future applications only to be submitted in the EPO’s working languages (English, French and German). The European Parliament has approved the use of the enhanced cooperation procedure, though its use is being challenged by Italy and Spain in legal proceedings commenced in May 2011.

eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

Table 1: EPO member states, by date of joining

Belgium Germany France Luxembourg Netherlands Switzerland United Kingdom Sweden Italy Austria Liechtenstein Greece Spain Denmark Monaco Portugal Ireland Finland Cyprus Turkey Bulgaria Czech Republic Estonia Slovakia Slovenia Hungary Romania Poland Iceland Lithuania Latvia Malta Croatia Norway FYR of Macedonia San Marino Albania Serbia

7 October 1977 7 October 1977 7 October 1977 7 October 1977 7 October 1977 7 October 1977 7 October 1977 1 May 1978 1 December 1978 1 May 1979 1 April 1980 1 October 1986 1 October 1986 1 January 1990 1 December 1991 1 January 1992 1 August 1992 1 March 1996 1 April 1998 1 November 2000 1 July 2002 1 July 2002 1 July 2002 1 July 2002 1 December 2002 1 January 2003 1 March 2003 1 March 2004 1 November 2004 1 December 2004 1 July 2005 1 March 2007 1 January 2008 1 January 2008 1 January 2009 1 July 2009 1 May 2010 1 October 2010

Proposed unified system

Meanwhile, the Court of Justice of the European Union (CJEU) had been considering a proposal for a unified patent litigation system – a court system which would have responsibility for the enforcement of the new unitary patents. In March of this year, the Court handed down its

9


TOWARDS A EUROPEAN PATENT LITI GATION SYSTEM (C on t.) opinion, stating that the current proposals were inconsistent with European law on several counts. A particular objection was that the proposed court would lie outside the EU jurisdictional framework and would lack accountability in the event that the court failed correctly to apply any applicable principles of EU law. New proposals have been drawn up which ensure that the patent court is subject to the same controls as national courts when dealing with EU law. A major consequence of this is that only EU member states will be able to participate in the patent litigation system, not other EPC-contracting states such as Switzerland. Separately the EU Commission has published draft regulations regarding the grant of the proposed unitary patent. One of the main points of contention in the proposals is the involvement of the CJEU in substantive questions of patent law. The lesson from the already centralised trade mark system is that national courts frequently consider it necessary to refer questions of law

to the CJEU, whose judges, in the main, are not specialised in IP. Industry needs certainty, but such referrals inevitably add to the cost of proceedings and result in considerable delays. Therefore, both industry and the legal community consider it very important that the CJEU not be granted jurisdiction in fundamental IP matters. Procedural matters, such as the availability and use of disclosure, expert witnesses and crossexamination are also likely to affect industry’s enthusiasm for any litigation system. Italy and Spain’s refusal to participate in plans for a central patent system on language grounds has caused headaches for proponents of the system, Both the Spanish and Italian pharmaceutical markets are large, being valued at $22.1 billion and $24.9 billion in 2009, respectively.3 This, combined with the presence of significant generics industries in both countries, means that pharmaceutical companies will want to protect their products in Spain and Italy regardless of whether the two countries sign up to the centralised

patent or not. Their self-imposed exclusion from the single EU patent will limit the reduction in cost and uncertainty for the industry, which the plans otherwise seek to achieve. Conclusion

Although plans for the EU patent currently appear to be more developed than those for the patent litigation system, neither is likely to be adopted without the other. The benefits of an EU-wide patent will only become apparent when accompanied by those of an EUwide litigation system that provides consistency and increased certainty of protection. References 1. Congressional Budget Office (United States CBO), ‘How increased competition from generic drugs has affected prices and returns in the pharmaceutical industry’, (Washington: 1998); Grabowski H, Vernon J. Brand loyalty and price competition in pharmaceuticals after the 1984 Drug Act. Journal of Law and Economics, 1992; 35(2): 331-350 2. Kanavos P, Costa-Font J, Seeley E, ‘Competition in Off-Patent Drug Markets: Issues, Regulation and Evidence’, Lisbon; 2007 3. Datamonitor, ‘Spain Pharmaceutical Market Overview’, (2010);Datamonitor, ‘Italy Pharmaceutical Market Overview’; 2010

For more information contact: www.euromedcommunications.com

10

european INDUSTRIAL PHARMACY • Issue 10 September 2011


ACHIEVING CLEANLINESS IN MEDICAL ENGINEERING by Doris Schulz

W

hether instruments, implants or accessories are involved, cleaning is an imperative step in the manufacturing process for medical devices. Modern cleaning processes make it possible to comply with the required degrees of cleanliness in a reliable and reproducible fashion with short processing times, thus contributing to enhanced value creation. On the one hand, sticky residues from the manufacturing process such as release agents, machining media, chips and dust must be removed from medical devices during the cleaning process in a reliable, reproducible and documentable fashion. On the other hand, biocompatibility is required. The cleaning industry offers various processes in order to fulfil these requirements both cost effectively and ecologically, such as wet chemical cleaning processes, cleaning with carbon dioxide, and plasma processes. Different processes are also frequently combined. Wet chemical cleaning – interaction amongst cleaning agents and process technology

The effectiveness of wet chemical cleaning processes, such as immersion, spray and ultrasonic cleaning, is determined by interaction between the dissolving performance of the utilised cleaning agent and the cleaning system’s process technology. The most commonly used cleaning media are aqueous cleaning agents and solvents. Essential criteria for the selection of the ideal cleaning process include the material to be cleaned, type of contamination, part shape, cleanliness requirements with regard to film-like contamination and particulates, as well as production

throughput. The most suitable process can be selected on the basis of these factors, and the final choice is frequently corroborated by cleaning tests conducted by equipment or cleaning agent manufacturers. Aqueous cleaning agents are based on an organic or an inorganic builder and tensides. The latter are able to “push” themselves in between the contamination and the material to be cleaned, and dislodge non-polar contamination such as oil and grease, as well as polar contamination (e.g. emulsions, salts and particles). In order to prevent residues left by the cleaning agent or surface spots which would impair quality or biocompatibility, a multi-stage rinsing process is usually required – often with deionised water in the final rinsing stage(s). Continuous monitoring of the bath and bath replacement at regular intervals are necessary for consistently good results. Solvent systems which are available as chlorinated hydrocarbons (CHC), nonhalogenated hydrocarbons, modified alcohols and polar solvents are distinguished by great diversity with regard to the type of material to be cleaned. Grease, oil, particles, etc. can be removed. Corresponding legal regulations regarding emissions limits and work safety apply to the use of solvents, and these must be taken into consideration in modern system concepts. In order to be able to achieve the desired cleaning results within the shortest possible period of time, the effectiveness of the cleaning medium is usually enhanced by means of various physical processes which demonstrate effects of varying magnitude, for example spraying, ultrasound and flushing under pressure. When manufacturing implants, for example, it’s advisable to use an intermediate cleaning step after each chip removing machining process. This

PARTS2CLEAN 2010

Doris Schulz is a journalist based in Korntal, Germany.

parts2clean, an International Trade Fair for industrial parts and surface cleaning will take place at the Exhibition Centre Stuttgart (Germany) from the 25th through the 27th of October, 2011. It allows visitors to gather comprehensive information regarding cleaning systems, alternative cleaning techniques, cleaning agents, quality assurance and inspection procedures, cleaning and transport containers, disposal and reprocessing of process media, handling and automation, services and consulting, as well as research and technical literature. www.parts2clean.com

eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

11


E F F I C I E N T A C H I E V E M E N T O F C L E AN L I N E S S I N M E D I C A L E N G I N E E R I N G ( C o n t . )

Cleaning with supercritical carbon dioxide – including GMP validation

Figure 1. This workpiece carrier for implants allows for easy accessibility by the cleaning agent from all sides. In order to prevent damage of the workpieces due to metal-to-metal contact, the part holders have a plastic coating. Image source: Metallform

reduces the risk of any accumulation of deposits in the micron range on the parts, which may lead to tolerance deviations during further processing. Beyond this, intermediate cleaning prevents any mixing of lubricants and processing oils on the parts, which often causes cleaning problems. Last but not least, the quality of downstream mechanical processing is improved by intermediate parts cleaning. Final cleaning is usually executed by means of a validated process with an aqueous medium which assures biocompatibility. Economic batch processes – using the right cleaning rack

Batch processes are often used to clean medical devices in bulk goods baskets, or in workpiece carriers which have been laid out specifically for the parts to be cleaned (FFigure 1). In addition to the utilised process technology, the selected chemical and the duration of treatment, the cleaning rack also has a decisive effect on cleaning results and operating costs. It frequently offers potential for optimising the cleaning process

12

with regard to cleaning results, processing time and costs.

When parts are cleaned with supercritical carbon dioxide, the CO2 is used in an aggregation state in which its physical characteristics lie between the liquid and the gaseous state. While in this state, it demonstrates only minimal viscosity and surface tension. Both of these attributes are important prerequisites for mass transport, which makes it possible to remove contamination such as oils and greases from even the smallest cracks and pores (FFigure 2). Cleaning with supercritical carbon dioxide, which usually takes place within a temperature range of 20 to 40°C, is thus even capable of achieving good results with porous structures. Additionally, “biological” parameters are favourably influenced as a result of lower cytotoxicity values than those found in conventional cleaning processes. Uses for CO2 cleaning in medical engineering include, for example, intermediate and final cleaning of implants, instruments and components made of various materials (e.g. metals and plastics). Amongst other things, a GMP validation package is part of the scope of delivery for manufacturers

Cleaning baskets made of round wire are ideal for assuring quick and reliable removal of contamination. They allow for easy, uniform access to the workpieces by the cleaning agent, so that the mechanical washing process can develop its full effectiveness and wash out film-like contamination and particulates as efficiently as possible. As opposed to closed containers or baskets made of perforated sheet metal, cleaning baskets made of round wire are also distinguished by significantly better draining characteristics. Consequently, considerably less contamination and cleaning agent is carried over, resulting in a longer service life for the cleaning Figure 2. Cleaning with supercritical carbon dioxide, a process bath, and thus which can be validated in accordance with GMP, makes it improved cleaning possible to remove grease and oil from parts and porous system availability surfaces made of metal, ceramics, plastic and composite materials. Image source: eCO2 and efficiency.

european INDUSTRIAL PHARMACY • Issue 10 September 2011


E F F I C I E N T A C H I E V E M E N T O F C L E AN L I N E S S I N M E D I C A L E N G I N E E R I N G ( C o n t . ) of systems for cleaning with supercritical CO2. CO2 snow – dry and residue-free

Liquid carbon dioxide is used as a blasting medium for CO2 snow jet cleaning. It is expanded through a nozzle and accelerated to ultrasonic speeds with compressed air. Thanks to a combination of mechanical, thermal and chemical effects, the CO2 snow jet gently removes numerous types of film-like contamination and particulates when it strikes the surface in a dry and residue-free fashion. Its characteristics make CO2 snow jet technology suitable for cleaning and activating almost all materials including metals, plastics, glass and ceramic substrates, even with finely structured surfaces (FFigure 3). The jet stream can be well focused, and the process is thus also capable of treating specific functional areas, for example sealing and bonding

Figure 4. The surfaces of a great variety of medical instruments and devices can be ideally prepared for the respective application, as well as for subsequent bonding, coating or printing processes, through the use of a plasma process. Image source: Reinhausen Plasma

surfaces, without subjecting the entire component to the complex processing which is necessary in order to achieve the levels of cleanliness which are only required for the functional surfaces.

BEFORE

AFTER

Figure 3. The CO2 snow jet process is suitable for cleaning and at the same time deburring sensitive and finely structured surfaces such as canulas. Image source: acp

Plasma – more than just clean

individual parts with this technology (FFigure 4). Depending upon the application, various plasma gases can be used, by means of which the surface is simultaneously cleaned and activated. This dual function is based on both physical and chemical reactions involved in the process: The atoms released in the plasma “bombard” the surface of the component to be cleaned. This functions like a miniature sand-jet in the nano-range, thus removing organic contamination which adheres to the surface such as oil and grease. At the same time, free ions and electrons are deposited on, and enter into a chemical bond with the surface. As a result, surface tension is adjusted to an ideal value for subsequent bonding, coating or printing processes.

Plasma is a gaseous mixture of atoms, molecules, ions and free electrons. Medical devices made of various materials, for example steel, non-ferrous metals, plastics, glass and ceramics, can be treated either in batch processes or as

Applications for biocompatible plasma in the field of medical engineering include, for example, final cleaning of stents, surgical and dental implants, as well as guide wires prior to coating with hydrogel or PTFE, increasing the surface energy of microtitre plates and other diagnostic instruments, silicone breast implants, catheters and syringes.

The process’s good inline capabilities and minimal space requirements allow for easy integration of cleaning into the manufacturing process, thus ruling out the possibility or renewed contamination of the component, for example during transport or storage.

Adapted with permission from article first published in June 2011 in Process Cleaning. eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

13


THE CHALLENGES OF BACTERIOPHAGE THERAPY by Alexander Sulakvelidze Introduction

B

acteriophages (also called “phages”) are viruses that kill bacteria. They are the oldest (3 billion-years-old, by some estimates) and most ubiquitous (total number estimated to be 1030-1032) known organisms on Earth. Phages have a specific prey-predator relationship with bacteria, and they have had and continue to have a key role in maintaining microbial balance in every ecosystem where bacteria exist. Initially, bacteriophages were used to prevent and treat human infections, a therapy which began shortly after their discovery during the second decade of the 20th century. Recently, however, nonclinical applications (e.g., those designed to improve food safety) for bacteriophages have been receiving increased attention. The term “phage intervention” may be more appropriate than “phage therapy” when discussing such nonclinical applications. However, for the purpose of this review, the terms “bacteriophage therapy” and “phage therapy” are loosely used for applications where phages are used to reduce the concentration of their specifically targeted pathogenic bacteria, irrespective of whether they are used in clinical or nonclinical settings. Historical perspective

Alexander Sulakvelidze, PhD, is Chief Scientist of Intralytix, Inc., Baltimore, USA.

14

Bacteriophages were first identified by Frederick Twort (in 1915) and, independently, by Felix d’Herelle (in 1917) who called them bacteriophages or bacteria-eaters (from the Greek phago meaning to eat or devour).1,2 At that time, with the age of antibiotics still in the future, bacteriophages were proposed to be a powerful cure for infectious diseases, and they were utilized therapeutically throughout the world during the preantibiotic era. The use of phages in humans was apparently very safe, with virtually no serious adverse reactions ever reported. However, phage therapy did not always work and, with the advent of

antibiotics that seemed like “magic bullets” against a very broad spectrum of bacteria, the use of phage therapy gradually fell out of favour in the United States and Western Europe. In an intriguing twist of fate, after all but eliminating “phage therapy” in the West and starting the “antibiotic era”, the commercial development of new antibiotics has been on the decline over the past 20 years. Thus, only nine new antibiotics were approved by the FDA during 1998-2003. The underlying reasons are complex but may be grouped into two categories. First, antibiotics were initially so effective that there appeared to be little need to continue developing new classes of antibiotics and other antibacterials. Second, from a business point of view, although the worldwide current market for antibiotics is still highly significant (ca. US$26 billion/year), it is still less profitable than medications for treating chronic conditions. Thus there is less incentive for pharmaceutical companies to invest in developing new antibiotics (typically used for acute conditions) than to develop drugs for treating chronic conditions. However, the emergence of multi-resistant bacterial pathogens and the need for “green” antibacterial interventions has rekindled interest in developing novel antimicrobial agents, including bacteriophages. Prevalence and safety of bacteriophages in the environment

Bacteriophages, the most ubiquitous micro-organisms on Earth, are viruses that infect bacteria. It has been estimated that there are >100 different phage species and at least 10 phages for each bacterium. Also, one tablespoon (ca. 15ml) of non-polluted water has been estimated to contain approximately 3 x 109 phage particles/plaque-forming units (PFU), and the total number of phages on Earth has been estimated to be 1030-1032 PFU. Furthermore, phages are consumed daily by humans as they are present in virtually all fresh and non-processed foods. Therefore, using naturally occurring, lytic bacteriophages for clinical and nonclinical applications may be the safest, “green”, antibacterial applications currently available.

european INDUSTRIAL PHARMACY • Issue 10 September 2011


T H E C H A L L E N G E S O F B A C T E R I O P H A G E T H E R AP Y ( C o n t . ) Bacteriophages can kill antibiotic-resistant bacteria

The beginning of the antibiotic era may be considered to have begun with the brief publication, entitled “Penicillin as a chemotherapeutic agent,” by Chain et al.3 which was published in Lancet in 1940. Since that time, antibiotics arguably have saved more human lives than any other medications in the history of mankind, and they were deservedly called “miracle drugs” by many. However, the antibiotic “safety net” against bacterial infections has

become increasingly fragile because of the emergence of multiantibiotic-resistant mutants. Also, the development of new antibiotics has been on the wane in general, and only two antibiotics approved by the FDA during 1998 to 2003 have novel modes of action – a critical consideration in the battle against antibiotic-resistance. In this context, phages offer a very attractive complementary tool for managing bacterial infections, including those caused by multiantibiotic-resistant bacterial pathogens, because (i) their mode of action differs from those of

antibiotics, and (ii) the mechanisms of resistance against phages aredifferent from those for resistance to antibiotics. These factors are briefly reviewed below. Modes of action. Antibiotics are lowmolecular weight compounds that kill bacteria (bactericidal antibiotics; e.g., streptomycin and vancomycin) or inhibit their growth (bacteriostatic antibiotics; e.g., chloramphenicol and tetracyclines). Lytic phages, on the other hand, are fairly large (approx. 100-200 nm) micro-organisms that kill their targeted bacteria predominantly via a lytic cycle – a complex

Figure 1. Replication cycle of lytic phages Step 1: The first step in the replication process is attachment of the phage to the bacterial cell, a two-step process: (i) reversible attachment is mediated by the phage's tail fibres which attach to a specific receptor on the bacterial cell surface, and typically occurs almost instantaneously after exposing the host cell to the phage, and (ii) irreversible adsorption occurs when the baseplate fibrils irreversibly attach the phage to the bacterial cell. Step 2: Injection of phage DNA into the bacterial host’s cytoplasm. Tail sheath contraction is triggered by expansion of the baseplate, and the injection step is typically accomplished in <1 min (?3 kb are transferred/second) under optimal conditions. Steps 3-4: Shut-off of synthesis of host components, replication of phage DNA and production of new capsids. The phage DNA takes over the host's biosynthetic machinery, and phage-specified proteins are synthesized. Step 5: Assembly of phages. Nucleic acids and structural proteins are assembled, and phage particles accumulate in the cell. Step 6: Intracellular mature phages are released by host cell lysis. The number of phage particles released per infected bacterial cell may be as high as 1,000 (usually it is 200-250 for the T4 phage).

Reproduced with permission from the American Society for Microbiology (Microbe, January 2006, p. 20-24). eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

15


T H E C H A L L E N G E S O F B A C T E R I O P H A G E T H E R AP Y ( C o n t . ) process consisting of a cascade of events involving several structural and regulatory genes (F igure 1). All lytic bacteriophages are, by definition, bactericidal rather than bacteriostatic. Resistance mechanisms. Mechanisms of bacterial resistance against antibiotics are fairly complex, and a single bacterium often possesses several of them simultaneously. However, in general, they may be grouped into three major categories: (i) enzymatic inactivation of the antibiotics. For example, many Gram-negative bacteria and some Gram-positive bacteria produce beta-lactamase, an enzyme that hydrolyzes the beta-lactam ring of beta-lactam ring-containing antibiotics, thereby inactivating them; (ii) limiting the antibiotic’s access to its intracellular target; e.g., resistance to tetracycline depends upon the bacterium’s ability to pump the antibiotic out of the cytoplasm (also called “efflux resistance”); and (iii) altering the antibiotics’ targets. For example, resistance to the quinolones often arises from point mutations that alter the affinity of DNA gyrase for those antibiotics, and resistance to rifampin often is due to mutations in the gene encoding bacterial RNA polymerase, so that the antibiotic can no longer bind to it. In contrast, resistance to phages typically results from changes in the (i) bacterium’s phage receptors, so that the phage tail fibres cannot “recognise” the target bacterium and attach to it, and (ii) bacterium’s anti-phage DNA-restriction enzymes. After attachment, a phage’s ability to lyse its bacterial host depends on its ability to survive the host’s restriction-modification defenses; therefore, if the phage’s DNA becomes susceptible to its host’s restriction-modification mechanisms, the phage may not be able to kill the bacterium. Thus, because of major differences between the mechanisms for

16

resistance to antibiotics and to phages, antibiotic resistance does not correlate with resistance to phages, and vice-versa. What this means in practice is that antibioticresistant bacteria remain sensitive to, and can be killed by, lytic phages – which provides an excellent safety net for preventing and treating diseases caused by multi-antibiotic-resistant bacteria. Challenges of phage therapy

Properly selected phages kill their specifically targeted host bacteria via mechanisms that are different from those of antibiotics and are apparently very safe. Therefore, it seems puzzling that phage preparations are not widely available for clinical and agricultural applications in the United States and Western Europe. The reasons are both technical (e.g. they involve the specificity of phages) and nontechnical (i.e., the “novelty” of the phage therapy approach) in nature. Novelty. This problem is counterintuitive because phages have existed on Earth for about 3 billion years and have been used therapeutically in humans for at least 90 years; hence, they are hardly novel antibacterial modalities. Nevertheless, because phage therapy applications were mostly forgotten in the West after the introduction of broad-spectrum antibiotics, they may seem to be novel and of unproven efficacy to many Western scientists and physicians. Also, since phage therapy is a significant departure from the modern, currently accepted small molecule antimicrobials approach, its “novelty” may be a factor hindering its acceptance. Specificity of phages. Paradoxically, one of the most important of the potential technical limitations involves the specificity of phages, which is also considered to be one of their strengths. In this context, bacteriophages are, indeed, very

specific; i.e., they will only lyse strains or subgroups of strains, typically within the same species. Therefore, incorrectly identifying the bacterial etiologic agent will render phage therapy ineffective; whereas, broad-spectrum antibiotics will be more likely to kill or prevent the growth of the etiologic agent. The high specificity of phages was one of the main reasons for the decline of interest in phage therapy when antibiotics became widely available. However, because the currently available, robust diagnostic approaches and tools have made it possible to identify bacterial pathogens much more rapidly and accurately than was possible during the early days of phage therapy, it should now be possible to select appropriate phages for many, if not most, clinical treatment regimens. Furthermore, the high specificity of phages can now be viewed as an advantage in certain applications, because it makes targeted therapy possible. Despite the above-noted advances in bacterial diagnostics, the high specificity of phages may still be problematic if the mainstream commercial phage product is not effective against one or more strains of the targeted species that happen to predominate in a particular hospital or clinical centre. One approach to address this potential problem is to have all targeted bacterial strains examined for their sensitivity to various phage preparations, and to select and use only the phages that have shown strong lytic potency against the infecting bacterial strain – much like antibiotics are used today. The ideal scenario – tentatively called the “Pharmacy Approach,” which takes advantage of the flexibility that phage therapy offers as an antibacterial approach – is to custom-design phage preparations for each patient. For example, the hospital’s clinical microbiology

european INDUSTRIAL PHARMACY • Issue 10 September 2011


T H E C H A L L E N G E S O F B A C T E R I O P H A G E T H E R AP Y ( C o n t . ) laboratory will determine the lytic potency of a library of wellcharacterized, cGMP-produced bacteriophages against the pathogen isolated from the patient. After identifying two or more phages possessing potent lytic activity against the isolated bacterial pathogen (we expect that phage cocktails will be always used rather than single monophage-containing preparations), the hospital’s pharmacy will prepare the optimal phage cocktails for that patient. Using such custom-designed phage preparations has been and still is a common practice in Eastern Europe. From a technical standpoint, it should be possible to use this approach, although it will require the development of phage sensitivity testing kits, streamlining of methods, and training hospital laboratory personnel to use them to perform phage sensitivity tests with the etiologic agents. Another challenge will be to develop strategies for properly regulating such products, as discussed in “Regulatory approvals.” Efficacy a nd other technical challenges. Bacteriophages are very effective in lysing their specific bacterial hosts in many in vitro and in vivo models. However, although phages significantly reduce the levels of their targeted pathogens in those systems, they do not always completely eradicate them, unless very high concentrations of phages are applied. For most practical applications, a phage preparation’s incomplete eradication of the etiologic agent may not be a problem as a significant reduction in the pathogen’s concentration is likely to help a patient’s natural defences deal with the infection. Thus, it is important to design intervention strategies based on a thorough understanding of the biological strengths and weaknesses of bacteriophages. Among other potential technical problems, the following three issues

are most frequently raised: (i) Rapid elimination of the bacteriophages may reduce available phages to levels insufficient to combat the infection; (ii) During i.v. administration of phages (e.g., to treat septicaemia), the development of bacteriophage-neutralising antibodies may negate the efficacy of long-term phage therapy; and (iii) Phage-resistant bacterial mutants may rapidly emerge and negatively impact the phage preparation’s efficacy. However, in practice, none of these potential scenarios has proven to be a significant problem, and could be relatively easy to circumvent, if need be. Regulato ry appr ovals. The first therapeutic use of phages in humans occurred in 1919, when Felix d’Herelle used phages to treat four children suffering from severe, bloody dysentery in France.4 However, the first published report of phage therapy appeared 2 years later, when Bruynoghe and Maising5 successfully used phages to treat human skin infections in Belgium. Since those two early uses, probably hundreds of thousands of people worldwide have been treated with various bacteriophage preparations. However, none of those preparations or clinical trials were subjected to the same regulatory approval processes that other antimicrobial agents must undergo today, before they are approved for human therapy or other commercial applications. One relatively little known fact is that the FDA actually reviewed bacteriophage applications for human use during the 1970s, 1980s and 1990s, when phage phi X174 was intravenously administered to patients with various immuno-deficiency disorders. In all of those instances, the goal of phage administration was to determine the immune status of the patients rather than to treat disease.

eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

The FDA also conducted a safety review of bacteriophages during 1973, after phages were found to be present in some vaccines used in the United States, and concluded that the phages were safe and allowed the continued use of those vaccines.6 Despite the above-mentioned FDAapproved uses, well-defined guidelines for obtaining governmental approval of phagebased human therapeutic products were not formulated at that time. The issue was further complicated by the fact that the existing regulatory guidelines developed for small molecule antimicrobials were not immediately applicable to bacteriophages. Thus, navigating the nuances of regulatory strategies for various types of applications was and remains a significant challenge for phage therapy, although this situation seems to be improving lately and several approvals were issued for various phage preparations during the last few years. For example, in 2008, the FDA approved a physicianinitiated, phase I clinical trial designed to evaluate the safety of a phage cocktail (containing eight distinct monophages targeting Staphylococcus aureus, Pseudomonas aeruginosa and E. coli) developed to treat patients with infected venous leg ulcers.7 According to www.clinicaltrials.gov, the recruitment of patients for at least two more phage therapy trials is currently in progress. Thus, the number of regulatory approvals for various phage preparations for food safety and clinical applications seems likely to increase in the future. Another, yet to be addressed, regulatory unknown is how the Western regulatory agencies might regulate phages for the “Pharmacy Approach” described earlier. That approach stipulates that customdesigned phage cocktails will be prepared (by licensed hospital pharmacists) from distinct, cGMPmanufactured phage lots, instead of

17


T H E C H A L L E N G E S O F B A C T E R I O P H A G E T H E R AP Y ( C o n t . ) all hospitals using the same commercial phage preparation. That approach is a clear departure from the traditional FDA approval process for other antimicrobials; i.e., it requires “thinking outside of the box”, and it may take some time to eliminate its psychological and technical obstacles. However, for phage therapy to reach its full potential, such custom-designing must be implemented. A positive development in that regard was the FDA’s flexibility regarding its recent approval of ListShield™ for food safety applications; i.e., the FDA approved that phage cocktail’s future efficacy to be updated with new phages, if and when necessary. All new phages will need to meet the same stringent safety and efficacy criteria as the original phages in ListShield™, and the manufacturing process (as well as all quality control protocols) approved for ListShield must be strictly adhered to for all new phages – but these are logical and technically-feasible requirements. Patent protection. Therapeutic phage applications have been made publically available since the previously mentioned publication by Bruynoghe and Maisin in 1921.5 Thus, the ability to protect the technology and/or phage-based products from competition is another challenge for the commercially successful establishment of phage therapy. Over the years, numerous other scientific papers were published concerning phage therapy. Also, several patents were obtained for various applications of bacteriophages after the first phage patent (US 1,668,814) was issued in 1926. The first patent was not clinically-oriented; instead, it focused on preventing the lytic activity of phages against bacteria used for industrial fermentation processes. Surprisingly, despite the fairly common sale of therapeutic phage

18

preparations by some major pharmaceutical companies, after the discovery of phages during 1915-1917, patents for therapeutic applications in humans were not issued until 1990, when two patents US 4,891,210 and US 4,957,686 were issued for the use of bacteriophages in oral hygiene. More recently (in 2000), the US Patent Office issued US 6,121,036 to Ghanbari and Averback for very broad-spectrum phage therapy claims. Given the fact that the patent’s issuance was preceded by almost 80 years of using bacteriophages therapeutically, and by hundreds of relevant scientific and general media publications from various countries (including the United States and Canada), it is not clear why that patent was issued – and its value may be questionable. However, the same reasons that make that patent potentially invalid also has made it very difficult for any other individual or company to obtain patent protection for phage therapy per se, which has created a significant problem for acquiring the funds required to advance the development and commercialization of products designed for phage therapy. Market acceptance. Finally, no matter how effective and safe phage-based products may be for specific applications in food safety or clinical settings, their popularity along with other modalities for preventing and treating bacterial infections is ultimately dependent on their “market acceptance.” The latter term encompasses a fairly broad range of issues, from consumer acceptance to the products’ cost. Even if the price is acceptable, educating the general public about the nature of phages, their ubiquity in the environment, and the safe (and natural/green) nature of their applications for managing bacterial infections is of paramount importance.

Conclusions

Several factors make bacteriophages very attractive antibacterial agents for a variety of applications. However, phages are not “magic bullets” and they have limitations that make them more effective for some applications than for others. Thus, it is important to understand their properties in order to design intervention strategies based on a clear understanding of their biological strengths and weaknesses. Moreover, several technical and non-technical problems must be overcome before phage therapy is widely accepted as a valuable additional tool for managing bacterial infections and contamination in clinical and nonclinical settings. However, the potentially devastating impact of multi-antibiotic-resistant bacterial pathogens makes those efforts very much worth pursuing.

REFERENCES 1. Summers WC. Bacteriophage discovered. Felix d'Herelle and the origins of molecular biology. New Haven, CT: Yale University Press; 1999. p. 47-59 2. Duckworth DH. "Who discovered bacteriophage?". Bacteriol Rev. 1976; 40(4):793-802 3. Chain E, Florey HW, Gardner AD, Heatley NG, Jennings MA, Orr-Ewing J et al. Penicillin as a chemotherapeutic agent. Lancet 1940;22:226 4. Summers WC. The hope of phage therapy. Felix d'Herelle and the origins of molecular biology. New Haven, CT: Yale University Press; 1999. p. 108-24 5. Bruynoghe R, Maisin J. Essais de thérapeutique au moyen du bactériophage du Staphylocoque. J Compt Rend Soc Biol. 1921;885:1120-1 6. Moody EE, Trousdale MD, Jorgensen JH, Shelokov A. Bacteriophages and endotoxin in licensed live-virus vaccines. J Infect Dis. 1975;1131(5):588-91 7. Wolcott R, Rhoads D, Kuskowski M, Ward L, Sulakvelidze A. Bacteriophage therapy of venous leg ulcers in humans: results of a Phase I safety trial. Journal of Wound Care. 2009;118(6):237-43.

european INDUSTRIAL PHARMACY • Issue 10 September 2011


INNOVATION – SCIENCE OR ART? by Robert Bates and Anna Bruns

D

espite more than doubling its spending on R&D in the last decade, the drug industry's success rate in finding new drugs has been disappointing. Middle managers of the drug discovery units of the major players ought to be key enablers in developing new ideas but this depends on behaviour not often taught or developed in the commercial world.

depending on the motivational aspects and facilitatory qualities of an employee’s working environment. Because willingness is both important for innovation and highly susceptible to influence, it is critical to identify those environmental factors that can speed up or facilitate innovation, or indeed slow it down. High WTI by employees therefore means high investment of energy in the innovation process. Above and beyond their duty

The innovation process

Employees’ performance can be broken down into two distinct categories. First, there is in-role performance, which refers to those activities clearly defined in an employee’s job description and directly related to that employee’s individual contribution to the company’s overall output. Second, is their extra-role performance which is less well defined, referring to an employee’s behaviour above and beyond their explicit duties – examples being excessive helpfulness to colleagues and clients, taking initiative and being a catalyst for change.

Innovation is inherently human. From the printing press to semiconductors, every invention first takes shape in the mind of its inventor.

Positive in-role performance helps maintain a company’s success. Extra-role performance, on the other hand builds on that success, significantly enhancing it.

“Innovation,” says Apple Inc. co-founder Steve Jobs, “distinguishes between a leader and a follower”. It has certainly been the cornerstone of his company’s success. In fact, innovation is critical to any company’s long-term prosperity. This is especially true in the pharmaceutical and life sciences industries where R&D accounts for a large proportion of invested time, money and manpower.

For most, innovation is an extra-role Ultimately, it is people – on their own or performance and probably the most in groups – who evolve and implement powerfully differentiating their own ideas, one. Innovation varies bringing them to life. Companies who Innovation,” says massively, even in R&D teams whose primary role is underestimate, or Apple Inc. co-founder generating and even ignore, the Steve Jobs, “distinguishes implementing new ideas. human factor of innovation and between a leader and a Capturing innovation invention do so at follower their peril. Despite WTI being an extrarole factor and not being When it comes to written into job descriptions, most line people, there are two key innovation managers know who their top performing ingredients. People need to be able to innovators are. However, the true create new ideas on the one hand, and differentiator that makes a team be willing to evolve and implement these successful does not always come from the new ideas on the other. The latter can be 10% of highly motivated, innovative referred to as Willingness to Innovate employees who have the greatest impact. (WTI). An interesting difference between these two ingredients is their stability Often it is the remaining 90%, only over time. slightly more or less motivated and innovative than they should be, who Ability – defined by personal traits, like make the biggest difference, either for intelligence – is somewhat fixed, especially better or worse – a slight deviation from in adult populations. Willingness, however, the innovation “norm” when uniformly can change significantly and rapidly,

Robert Bates is Managing Director and Anna Bruns is Psychologist and Project Manager at the life sciences executive search and interim management company, RSA Consulting GmbH. Email: Robert.bates@thersagroup.com

eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

19


INNOVATION – SCIENC E OR ART? (Cont .) present in the majority of employees can dramatically affect the ROI. In order to minimise the risk of missed opportunities and lost revenue it is necessary to audit the WTI of not only a few individuals, but of all employees. This is of utmost importance in the R&D department where commercially successful innovation is the number one priority. Continuously monitoring innovation can identify creative hot spots and weak spots, give insight into the presence of factors that either promote or hinder innovation, and provide the foundation for carefully designed, carefully delivered interventions to maintain or enhance innovation. Peaks and troughs

Monitoring WTI is especially important during times of change and on a regular basis thereafter. This is because a change to working conditions can have a dramatic impact on an employee’s motivation and hence WTI, whether it’s a move between companies, within a company or restructuring. Our research data show that typically, in a new unit or role employees tend to be

From an extremely high level WTI in their first six months within a leadership position, an employee’s motivation falls off sharply to its minimum in the second half of their first year.

highly innovative for up to one year, the degree of their motivation increasing with time (see Chart 1). During their second year, WTI falls dramatically to its minimum of their complete time of employment. After that time, to reach the heady one-year height of WTI, it usually takes more than 20 years in a stable working environment and a personnel development plan, based on a programme of consistent monitoring and intervention.

Similar results can be found for employees recently promoted to leadership positions, although here the effects are more marked. From an extremely high level WTI in their first six months within a leadership position, an employee’s motivation falls off sharply to its minimum in the second half of their first year. After that, it takes more than 20 years of hard work both from the employer and employee, for the innovation peak to be regained. Measuring innovation scientifically

Of course, this rise and fall in innovation is susceptible to influence and intervention. However, in a similar way to medicine, before treatment comes diagnosis. It is for this reason that the routine monitoring of WTI on a regular basis is so important.

What is needed are tools that can provide validated, reliable, objective scales for measuring the requirements for innovation. Only these will allow companies to The good news is, that with the conduct meaningful innovation company showing a commitment to audits, the results of which will the development of their allow comparison of WTI within employees, both employee retention different departments, detect and innovation can be greatly changes in innovation over time, improved. and help guide the Chart 1: Employees’ Willingness to Innovate (WTI) depending on the duration of employment. design and delivery of interventions to help maintain or enhance innovation. These tools now exist and can help to ensure the longterm success of the company, contributing to an environment in which each and every employee can research their full potential. In the world of diminishing pharma pipelines this is critical to ensure that valuable R&D employees are working together with maximum creativity and motivation. Adapted with permission from article first published in June 2011 in InPharm.

20

european INDUSTRIAL PHARMACY • Issue 10 September 2011


BOOK REVIEW WHO Expert Committee on Specifications for Pharmaceutical Preparations Reviewer: Andrei Meshkovsky This latest report contains a wealth of practical recommendations relevant to manufacturers as well as those involved in QC and supply system in the Pharma sector. While the advice is addressed predominantly to professionals working outside the three ICH regions, some pieces might be of practical interest to colleagues from countries with highly evolved National Medicines Regulatory Authorities (NMRAs). This may be true for annexes on HVAC systems, technology transfer, GMP for blood establishments, storage and transportation of unstable pharmaceutical products etc. Some might consider that the WHO GMP Guide is inferior to other well-known standards such as those of the EU or the US FDA. It seems that this negative view was formed because on the national level WHO is often supported by a weak inspection system making its GMP certificates less reliable than those issued by widely recognised NMRAs. However, it should be borne in mind that the WHO GMP guide is used in some 100 member states and serves as a basis for the WHO Certification Scheme on the Quality of Medicines in International Commerce. The material presented in the annexes is highly diversified. For the purpose of this review only two areas are commented upon: GMP and the Distribution system.

GMP

WHO good manufacturing practices: main principles for pharmaceutical products (Annex 3) This is a revised text of the WHO GMP guide (main part) published in 2003. The part on main principles corresponds to Part 1 of the EU GMP guide. The text includes a new section on “Product quality review”, as well as reference to the concept of quality risk management. A new wording: “quality unit” is introduced and “drugs” are replaced by “medicines”

throughout the text. These additions and amendments brought the text more in line with the two other internationally recognized guidelines: those of EU and PIC/S. This main text on GMP is supported by five supplementary annexes: on GMP for blood establishments, on technology transfer, and on drafting site master files (new guidelines) as well as on GMP for sterile products and on HVAC systems (revision of previously published material).

Distribution system

Good pharmacy practice: standards for quality of pharmacy services (Annex 8) This annex is of special interest to FIP since it was developed in close cooperation with the Federation. The first version of GPP developed jointly by FIP and WHO was appended to the 35th EC report in 1999. Since then, significant developments in pharmacy practice, science and technology as well as in policy have occurred. On the WHO side, important WHA resolutions were adopted recently, e.g. on accessibility of essential medicines, quality of care, and rational use of medicines. On the side of FIP, an initiative was established in 2007 with the view of updating the guidelines on GPP. The issue was discussed in 2008 in Basel during the 68th FIP Congress. The revised GPP guidelines are based on the premise that it is up to countries to determine what can be done according to existing regulatory framework. The document is addressed to civil society as a baseline to be adjusted to the needs of each specific country. A considerable part of the report is related to the Prequalification of pharmaceutical products (Annexes 10 to 15). This area of work requires detailed explanations and may be the subject of a separate review. Andrei Meshkovsky is Assistant Professor at Moscow Medical Academy, Department of Postgrade Training for Pharmacists and WHO expert on the International Pharmacopoeia and Pharmaceutical Preparations. Email: meshkvskijj@rambler.ru Published by WHO Press, Geneva, 2011 Price: CHF/US$ 70.00; in developing countries CHF/US$ 49 428pp paperback ISBN: 978-92-4-120961-8

eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

21


BOOK REVIEW

The Future of Pharma

Evolutionary Threats and Opportunities

Reviewer: Gino Martini This volume is not the usual fare describing the woes becoming the Pharmaceutical Industry (or Pharma). True it does discuss the ‘perfect storm’ swamping the Industry in the form of lack of innovation, lower productivity, increased regulation, changes in attitudes towards risk and reimbursement challenges affecting ‘me-too’ medicines. However, where the text differs and differs markedly is that Professor Smith proposes that the Theory of Natural Selection first proposed by Charles Darwin in 1859 can be applied to the Pharma Industry. To remind the reader, natural selection is the process by which heritable traits that increase an organism’s chances of survival and reproduction are favoured more than less beneficial traits. Natural selection is the process that results in the evolution of organisms. The author believes (and provides supportive material) that Evolutionary Theory provides a clearer explanation of how the Industry has developed and more importantly how it will develop in the future – it is refreshing to see an author come off the fence for a change! The drivers for natural selection are as follows: A maturing concept of value A bigger fragmented market ● A more risk averse market ● A more informed, sceptical public ● Contemplative investors ● A more preventative approach to healthcare These drivers have precipitated the following reactions or strategies by the various Pharma companies which revolve around: ● ●

● ● ● ● ●

A quest for innovation leadership Expansion out of the developed markets The drive to demonstrate value Dealing with risk Extension of the pharmaceutical value proposition

22

What makes this text a transition from an ‘interesting read’ to a ‘must do’ read is that Professor Smith has had remarkable access to senior leaders within the industry and as such, he is very well informed. Of the Future? Professor Smith believes that the industry will evolve into seven distinct entities with differentiating capabilities that allow them to compete or gain competitive advantage. These entities are described as follows: ●

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. Radical stuff indeed and that’s why this book is well worth a read if only to stimulate thinking and debate. Even if you do not share in Professor Smith’s vision of the future, one thing is sure – change is on the horizon for Pharma and the timeframe is scaringly short with 2012 to 2015 being viewed by most observers as the critical period for survival.

I leave this review with a quote from Darwin himself, which I feel supports Professor Smith’s hypothesis and my own views of how Pharma will evolve in the next 5 years as follows: “It is not the strongest of the species that survives, nor the most intelligent that survives. It is the one that is the most adaptable to change.” Charles Darwin, The theory of evolution by natural selection. Luigi G Martini is Professor of Pharmaceutical Innovation at King's College, London. Email: luigi.g.martini@kcl.ac.uk Author: Brian D Smith Published by: Gower Publishing, 2011. Price: £65; 214 pages ISBN: 978-1-4094-3031-5 (hardback) 978-1-4094-3032-2 (e-book)

european INDUSTRIAL PHARMACY • Issue 10 September 2011


REGULATORY REVIEW

Review of developments in GMP and the regulation of Medicines July – September 2011

by Malcolm Holmes Introduction

The current review period has seen a number of actual/proposed changes in the regulation of medicines and regulatory guidance in both the EU and USA. Worryingly it has also seen incidents related to the deliberate contamination of pharmaceutical products which in one case led to the deaths of a number patients in the UK. United States of America

The United States Food and Drug Administration (FDA) has. Issued New/ Updated/Draft Regulatory Guidance covering the following topics:

Validation of the Limulus Amebocyte Lysate Test (withdrawal)

FDA has withdrawn the 1987 Guideline on Validation of the Limulus Amebocyte Lysate (LAL) Test as an End-product Test. Drug manufacturers are now advised to use the United States Pharmacopeia (USP) General Chapter <85>Bacterial Endotoxins Test, which provides information on the performance and acceptance criteria for endotoxin testing. (The LAL test is harmonised in the USP,JP and EP.).

Tablet Scoring (draft).

Insurance companies and doctors in the USA are increasingly recommending that patients split tablets, either to adjust the patients’ dose or as a cost-saving measure. FDA believes that in some cases, there are possible safety issues, especially when tablets are not scored or evaluated for splitting. Prime concerns with splitting a tablet included variations in the tablet content, weight, disintegration, or dissolution, and potential stability issues.

Europe

EMA and US FDA receive first parallel quality-by-design application.

The EMA and the United States FDA

have agreed to accept the first application under their pilot programme for the parallel evaluation of MarketingAuthorisation (MA) applications involving 'quality by design' (QbD).

Potential use of membrane systems for the production of Water For Injections

Following review of the output from an Expert workshop EDQM considers that sufficient reasons had been provided for the European Pharmacopoeia Commission to recommend initiating discussions regarding potential use of membrane systems for the production of Water for Injections. It is probable that future discussions will be held in a multidisciplinary forum involving the various stakeholders.

Position statement CJD and Advanced therapy medicinal Products (ATMPs)

For human cells contained in ATMPs, there is no manufacturing process to add a further barrier to transmission of a TSE agent. The final risk-benefit for the therapeutic use of these medicinal products derived from human cells and tissues will have to be decided on a case-by-case basis. The collection and storage of cells from umbilical cords is becoming increasingly common Such cells are of foetal origin but the possibility of low levels of contamination with maternal blood cannot be definitively excluded.

Guideline on stability testing for applications for variations to an MA (Draft)

Guidance is provided on the stability data which have to be generated in order to support a variation to an MA. Guidance on stability testing for type I (A and B) variations plus data requirements for widely encountered cases of type II variations are covered.

european INDUSTRIAL PHARMACY • Issue 10 September 2011

ICH guideline Q11 on development and manufacture of drug substances (chemical & biotechnological/ biological entities)

EMA and FDA have published this ICH document for comments by 30 September 2011. It describes approaches to developing process and drug substance understanding. It also provides guidance on what information should be provided in CTD sections 3.2.S.2.2 – 3.2.S.2.6.

Products Deliberate adulteration of pharmaceuticals.

There is already considerable focus on the security of the supply chain for medicines, but once again our industry and the patients it serves have come under threat from criminal activity within the supply chain. Two serious incidents are under investigation. The first, involving contamination of saline drips with insulin has resulted in the death of patients at Stepping Hill hospital. The second, involving Nurofen Plus tablets has involved strips of the Nurofen Plus tablets being substituted within the strips with potent prescription only medicines from two different manufacturers. International

Q&A – Distribution Activities for APIs

A PIC/S Expert circle has provided this Q&A as guidance to inspectors when inspecting Supply Chain & Distribution and Repackaging & Relabelling operations. It should also be of use to Industry. For further information on these and other topics we suggest you refer to the websites of relevant regulatory bodies and to current and past GMP Review News” editions of “G published by Euromed Communications. To subscribe to this monthly news service contact: info@euromedcommunications.com

23


PHARMACEUTICAL FORUM The following is a selection of the questions and answers taken from recent exchanges in the PharmWeb GMP Discussion Group. This Forum is held on the Internet at www.pharmweb.net/gmp.html and sponsored by the publishers of Industrial Pharmacy and GMP Review. The Forum is free of charge and open access. It serves as means of exchanging views within the context of international regulations affecting the manufacturing side of the pharmaceutical industry. Your own questions and answers are very welcome. Send them to www.pharmweb.net/gmp.html but please remember to write your name and email address at the bottom of your message.

Q

Can someone advise on the process for obtaining an EU Certificate of GMP compliance for a Pharmaceutical Manufacturing facility? Does this involve the contracting of an authorised third party to conduct an inspection based on EU standards or does the EMEA directly inspect the site?

Response: 1 Up to now, there is not any third party involved in the EU scheme of GMP inspections. Moreover, what we call “EU” inspections are generally inspections performed by inspectors of one of the 27 European countries. The conclusions of such an inspection are automatically endorsed by the 26 other authorities. For example a German inspection in Asia will be used by the other countries. The status of every non-European site inspected in that scheme can be found in the EUDRAGMP file maintained by the EMA (ex-EMEA). Speaking about EMA there are also some “European” inspections scheduled on behalf of the EMA but performed by a team of inspectors from one or two European countries. These inspections have the status as the other European inspections. The main difference is that they generally focus on one or two named products. So, how to obtain a EU-GMP Certificate of Compliance? Simply by being successfully inspected by one or more European inspectors on behalf of EMA or another National European Authority. Such inspections are only triggered when the concerned manufacturing site is named in a Marketing Application or a variation of an existing Marketing Authorisation. You will therefore not find any private company whose conclusions could be endorsed by European authorities. But, of course, you can select who is trained in receiving a European-style GMP inspection while awaiting the real official inspection.

24

Response: 2 The answer is correct if you refer to manufacturing facilities of marketed products. For manufacturing facilities of clinical materials, you can get a GMP certificate from a European certified Qualified Person.

Response: 3 For clinical supplies, it is the QP of the importer in the European Union that will establish and document the verification of the compliance of the clinical manufacturing site. Usually, the QP can also reply on third party audits provided he has himself checked the qualification and the professionalism of that third party. But in no way can this declaration be considered as a “GMP Certificate of Compliance” which is solely issued by authorities.

Q

As we know, non-dedicated equipment should be validated for cleaning procedures. But what about the dedicated equipment? If these procedures should be validated too, what is the acceptable criteria of the residue?

Response: 1 There is no regulatory obligation to systematically validate the cleaning of dedicated equipment for residues. You can also refer to WHOGMP guide paragraph 13.12 Having said that, there might be a NEED to validate such cleaning, taking into consideration the cleanability of the product and the risk of leaving degradation products on the inner parts of the concerned equipment.

Response: 2 What really matters is how we convince FDA in this matter of cleaning validation. Acceptance criteria for dedicated equipment are no different from that of non-dedicated equipment. Limits for detergents must be based on toxicity; standard industry practices are followed for bioburden determination evaluation; visually clean criteria are based on the active ingredient used.

Response: 3 A company’s decision should be based on FDA 483 citations too. There are no rules of thumb based on WHO guidance or whatever guidance we refer to or follow. One must evaluate based on good science and risk management which has its priority focus on patient compliance.

Response: 4 At least for the FDA, the “Guide to Inspections: Validation of Cleaning Processes” section IV says “When the cleaning process is used only between batches of some of the same product (or different lots of the same intermediate in a bulk process) the firm need only meet a criteria of, “visibly clean” for the equipment. Such between batch cleaning processes do not require validation.” However, if you use a detergent, you should confirm removal of the detergent between batches as well.

european INDUSTRIAL PHARMACY • Issue 10 September 2011


P H AR M A C E U T I C A L F O R U M ( C o n t . )

Q Can anyone comment on capsule dissolution/disintegration requirements? A given product which has only one component (API) shows bioavailability when reconstituted with water in a vial and dosed. The product is then formulated in a hard gelatin vial, again with API only, and bioequivalence studies are successful. Is there a need for routine dissolution or disintegration testing? Experimental dissolution results show that complete dissolution is reached very quickly.

Response: 1 The answer is definitely that you need a specification and testing. There are a number of possibly changes, albeit somewhat theoretical, in the case you mention. As examples, you might have polymorphic transitions, or hydration, or you could have pellicle formation caused by gelatin cross-linking. All of these could alter the dissolution, so you would be required to have dissolution as part of a stability program. If it is part of a stability program then you must also have it at time zero, ie. at product release.

Response: 2 Is there any other test in your specifications that gives assurance of drug release for every lot/batch? Dissolution specifications are necessary to show that the drug will be available for absorption from each lot.

Response: 3 As per ICH guideline Q6A, if dissolution is more than 85% in 15 minutes in all physiological media then an upper time limit for disintegration time is acceptable.

Q

I am facing a problem with cleaning validation of an API multipurpose plant: usually I would select the worst case and process three consecutive lots performing a complete cleaning analysis. However, someone told me that ideally there should be 10 lots, and at the same meeting another manager asked me to perform only one…I have never heard of performing 10 lots of cleaning validation, and in my opinion one lot is not enough. I wonder if some of you could share your opinion/experience on this issue.

Response: 1 You are right. It is most unlikely that a unique (cleaning) validation cycle would be accepted by an inspector. The right number of cycles depends on how much your cleaning process is automated or, if manual, how many different operators are concerned.

However, 10 batches? No idea where that comes from. With all validations there is always the question of how many and although there is no statistical basis the number that seems to keep every happy is three. I think that one is not a good number but I have seen, mainly in finished dosage plants, that one seems to be accepted.

Response: 3 Ideally three consecutive batches should be selected because when FDA was asked why we do cleaning validation three times, the answer was that if a result comes out right once – it might be an accident; twice – a coincidence; three times – validation.

Response: 4 Validation should be a demonstration of what you already know, not an experiment to find out what’s going on. If a process (equipment, materials, methods, people, etc) has been properly designed, developed and implemented, then the performance characteristics of the critical parameters will be understood and in control – and this will be known before the process is run. Validation is simply a practical demonstration that the process is reliable and repeatable. Three consecutive, successful runs is usually sufficient. (I understand that the concept of three batches came from the FDA many years ago where a comment was made along the lines of there being a need to balance statistical relevance against the cost of validation and that a “minimum of three consecutive batches within specification” was considered to demonstrate control. Note the inclusion of: MINIMUM.) If “validation” is being carried out to find out how a process performs, then a full statistical analysis will be required. This will involve the collection and analysis of 50 or more sets of data – and the results may demonstrate that the process is not in control! The latest Guidance for Industry: General Principles and Practices – http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ UCM070336.pdf is the most up-to-date reference document on the topic. The EU Commissioners are due (overdue) to issue an updated version of the EU Guidance on the topic which, it is understood, will be similar to the published FDA guidance.

Response: 5 An old boss of mine always asked the question “If that process were an aircraft, would you get on it?”.

Response: 2 As long as the analytical work is well validated and you have a good sampling program then the only issue in a multipurpose API plant is to make sure you really have a worst case…often you may need two worst cases because of the range of chemicals and solvents used.

Readers are invited to send their Q&A to: www.pharmweb.net/gmp.html

eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

25


NEWS FROM THE EIPG Representation

Education

Membership

The green paper on Modernising the Professional Qualifications Directive has been published and the EIPG response will be added to our website during the next few days.

Following Par Tellner’s contacts in EFPIA, EIPG has been invited to send a representative to an Innovative Medicines Initiative (IMI) workshop in Manchester to discuss a common framework of continuing professional development programmes for staff in medicines research and development.

We welcome Ms Margarita Efthymiopoulou, Business Development Manager for Viofar Ltd as the new Greek representative to EIPG

Since publication of the Falsified Medicines Directive on 1st July, EIPG is keeping a watching brief on the Commission’s moves towards its implementation. The EIPG responses to the consultation are published on the Commission’s website along with those of various other organizations. José Manuel Massó, a member of AEFI in Spain will represent EIPG at an EMA Ophthalmology Workshop in London on 27-28th October.

26

Student contact

Inkatuuli Heikkinen, EPSA Education and Professional Affairs Coordinator has indicated that career planning, some industrial career profiles and an indication of the main areas of employment in industry will be added to the EPSA website.

We are still looking for pharmacists in Member Associations with an interest in production/GMP issues, quality assurance, regulatory and commercial/marketing aspects of industry to help with commenting on scientific guidelines, codes and directives. Anyone interested in assisting with lobbying, please contact your national representative or me at jane@nicholj.plus.com Jane Nicholson Executive Director EIPG,

european INDUSTRIAL PHARMACY • Issue 10 September 2011


EVENTS OCTOBER

3-6 October 2011 – Rome, Italy PK/PD data analysis: a hands-on course using phoenix WinNonlin www.efmc.info 5-7 October 2011 – Prague, Czech Republic The GMP lead auditor www.improvingsolubility.co.uk" 5-8 October 2011 – Amboise, France 12th International Conference on Bioencapsulation www.irnpascience.eu 11 October 2011 – Stockholm, Sweden Pharma package – Pharmacovigilance in the Nordic Countries beyond 2012 www.lakemedelsakademin.se 11 October 2011 – London, UK Good Manufacturing Practice (GMP) mhraconferences@mhra.gsi.gov.uk 11-13 October 2011 – Nuremberg, Germany TechnoPharm 2011 www.technopharm.de 12 October 2011 – London, UK Good Distribution Practice (GDP) mhraconferences@mhra.gsi.gov.uk 13 October 2011 – Cirencester, UK Environmental Monitoring and CAPPA investigations – PHSS Autumn Conference www.phss.co.uk 13 October 2011 – London, UK Analytical challenges in the qualification and validation of pharmacodynamic biomarkers www.rpharms.com 18-19 October 2011 – Manchester, UK Risk-Based Decision Making for Quality Professionals and QPs www.nsf-dba.com 18-20 October 2011 – London, UK World Pharma Innovation Congress terrapin@uk.terrapinnmedia.com 18-20 October 2011 – Biarritz, France 24th Congress of A3P www.a3p.org

19 October 2011 – London, UK Funding the future of drug development in the UK www.inside-pharma.co.uk

14-15 November 2011 – Mumbai, India Nanomedicine: prospects and challenges www.ictmumbai.edu.in

19-20 October 2011 – London, UK Pharmaceutical labelling www.informa-Is.com/pharmalabelling

14-16 November 2011 – Cambridge, UK Tabletting technology for the pharmaceutical industry www.rpharms.com

19-20 October 2011 – Berlin, Germany Bioproduction www.bio-production.com 23-27 October 2011 – Washington DC, USA 2011 AAPS Annual Meeting and Exposition www.aaps.org 24-25 October 2011 – London, UK Point of care diagnostics – market adoption and technology trends www.pointofcarediagnostics.com 24-27 October 2011 – Manchester, UK GMP for Clinical Trials Manufacture and Supply www.nsf-dba.com 25-27 October 2011 – Stuttgart, Germany Parts2clean www.biztradeshows.com 25-28 October 2011 – Barcelona, Spain Pharmaceutical freeze-drying technology www.pda.org 31 October – 1st November 2011 – Basel, Switzerland European pharmaceutical pricing & reimbursement www.smi-online.co.uk/ 2011europricing.asp

NOVEMBER 8 November 2011 – Florence, Italy 3rd International Congress on Biohydrogels www.biohydrogels2011.it 8-10 November 2011 – Budapest, Hungary GMP meets GCP www.good-development-practice.org 10 November 2011 – London, UK Blue pill, pink pill? does gender matter? www.rpharms.com

eur opean INDUSTRIAL PHARMACY • Issue 10 September 2011

16-17 November 2011 – Coventry, UK European Isolator & RABS Conference www.phss.co.uk 21-22 November 2011 – London, UK Cell-based assays www.smi-online.co.uk/cell-based.asp 29 November 2011 – Berlin, Germany 10th Annual World Drug Manufacturing Summit www.allconferences.com 29-30 November 2011 – Manchester, UK Clean validation www.nsf-dba.com 29 November – 1 December 2011 – Manchester, UK Pharmaceutical water systems: troubleshooting and risk assessment www.nsf-dba.com

DECEMBER 5-6 December 2011 – London, UK Cold chain distribution: Temperature control management www.smi-online.co.uk/2011coldchain.asp 6-7 December 2011 – Bordeaux, France Modern biopharmaceutical manufacturing www.pda.org 8 December 2011 – London, UK Predictive tools in the development of solid oral dosage forms www.ipag.org 12 December 2011 – Cambridge, UK Dissolution testing for the pharmaceutical industry www.rpharms.com

27

european Industrial Pharmacy Issue 10 (September 2011)  
european Industrial Pharmacy Issue 10 (September 2011)  

European Industrial Pharmacy is the electronic journal of the European Industrial Pharmacists Group (EIPG). The journal contains articles, n...

Advertisement