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contents

7

12

36

21

7

Adamed buying Polfa Pabianice

10

Privatisation of Polfa Warsaw

12

Regulatory e-Publishing Challenges Challenges to overcome before one can say: Veni Vidi Publicati

16

Electronic commerce for the sake of pharmacy Part I

20

Logistics under close scrutiny

21

System ERP in a regulated environment

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27

Automating the validation of measurement methods

34

Realization of complex projects in pharmaceutical industry

36

Industrial design registrationfor protecting product appearance

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16

50

42

42

Water Quality in the Pharmaceutical Industry

46

Innovative concepts for sterilizing-grade gas filtration

50

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New trends in solid dosage forms production

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58

54

54

Rapid launch of a new medicinal product packaging – feasible and cost-effective

56

The Internet and the pharmaceutical branch

58

Pharmaceutical distribution market in 2010 Consolidation, privatisation and development of new forms of distributioni

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It will be happening... Honorary Host: 2 Congress World of Pharmaceuticals Industry 2010

| pol

The Farmacom publishing house, the editorial office of the “World of the Pharmaceutical Industry” quarterly and the Honorary Host - Sanofi-Aventis Sp. z o.o., cordially invite you to take part in 2 THE WORLD OF THE PHARMACEUTICAL INDUSTRY CONGRESS 2010 This event is organised to be held on 10-11 June 2010 at the Hotel Wellness&SPA Nowy Dwór in Świlcza near Rzeszów. Representatives of pharmaceutical manufactures and companies are invited to participate with specialists of the industry in this meeting devoted to the latest trends and technologies employed in pharmaceutical production. Experts from pharmaceutical manufacturing, universities, institutions, and organisations related to the pharmaceutical industry will ensure the high level of the Congress. The thematic scope of the Congress programme will include all of the main stages of pharmaceutical production, from supplies of raw materials to the storage of ready products and their forwarding. The next, June edition of “World of the Pharmaceutical Industry” will be a SPECIAL CONGRESS EDITION, additionally distributed during the Congress. WE ARE LOOKING FORWARD TO SEEING YOU AT THE CONGRESS! More information will be soon available on our website http://www.farmacom.com.pl

Programme Board

prof. dr hab. Zbigniew E. Fijałek

Daniel Gralak

– President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

– director of the National Institute of Medicinesw

– Director of GMP Inspection Department in Main Pharmaceutical Inspectorate

Andrzej Szarmański

– Vice President for Medicinal Products of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

Grzegorz Cessak

– President of ISPE Poland, Quality Director at Polpharma SA Pharmaceuticals

Irena Rej – President of the Polish Pharmaceuticals Chamber of Commerce

Marcin Kołakowski

Marek Gnyś – chief technologist Polfa Warszawa

Editor-in-chief „Świat Przemysłu Farmaceutycznego”

dr Jarosław Jan Hołyński – Polish Pharmaceutical Association

dr n. farm. Leszek Borkowski – EU expert of the matters of medicines, former President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

List of advertisers: Quarterly, published by FARMACOM Wodzisław Śląski 44-300 ul. 26 Marca 31/11 farmacom@farmacom.com.pl www.farmacom.com.pl

Payments may be made to the account: ING Bank Śląski O/Wodzisław Śląski 56 1050 1403 1000 0023 2091 8119 Editors

Maria Kubsz, Tomasz Butyński,

Editor-in-chief Robert Miller tel./fax 032 455 31 61 tel. kom. 502 084 101 robert.miller@farmacom.com.pl

Teresa Kubsz-Miller, tel./fax 032 456 60 79 redakcja@farmacom.com.pl

Subscription and distribution Publisher FARMACOM Wodzisław Śląski 44-300 ul. 26 Marca 31/11 tel./fax 032 455 31 61 prenumerata@farmacom.com.pl

Printing: Drukarnia BIMART.

Issue price „ŚPF” – 10 zł Annual subscription price – 35 zł

DTP : Wiktor Adamiec wiktor.adamiec@farmacom.com.pl Number of copies printed: 2 500 egz. Partner:

www.ispe.org.pl

The magazine is addressed to process and production engineers, automatic systems specialists, heads of production, control and quality assurance divisions, heads of logistics and procurement divisions and product development divisions at pharmaceutical companies. The magazine is also purchased by organizers of trade fairs, conferences and industry training courses, government offices, ministries, institutes, higher educational institutions offering pharmaceuticalsrelated courses, and design firms. The editors reserve the right to shorten and edit material. The editors are not responsible for the content of advertisements. The use of materials and publication of advertisements produced by the publisher is permitted only with the editors’ consent.

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Adamus HT Sp. z o.o. Arcon Polska Sp. z o.o. BALTON Sp. z o.o. Bio-Chic Sp. z o. o. DRUK-PAK S.A. ECOLAB Sp. z o.o. EMO Wytwórnia Artykułów Farmaceutycznych i Kosmetycznych GraSon s.c. HLP HYDROLAB POLSKA I.E.S. International Polska Sp. z o.o. IKA POL IKA-TECHNIK Sp. z o.o. i ZMR S.C. INFODRUK IRtech Kraków Kosmetyka Naturalna LabStand MIKROLAB PALL POLAND Sp. z o.o. PHARMINTECH PROBIT RADWAG Wagi Elektroniczne Sartorius Mechatronics Sartorius Stedim Technical Engineering Group Technopomiar Sp. z o.o. TRADE&CONSULT Sp. z o.o. TUSNOVICS INSTRUMENTS Polska Sp. z o.o.

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| polski przemysł

polski Polishprzemysł industry | 7

Adamed buying Polfa Pabianice

Robert Miller

Adamed has bought 85% of the shares in Pabianice’s Polfa SA Chemical Plant from Polski Holding Farmaceutyczny and the State Treasury. This brings to an end the process of privatising the first of the three Polfa companies which make up Polski Holding Farmaceutyczny.

The strategic investor’s entry into Polfa Pabianice completed one of the largest privatisation processes in the pharmaceutical industry in recent years. A contract was signed by Adamed’s chairman Maciej Adamkiewicz and the chairman of Polski Holding Farmaceutyczny Artur Woźniak in Warsaw on February 4th. Adamed’s bid proved to be the best among the 70 companies from all over the world which were invited to take part in three privatisation process. Apart from attractive financial conditions, the Polish pharmaceutical company also proposed a dramatic expansion plan for Polfa Pabianice. “We’re happy that we bought Polfa Pabianice. Our aim is to ensure this company further expansion. This process will be supported by Adamed’s scientific and research back-up, based on

Polski Holding Farmaceutyczny S.A. was founded in 2004 by the Treasury in order to consolidate the state-owned Polish pharmaceutical industry. After a change of strategy by the government and abandonment of the consolidation plans, PHF S.A.’s new task was the sale of the three state Polfa companies: in Pabianice, Tarchomin and Warsaw. After analysing the financial situation of these plants it was decided that the first to be privatised would be Polfa Pabianice. This company’s market condition was assessed as good - in 2008 Polfa Pabianice had a net revenue of 17.6m zł (over 1.4m zł more than in 2007). In the first six months of 2009 the company achieved 14m zł of net revenue. PHF has an ownership package of 80% of the shares in Polfa Pabianice, 5.04% of the shares are owned directly by the Treasury, and 14.96% of the share belong to employees and minor shareholders. Invitations to submit tenders were sent to 70 potential investors, after the business standing of over 700 pharmaceutical companies from all over the world were studied. This group included companies from Europe, Asia and the United States. One key aim was to find an investor within the industry, who would guarantee continuity of production at Polfa Pabianice and the introduction of new technology. On August 4th 2009 Polski Holding Farmaceutyczny announced that the shortlist for Polfa Pabianice included four companies. These were the Italian investor Recordati and three Polish companies: Adamed, Polpfarma and Polfarmex.

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88 | Polish polski przemysł industry

on offer, fits in excellently with our development strategy,” said Maciej Adamkiewicz, Chairman of Adamed. Integration with Polfa Pabianice represents another step for Adamed towards building up a market advantage in the region. Altogether, the Adamed group’s plants will employ nearly 1,500 people and around 200 scientists. Through the merger, Adamed will achieve larger market shares, a synergy in exports, a larger synthesis department, dynamic developments of projects seeking innovative medicines. This allows our products to compete successfully on the world pharmaceutical market,” stresses Maciej Adamkiewicz, chairman of Adamed’s Board of Management. Adamed’s entry into Polfa S.A.’s Pabianice pharmaceutical plants is

greater logistical and storage back-up and also new technology and the opportunity for greater development of the research and development departments. Polski Holding Farmaceutyczny also stresses the advantages of having Adamed as a partner in the privatisation process. “The process

an opportunity to take advantage of synergy effects in: expanding the

of privatising Polfa Pabianice was realised according to the strategy I

drug portfolio, increasing the production capacity and diversification of

envisaged. Polfa Pabianice is in the hands of a good, Polish investor

export markets. Further Eastern European and Asian markets represen-

in the industry, which has the experience, know-how and means to

ted by Polfa Pabianice have now been added to the portfolio of 22 foreign

expand the company, and equally importantly it is researching innovative

markets where Adamed is already present. “Buying Polfa Pabianice

medicines. Thus we have met all the conditions for the privatisation

allows us to make a significant increase in our market share, build up a

of this company, obtaining a satisfactory price for its shares,”- said

synergy between the R&D departments of both companies and create

Chairman Artur Woźniak of Polski Holding Farmaceutyczny.

support for new innovative drugs. At the same time, the acquisition of

source: PHF, adamed

new manufacturing technology, which complements what Adamed has

On October 15th 2009, after a review of the books (due diligence), it transpired that all four companies had submitted binding purchase offers. This was considered by PHF as the best recommendation of the attractiveness of Polfa Pabianice and a confirmation of the painstaking preparations for the privatisation process. A major influence on this was Polski Holding Farmaceutyczny’s good cooperation with the privatisation consultants – Poznan’s F5 consultancy group, Eksi Consulting and the legal office of Prof. Marek Wierzbowski. Taking into consideration the offers submitted, and the investors’ credibility and potential, Polski Holding Farmaceutyczny S.A. decided to sell Polfa Pabianice to Adamed, and on January 18th 2009 a sale contract was initialled between PHF and the purchaser. This is one of the largest privatisations in the pharmaceutical industry for many years, and also one of the largest realised recently by the Treasury. After concluding negotiations with the Investor and representatives of the workforce and trade unions, PHF S.A. helped open the way to finalise the sale of the Company. Meanwhile PHF is conducting the sale of the two remaining Polfas. The Warsaw plant is to be privatised second. On January 6th 2010, the deadline for submitting bids passed. The successful privatisation of Polfa Pabianice is seen as a good sign for Polfa Warsaw and Polfa Tarchomin which remain in PHF’s portfolio.

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Polish industry | 9 Adamed is a Polish market leader for new generation drugs in many therapeutic fields, including psychiatry, cardiology, pulmonology, gynaecology, ophthalmology and treatment of urinary tract infections. The company was founded in 1986 and has 100% Polish capital. During the first few years of its operations, it specialised in gynaecological preparations. In 1991 Adamed introduced Furaginum, a preparation for treating urinary tract infections, onto the market. This drug quickly became a market leader. This preparation remains a universally recognised brand today. In 1994, the first modern production facility was opened in Pieńków near Warsaw. In 1996, the company was transformed into a limited liability company. Two years later, Adamed introduces Amlozek onto the market – this is a medicine for arterial hypertension and a calcium channel antagonist, which instantly became the best selling preparation in its category and one of the first Polish drugs registered in the European Union even before Poland’s accession. This success became a powerful impulse for the company to expand, enabling the strategic decision to be taken in 2001 to commence research into original drugs. In 2002 a production plant was opened in Ksawerów, in the Lodz Special Economic Zone. The same year Adamed registered Zolafren, a new generation schizophrenia drug. This product is a huge market success. Another major event took place in 2004, when the company registered its innovative Colpexin medical appliance on the US market with the Food and Drug Administration (FDA). Subsequent ears saw the introduction of more new products, including: Zafiron, Xartan, Areplex, Axtil, Anesteloc, Luteina, Rozalin and in 2009 : Milukante, Kwetaplex, Nebilenin. In 1993 Adamed was a co-founder of the Polfarmed Chamber of the Polish Pharmaceutical Industry and Medical Products. The company also belongs to the Polish Association of Pharmaceutical Industry Employers. In September 2005 Adamed, along with other leading Polish pharmaceutical companies, found itself among the founders of the Polish Platform of Innovative Technological Medicine. Then in 2008 it joined the founders of the Polish Advanced Technology Chamber of Commerce. Among Polish pharmaceutical companies, Adamed is a pioneer in investment in research into seeking new drugs. It is constantly expanding its research departments, perfecting laboratory equipment and giving work to Polish scientists. The company’s Research and Development department was created to look for effective new therapies in selected therapeutic fields (the search for innovative molecules) and to develop and introduce new methods for synthesising and formulating generic drugs.. The company’s mission is to discover new, original drugs for diseases of civilisation such as: cancer, diabetes and schizophrenia. The company fully meets European Union requirements regarding its chemical and analysis laboratory, biology laboratory and pharmaceutical technology laboratory. It has one of the country’s most modern microbiological quality control laboratories. In late 2002 Adamed initiated a specialised isotopic laboratory, certified by the Polish Nuclear Agency. Recently, In Silico and biotechnology research labs have also been opened. In its business, the company takes particular care to ensure the quality of its products. To do this, Good Manufacturing Practices (GMP) have been introduced, along with other Good Practices necessary to ensure the quality of the drugs produced. Workplace comfort is also being improved by implementing the newest achievements in the fields of technology, techniques and organisation. In 2002, even before Poland joined the European Union, the company received its first quality certificate, confirming that its actions conform with GMP requirements. Another success for the company is the ISO 9001 certificate issued in 2008. In recent years, nearly 200 million zlotys have been invested in research projects regarding innovative drugs, and more than 20 patents have been produced for our own drug formulas. Adamed conducts scientific research in collaboration with leading academic centres all over the country, including: the Pharmaceutical Institute, Gdańsk Technical University, Warsaw University, the Jagiellonian University, Gdańsk Medical Academy, PAN’s Nencki Institute in Warsaw, Wrocław Technical University, IITD PAN Wrocław, Collegium Medicum Kraków, the Institute of Psychiatry and Neurology. The company’s own R&D centre conducts research as part of three platforms. The first of these is the metabolic platform, which covers the search for drugs to treat type II diabetes. It should be pointed out that Adamed was the first Polish company to carry out a project seeking innovative drugs, from the conception to the clinical tests in its own labs. The next platform is the ontological, in which work is taking place on the ONCO - 3CLA guided biotechnological cancer drug project. The neuropsychiatric platform, the third research platform initiated, is the development of an innovative Polish drug to be used in treating diseases of the central nervous system.. Adamed is in the top 20 Most Innovative Polish Enterprises, according to a ranking by the Polish Academy of Sciences’ Institute of Economic Science, as confirmed by the Certificate of Innovation awarded in 2009. For 11 years, Adamed has seen a rapid growth in employment levels. In June 2009 it employed over 870 people. The company is constantly investing in its research departments and developing its laboratories, giving work to over 100 Polish scientists. Over 73% of the workforce have a higher education. For several years Adamed has been experiencing a dynamic growth in sales both domestically and abroad. Adamed is the first Polish pharmaceutical company present on European Union markets. Adamed sells its products to 22 countries: the Czech Republic, Slovakia, Hungary, Croatia, Lithuania, Estonia, Finland, Spain, Portugal, Turkey, Ukraine, Bosnia and Herzegovina, Slovenia, Denmark, Albania, Kuwait, Greece, Latvia, Kazakhstan, Romania, Kosovo and Cyprus. Source: PHF, Adamed

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10 | Polish industry

Privatisation of Polfa Warsaw Robert Miller

Companies interested in buying Polfa Warsaw had until January 6th 2010 to submit their initial offers. By that date, Polski Holding Farmaceutyczny, responsible for the privatisation process of the state-owned Polfas in Warsaw, Tarchomin and Pabianice, had received five bids from well-known pharmaceutical companies from Poland and abroad, including from outside Europe.

I’m happy with the type of offers which have come in, said Artur Woźniak, chairman of PHF S.A., at the time. On February 4th 2010 Artur Woźniak, chairman of Polski Holding Farmaceutyczny announced the shortlist of investors for Polfa Warsaw. Three of the five interested companies were selected for the next stage of the sale. These were Polpharma SA Pharmaceutical Plants, the Adamed group and the American Perrigo Company. The stage of checking the companies’ books (due diligence) should commence in the second half of February. Binding offers for the purchase of Polfa Warsaw can be expected at the beginning of April 2010. “the initial offers of the three shortlisted investors are satisfactory and allow hope for a good sale of Polfa Warsaw, guaranteeing its future development. all three bidders have an established brand and position in the pharmaceutical industry,” says Artur Woźniak. The publication of the shortlist of those interested in buying Polfa Warsaw coincided with the signing of a sale contract for another of the Polfas in PHF’s portfolio - Polfa Pabianice. The purchaser is Adamed, who also placed a bid to purchase the Warsaw plant. This means that Polski Holding Farmaceutyczny now consists of Polfa Tarchomin and the recently privatised Polfa Warsaw.

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11

Brief Description of the Potential Investors The Perrigo Company Perrigo, based in Allegan (Michigan, USA) is a leader on the world market for health protection services, which researches, develops, manufactures and distributes over the counter pharmaceuticals (OTC) and generic prescription drugs (known as Rx), diet supplements, active pharmaceutical components and pharmaceutical and medical products for diagnosis. Perrigo is the world’s largest producer of OTC pharmaceuticals which are generic medicines. Perrigo currently operates its business in Great Britain, Mexico, Israel, India and China. As part of its international market strategy, Perrigo has designated seven European countries, including Poland, as key markets for the company’s expansion. In 2009 Perrigo achieved sales revenue of around 2 billion USD. This company is floated on NASDAQ (the off0exchange regulated share market) in the USA and on the Tel Aviv Stock Exchange.

Polpharma SA Pharmaceutical Plants ZF Polpharma based in Starogard Gdański is Poland’s largest producer of (generic) reproduction drugs and pharmaceutical substances, specialising in the production of cardiological, gastrological and neurological prescription medicines and those used in institutions. ZF also produces a wide range of OTC medicines. Polpharma SA Pharmaceutical plants were founded in 1935, nationalised after the Second World War, then incorporated into the Polfa United Pharmaceutical Industry, and in 1995 transformed into a single-shareholder company of the Treasury, which was then privatised in 2000. The majority share in ZF Polpharma S.A. was bought by Spectra Holding Sp. z o.o. controlled by Mr Jerzy Starak. ZF Polpharma’s revenue in 2008 stood at around 1 billion PLN.

The Adamed Group Adamed, based in Czosnów near Warsaw (Pieńków) has been active on the Polish market for 23 years. The core area of Adamed’s business is the development, promotion and sale in Poland and abroad of the newest generation of drugs for the most common diseases of civilisation. Among Polish pharmaceutical companies, Adamed is a pioneer in investment in research into seeking new drugs. Adamed is oriented towards developing innovative therapeutic products and increasing sales on the Polish market and internationally. As well as being present on the Polish market, Adamed’s products are also available in 14 other countries. In 2008, Adamed achieved consolidated sales revenue of around 400m PLN. source: PHF, Polfa Warszawa

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12 | Polish industry

Regulatory e-Publishing Challenges Challenges to overcome before one can say: Veni Vidi Publicati Raoul-A. Lorenz LORENZ Life Sciences Group

Moving to e-publishing brings about many challenges for regulatory affairs professionals. Although the focus of e-publishing has conventionally been the end result of being able to submit electronically, the electronic submission in itself is really only the output of the e-publishing capabilities of a company. E-publishing as an end-to-end process is the more critical capability for a company to create and fine tune.

Raoul-A. Lorenz has been the CEO of the LORENZ Life Sciences Group since 2006. After he completed his studies at the European Business School in the UK, he started with LORENZ in 1996. In 1999, he became CEO of reg123.com Limited, a regulatory affairs information portal. Since 2000, he has taken on successive Directorships at LORENZ, including the UK, US, Canadian, German and finally the Indian divisions of the LORENZ Life Sciences Group. Prior to becoming the CEO, Raoul was appointed VP Sales & Marketing for the Group in 2003. Raoul has also led workshops at numerous events on electronic submissions in Europe, North America and Australia, as well as presented on the topic at DIA, BIRA/TOPRA, and others. He was also the chairman of the Drug Information Association (DIA) Special Interest Area Committee for Communications & Publications in 2001/2002.

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13

The move towards e-publishing has come in waves, hand in hand with the advancements of technologies and the evolution of standards.

For example, companies such as Berlin-Chemie AG (Berlin, Germany), today part of the Menarini Group, significantly increased their capabilities in generating submissions: from 1995 to 1999 they compiled and submitted 29 submissions.

Definitions

In 2000 alone, they had compiled and submitted 21 sub-

In this context, we will refer to e-publishing as the creation of a submission for regulatory filing. The submission itself can take the form of paper or electronic. However, the source documents for either output would have been electronic.

History of e-Publishing When e-publishing gained more momentum in the early to mid-nineties, engaging in this luxury took considerable time and effort for regulatory affairs departments. The reason for this was simple: the entire document and submission creation value chain continued as before, and it was left

missions. According to Berlin-Chemie, this goal could not have been achieved without the rigorous implementation of a digital process for the compilation of submissions. By 2000, of course, the US Food & Drug Administration had also had their two years of experimenting with standardized electronic submission formats. It became clear that e-publishing to an electronic output was no longer just an option to generate more efficiencies in the document and submission creation processes, but that in fact the “e-submission” would well become a mandatory format at some point in the future.

up to regulatory affairs to “bolt on” an electronic publishing process at the end of the process. What usually happened was that all departments continued to deliver their results in paper. The regulatory affairs departments then scanned these results in to convert them back into an electronic format, in order to then create an electronic output. In essence, the result was an exact digital version of the paper format that existed. The result of the above process was that electronic publishing was seen as time consuming and expensive. It delayed the potential submission date, and at the same time

Change Management Today, the vision is even clearer, and most regulatory agencies participating in the International Conference on Harmonization (ICH) have made statements confirming that electronic is the way forward, with some even making it mandatory. However, many companies still struggle to make the transition from a paper-based approach to an electronic-based publishing approach. There are several reasons for this: A different skill set is required in regulatory affairs in order

it made those working in the value chain prior to regulatory

to operate in an electronic environment., Regulatory affairs

affairs work harder to complete tasks faster - ultimately, to

managers today need to have a solid understanding of IT

leave time for the e-publishing “bolt on”. However, with time came greater insight into the organizational document creation processes. Some companies began to see e-publishing as a means to streamline their entire document creation value chain - and in fact looked at e-publishing not as an end, but merely as a means to an end. With the focus turning from “How do I get an electronic submission to an agency?” to “How can I digitize and optimize my entire document and submission creation value-chain?” the electronic submission in itself became less important: the output could have been paper too. What

and technical guidelines, while in the past their focus was only on content and understanding the scientific guidelines and interpretations. In order to overcome this hurdle, many companies have set up dedicated e-publishing departments that work closely with regulatory affairs and focus solely on compiling electronically and publishing electronically. Many companies still fail to look at the entire document and submission creation value chain. Electronic publishing is still treated as a “bolt-on” and seen as an additional expense, rather than an investment into the submission infrastructure capabilities of a company. Furthermore, the concept of submission lifecycle, defined as the history of changes

really became important was the focus on electronic compi-

to an original submission over time, is still underestimated.

lation - taking electronic documents right from the start to put

While many accept that a document has a lifecycle which

together a submission. The publishing process could then create an electronic as well as a paper output. Some companies used this technique to significantly reduce the time they needed to create their submissions.

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must be controlled, few understand the exponentially greater complexity (measured in numbers of hyperlinks, pages and documents) of managing the lifecycle of a submission.

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14 | Polish industry

Continuous education is critical. Publishing to digital standards and specifications means that companies are subject to constantly changing requirements. This is the nature

vendors in this field may also have contributed in building up an unreasonable expectation to gain a customer. Finally, the investments into the wrong type of products

of technology: nothing remains constant. Specifications are

and services to realize the e-publishing capabilities may

like software development, they are constantly upgraded or

also become a problem. It is vital that companies looking

improved upon to iron out weaknesses. Companies that don’t

to invest into e-publishing capabilities fully understand their

keep their regulatory affairs or publishing staff up-to-date may

requirements so that they are able to distinguish between

find they are publishing to old and outdated standards rather

the different solutions on the market. Vendor selection

than current ones. Understanding where standards are going

based on superficial knowledge and an over-reliance on any

is equally vital: it may well have an impact on the document

one vendor itself has cost many companies much time and

creation strategy for submissions several years down the line.

money, often leading to costly mistakes or no result what-

Misaligned expectations can form a sense of frustration.

soever. Talking to user groups, references and attending

Regulatory affairs may have unreasonable expectations of what an electronic publishing process can do for them forgetting, that the technologies and software are meant to support the process rather than replace it. In part, software

relevant conferences is a vital component of research that needs to be done prior to any vendor selection.

The Future

The future will bring even more challenges, as epublishing begins yet another transition. Firstly, the current standard, the electronic Common Technical Document (eCTD), is set to be replaced by another standard, Regulated Product Submission (RPS) in the coming years. The eCTD currently only allows for a one-way communication between sponsor and agency and is very much focused on human

Dlaczego warto budować swoje eCTD w docuBridge®? Skontaktuj się z nami i dowiedz się.

medicines. RPS is will not only allow for a two-way com-

Polski Urząd Rejestracji jest piątą Agencją na świecie, używającą docuBridge do przeglądu dokumentacji eCTD, zgodnie z wymogiem EMA: • Health Canada, Kanada • BfArM, Niemcy • AGES, Austria • JAZMP, Słowenia • Urząd Rejestracji Produktów Leczniczych, Wyrobów Medycznych i Produktów Biobójczych, Polska

standard and could necessitate new hardware/software/

lorenz

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munication, but it will also deal with more submission types. With some vendor technologies, this could mean a change or delay in e-publishing capabilities adherent to the RPS training investments by purchasing companies. Secondly, as can be seen from standards such as the US Structured Product Labeling (SPL) and the European Product Information Management (PIM), exchange of information is increasingly data-based, rather than documentbased. This will have a significant impact all the way back to the authoring process: companies who believe that they can “bolt-on” the data submission types at the end of the submission process will find themselves in a costly no-win situation similar to those companies which chose the “bolt-on” route when the concept of electronic submission was first gaining momentum. Again, the same case for action and the same criteria for success apply even as e-publishing enters a new phase: Embracing e-publishing means it is necessary to look at the complete publishing process and re-engineer that value chain with a holistic view, as opposed to living with band aid solutions which cover up fundamental process flaws.

Kontakt: Agnieszka Sielicka, Tel: +48 503 177 690, Email:asielicka@lorenz.cc

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16 | Polish industry

Electronic commerce for the sake of pharmacy

Part I

Anna Kosmacz-Chodorowska Instytut Logistyki i Magazynowania – GS1 Polska

This text begins a series of articles related to currently the most efficient electronic commerce tools (e-commerce) whose implementation improves the way pharmaceutical companies function. This concerns both internal processes of each company and its contacts with customers. The following issues will be discussed: automatic and electronic data exchange systems as well as local and international agreements concerning barcoding – beginning with individual packaging forms e.g. retail units, through intermediate collective packaging forms, ending with logistics units.

Moreover, we will also describe the most up-to-date solutions

although they have been available for 20 years. However, they are

in this respect adopted by the world trade and sector institutions.

applied more often. These solutions include: automatic identification

We will also introduce the most efficient e-commerce systems

and data capture through barcodes and exchange of electronic

and tools to be used by companies in our sector as well as some

documents, e.g. Electronic Data Interchange (EDI).

examples of their implementation. We will write about traceability solutions, harmonisation of European logistics labels, ‘radio’

Implementation of these solutions leads to fundamental changes

barcodes and new barcode symbologies used to encode business

in the approach towards business activities globally, locally and from

data e.g. date and batch number on retail units. The aim of this

the point of view of a single company guaranteeing effectiveness

series is to present our Readers with methods of implementing

and competitiveness of activities. Providing information concerning

these tools in order to increase the competitiveness of manufac-

various opportunities related to these solutions and methods of

turers of pharmaceutical products and improve the whole supply

benefiting from them is in our opinion the answer to our Readers’

chain.

expectations.

Barcodes in pharmaceutical sector

The broadening of markets and requirements of modern turnover of goods have made tradesmen seek for new ways of gathering and exchanging data. Rapid development of technique has made it

The content of articles

possible to develop various tools to gather and exchange data out

will let our readers get familiar with issues concerning new IT tools

of which barcode technique has become most widespread. To begin

which have successfully been used for over 30 in commerce of better

with, a few words concerning automatic data identification and

developed countries. In our country they are not enough known

capture (ADIC) as well as barcodes.

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17

In order to encode the biggest possible number of characters on the smallest possible space, hundreds of barcode types and kinds have been developed. Some of them have become widely applied, especially in industry and trade functioning as universal or sector-specific, international standards.

Possibilities of barcodes By means of barcodes, AIDC is widely used in processes like: manufacturing, warehousing and transport, for the sake of cooperation and wholesale trade as well as many other fields of human activities. That is why absolutely everyone can benefit from the effects of barcodes, both for the sake of their own business activities and for the sake of business

Automatic identification and data capture (AIDC)

contracts. For example, a manufacturing company uses AIDC:

Two AIDC features are as follows:

•     warehousing processes – in order to improve and automate inventory

AIDC is a modern IT technique, replacing manual data entry to

in internal processes of the company: and circulation records, goods shift and storage, goods picking and

IT systems with specialized automatic methods. AIDC, replacing

stocktaking; both in a raw-material and packaging warehouse and a

manual data entry – being time consuming and causing mistakes

finished goods warehouse;

and false readings – with automatic data reading makes it possible to

•     work time registration,

enter detailed data very quickly and correctly.

•     document circulation systems,

AIDC is also a set of techniques of machine writing and reading of

•     assets management;

identification codes; object identification (e.g. goods, including for example pharmaceuticals, people – for example staff, locations – for

in external processes related to business contracts:

example ‘from where’ and ‘to where’ goods should be delivered) is

•     concerning procurement and sales processes, trading with suppliers

aimed at differentiating between objects and providing particular

and recipients of procurement materials and finished goods,

information describing them more precisely.

additionally to the earlier mentioned basic warehousing functions:

In practice, different AIDC techniques are used, depending on individual conditions and needs, e.g. magnetic paths/tapes on magnetic cards (telephone or bank cards), radio frequency, voice recognition, etc. and barcodes, the latter being most popular and

•     in control of processes concerning acceptance of goods and material and raw material issue, •     in control of processes concerning acceptance and issue of finished goods.

easily accessible. Barcodes are also the cheapest AIDC method. We will get familiar with it then.

Barcodes may be used by cooperators and suppliers of raw materials and finished goods including:

Barcode

•     semi-finished articles and raw materials to be used by finished goods

A barcode is a determined combination of linearly composed

manufacturers

light and dark bars (they do not always need to be black and white)

•     and also by manufacturers of:

or other figures (the so called composite codes) of different width,

•     pharmaceutical products, medical materials and other consumer

reflecting various characters in a determined way: numbers if these are numeric codes or numbers, letters and other characters (alphanumeric codes) for the sake of their machine reading. Reading of

goods, e.g. cosmetic and food products being in turnover in this sector (in unit packagings offered in retail and pharmacies); •     goods in collective packagings (multipacks, boxes, etc.) for

barcodes is performed with the help of specialized electronic devices

wholesale and in logistics packagings (cases – plastic containers,

(usually with a built decoder), called readers or scanners. There are

pallets, etc.) prepared for warehouse and transport purposes,

many types and kinds of scanners chosen adequately to the needs of

mass and individual orders whose content may be homogenous

barcode users.

or heterogeneous).

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18 | Polish industry

it, a uniform system for marking products with appropriate symbols was necessary. As a result of cooperation between manufacturers and retailers in 1973 a 12-digit identifier (its shorter version had 6 digits) presented in a UPC barcode was approved. UPC (Universal Product Code) includes UPC-A i UPC-E (for small products). UPC system was governed by Universal Code Council in USA and was in force in the beginning in USA and Canada. These barcodes are still used in these countries but goods from Poland and other countries exported to USA and Canada had had to be marked this way until 2005. Nowadays international barcodes, called EAN, are accepted.

Barcodes in Europe and worldwide Benefits resulting from application of barcodes and possibilities of automatic identification in points of sale in USA and Canada raised interest in the system abroad, especially in Europe. In 1974 representatives of manufacturers and distributors from 12 most industrialized European countries started works on creation of new uniform product identification system for our continent. As a result, in 1976 European Article Numbering system was created, modelled on American UPC which was governed by European Article Numbering Association with headquarters in Brussels, aimed at coordinating all activities concerning practical implementation of EAN barcodes. Other countries, among others Japan, Australia, Argentina, Mexico, soon noticed advantages of the EAN barcode system and joined the association in order to be able to mark their products. This made EANA evolve into an international association IANA in 1981. The association returned to its original name in 1992, namely EAN (as the name of the system) adding the word ‘International’ in order to underline an international character of activities. Barcodes, the so called EAN-13 and EAN-8, printed only on In further articles we will provide our Readers with information

consumer products in the beginning, became very useful on pharma-

concerning the extent to which barcodes may improve production,

ceutical products, although it had taken some time before they were

wholesale and retail and also software and device requirements of

appreciated in each country. Since pharmaceutical products are so

such a system, e.g. all information that some should be familiar with

specific due to the role they play in our life and safety, in majority of

before implementing barcodes. In this article we will concentrate on

countries they are registered centrally by governmental authorities –

some basic information concerning the history of barcodes in Poland

e.g. equivalents of our Ministry of Health. We will soon describe the

and their range.

way this influences barcoding of these products.

It began in America

Barcodes for collective wholesale and logistics packagings

A glance on the history of barcodes will make it possible to get familiar with their development directions and appreciate all benefits related to barcodes. For the first time barcodes were used on a large scale in retail.

In wholesale trade, next to UPC and EAN symbols, ITF had become more and more popular (a numeric barcode of lower requirements concerning symbol quality than EAN and UPC). ITF was commonly

The main reason for introducing barcodes was the need to improve

accepted to be used on wholesale collective packagings and is often

productivity, customer service and product record in points of sale.

applied on non-retail collective packagings when information like

Later on attention was drawn to the possibility to use barcodes in

batch number or date does not need to be barcoded. Manufacturers

industry and other constantly expanding areas.

of boxes usually deal with this symbology when the ordering party

Rapid development of supermarkets in the 60ties in USA and

requires this symbol together with information encoded related to

Canada contributed to development of standard solutions enabling

the future content of each box as a wholesale and trade packaging for

automatic identification of goods at cash desks. In order to achieve

goods included in it.

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Polish industry | 19

The characteristic of first barcodes was possibility to encode

is concerned, ITF called interleaved 2 of 5 (composed of 14 digits)

numbers only. These barcodes did not allow to include detailed

and GS1-128 which should be used on collective and logistics

information required in some sectors, e.g. lot number, supplier’s

packagings in our sector as the most important barcode symbol in

number, etc. In order to meet such needs, new barcodes were develo-

pharmacy. What should be done in order to make these symbols easy

ped, namely alphanumeric codes, including Code 128, developed in

to apply in practice providing the best effects, both in manufacturing

1981. It is possible to encode 128 different characters in this code.

and trading processes concerning pharmaceutical products? We will

Due to advantages of Code 128, in 1989 UCC and EAN International

answer this question in our further articles. Next article will concern

adopted a variety of this code called GS1-128 (previously: UCC/

principles of functioning of pharmaceutical companies in this

EAN-128 or EAN-128) to encode additionally information concerning

international system as well as authorisation to use barcodes and

products themselves and their transport, delivery location, etc.

identifiers allocated during the registration process.

In pharmaceutical sector this symbology is usually used to mark logistics packagings, e.g. pharmaceutical products in collective logistics packagings. As far as manufacturers are concerned these are usually boxes and homogenous pallets and as far as wholesalers

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are concerned these are usually heterogeneous containers. In 1999 UCC and EAN fully coordinated all standard solutions and now it is possible to state that there is only one multi-sectoral system called EAN•UCC until 2005. This system is a set of global standards and solutions aimed at improving logistics and management with the help of two modern IT tools: automatic and electronic data interchange with the use of barcodes. This system is currently called GS1: Global System 1.

Most current news Recently, two-dimensional barcodes or composite and reduced barcodes have gained much interest, especially in applications where there is not enough space on a packaging or label. Although such codes were developed in 1987 for the first time and continuous elaboration of new codes proves their constant development, it is in 2010 that such codes will be used in an open environment based on mutual agreements. Their broader use is scheduled after 2014. These codes are called: GS1 DataBar. These codes are in their initial stage of implementation now and until they become common, previous codes will dominate on packagings. There are also two-dimensional barcodes: GS1 DataMatrix. Possible plans concerning common adoption of this new symbology are the subject of international discussions right now. There is an important discussion going on right now in our sector concerning introduction of new symbologies on retail packagings of pharmaceutical products in order to make it possible to encode batch number and date in one barcode symbol apart form product identification number. All issues related to this topic will be presented to our Readers. In summary: EAN-13 i EAN-8 (composed of 13 and 8 digits), UPC-A and UPC-E (composed of 12 and 6 digits) numeric barcodes are dominant as far as the global standard for industry and trade

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20 | Polish industry

Logistics

under close scrutiny Consafe Logistics

Patients’ health, or even life, may depend on pharmaceutical companies’ logistics. Drug distributors are obliged to keep a close track of drug batches, and withdraw them from the market if they turn out to be harmful. Is this still possible without IT systems and new technologies?

Today, IT systems and new technologies are the foundation of

impossible these days. “An interesting solution for the pharma-

proper operation of any warehouse. Without the right IT systems,

ceutical industry are warehouse terminals. Examples include the

keeping track of large batches of goods outgrows human capacity.

MC3090 inventory terminals, due to their weight meant primarily

Automatic conveyors, radio terminals, and bar codes, as in other

for women working in pharmaceutical distributors’ warehouses,

industries, are also used by leaders in the pharmaceutical industry.

or the MC55 model, a mobile terminal for transport drivers with

This way, businesses already have the right tools, with tailored

GSM-enabled communication and an a built-in GPS,” adds Łukasz

software enabling them to deliver their products to recipients – fast

Gałecki, Consafe Logistics.

and error-free. “The pharmaceutical branch is specific in that it

IT solutions that streamline warehouse operation enjoy growing

involves the need to keep track of drug batches, as the law requires

popularity. Today, not only leaders of the pharmaceutical industry,

distributors to withdraw a specific batch from the market if need be.

but also a majority of companies trying to modernize their ware-

This would not be possible without IT systems. Supplies are also

houses want to monitor staff performance, and optimize logistics

becoming increasingly atomized. At the very bottom of the distri-

processes. For Prosper SA, the primary goal was to control the

bution system, there are small containers, of which only a few drug

process of accepting and releasing drugs. “With the bar code

packets go to pharmacies,” says Janusz Budek, Prosper SA.

system and mobile devices, we are now able to closely monitor, how

The primary goal for businesses is to control the distribution of

batches of goods are released from our warehouse. We now have

product batches, i.e. to accept and distribute them based not only on

the means to oversee the entire warehousing process, and make

orders, but also on batch numbers. The WMS system, now available

comparative analyses enabling us to keep track of staff perfor-

on the market, seems to be an excellent tool for managing a high-

mance,” say company representatives. Besides, if pharmaceutical

storage warehouse. “WMS systems are designed for order-picking

companies want to stay among key players on the market, and gain

without using paper documents. Customers can think about using

a competitive edge, they must offer their customers only the best

these kind solutions as radio terminal-based systems and voice

– fast and error-free deliveries. The only thing left is to choose the

recognition solutions. Regular release orders are also available. The

right partner. “The main principle is – the bigger, the better. When

system boosts performance, and ensures return on investment within

choosing the partner for such deployment, market position should

several months from deployment. In addition, such system is a major

be the main criterion. A small company usually offers a lower price,

step towards a state-of-the-art warehouse on a European level,” says

but it is unlikely that it can ensure sufficient technological and

Łukasz Gałecki, Hardware Sales Team Manager, Consafe Logistics, a

business support, or proper maintenance. In such case, benefits

company providing end-to-end IT solutions for businesses.

may not meet your expectations. Previous achievements of the

Apart from an integrated WMS system, the offering for the pharmaceutical industry also includes warehouse terminals and

company, as well as opinions and information on its functioning, are of crucial importance,” says Janusz Budek, Prosper SA.

barcode printers, without which warehouse operation would seem

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System

ERP in a regulated environment Carlo Candotti Pharma Quality Europe

In the last decade, the use Enterprise Resource Planning (ERP) system is being widely increased in the Regulated Companies (Pharmaceutical, Medical Device, Biotech, Distributors, Herbal). Challenges of an ERP implementation Although many ERP suppliers have a wide knowledge in system integration, the Regulated companies which plan to implement an ERP System may face a number of difficult challenges since this type of

•     implies a deep impact on the Company organization and it may require a deep effort to adapt the process flows to the system functionalities •     needs a deep integration with the Quality System of the Regulated Company

systems: •     covers functionalities in all supply chain areas (e.g. Accounting, Sales, Purchasing, Warehouse, Production, Quality Controls,

Need for System Validation In addition to these intrinsic challenges, the ERP systems in the

Maintenance) •     is highly configurable and its potential capabilities are difficult to address in the system selection phase •     is often designed for multi country and for different industrial areas •     needs a detailed process mapping to be implemented

Regulated Companies are planned to manage a number of processes which have impact on the product quality and traceability. As a consequence, every Regulated agency (e.g. EMEA in Europe, FDA in US, MHLW in Japan) requires the Regulated Companies to

Carlo Candotti from 1990, after the degree in Engineering at ‘Politecnico’ in Milan, Carlo Candotti has worked at the ERP system’s integrator as a logistic and production consultant, ERP implementation project leader and consultant manager in a Software Factory and System integrator vendor. In these roles he has managed more than 20 ERP go-live in pharmaceutical industries, supporting the validation process from a System integrator perspective. The expertise in numerous ERP projects in software factory, standard ERP (SAP™ and others) implementations and ERP validations has allowed him to approach ERP Validation in an integrated manner addressing the system functionalities against the particular Company organization, Quality System and Validation exercise. In 2005 Carlo joined PQE as a ERP expert managing a high number of ERP validation processes, software selections, assessments and remediation plans in major local and international Life Science Companies.

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22 | Polish industry

ensure that these systems are reliable before they are used for the actual

a controlled lifecycle for producing a computerized system starting

production activities.

from planning, to analysis, design, deployment, testing, on going and

Companies are periodically inspected by the Regulated agency whenever the product or a product component (e.g. API) is sold in the

decommissioning of the system. As the ERP operators relies upon the Electronic Records created and

relevant market; each Company which produces a regulated good (e.g.

maintained by the ERP, the validation shall include the verification of the

pharmaceutical drug, medical device), one of its components (e.g.

compliance with respect to the provisions set forth by the regulations

API) or distributes it to the market is subject to an official inspection by

related to Electronic Records & Electronic Signature Management e.g.

regulatory agencies themselves or by the customers of the Company.

US 21 CFR Part 11, EU GMP Annex 11; these regulations are planned

In the last years, the number of violations due to a absence or

to be updated and a regulatory enforcement on the these provisions

incomplete validation documentation of a computerized system is rapidly

is currently applied by the Regulatory entities and it is expected to be

increasing; these violations may lead the Regulated Agency to issue an

further increased.

import ban to the Regulated Company or to prevent the customers to outsource the services to the Regulated Company. As a matter of fact, the Validation requirement holds for every Company involved in the life cycle of a regulated good. The Regulated Companies are required to verify the system reliability through the execution of the Computer Validation process, which is a process

ERP are expected to verify the provisions set forth by the 21 CFR Part 11 & EU GMP Annex 11 related to the Electronic Records & Electronic Signature Management

oriented to provide documented evidence that system “leads to the expected results”. An international recognized standard for system validation has been set forth by the Good Automated Manufacturing Practice (GAMP™)

ERP evolution The ERP offering has changed a lot during the last years. Nowadays,

Guide for Validation of Automated Systems (currently version 5) issued

bespoken products are nearly absent in the SW market and also national

by the International Society for Pharmaceutical Engineering™ (ISPE); the

products are confined in local small Companies with domestic market:

GAMP guideline describes a set of principles and procedures that help

it’s the time of complete and international products as the globalization

to ensure that pharmaceutical products have the required quality when

of Pharmaceutical market has forced the internationalization of Computer

automated systems are involved. One of the core principles of GAMP is

Systems. On the other side the Regulated Companies, after a first period

that quality cannot be tested into a batch of product but must be built

of a number of out of budget projects cost with a rate 2-3 times between

into each stage of the manufacturing process. As a result, GAMP defines

planned and actual costs, require fixed price and time frame.

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Polish industry | 23

In order to meet the expectations of their customers, the ERP SW suppliers and the System integrator have created specific Computer Systems for each industrial area (e.g. Pharmaceutical, chemical) and have tailored the project methodology to the specific needs of each area through the definition of ERP Best Practise (the so called “verticalized package”). In case the Regulated Company is expected to adapt its organization to these best practises without significant gaps, a System Integrator can typically define a fixed price and define a short time frame for the System Go Live: at this stage, a number of critical issues may arise since the System Integrator evaluates the required effort without a deep knowledge of the Company organization/process flows and Company does not usually have enough information about the product functionalities. In addition, in order to further complete the cost scenarios, the ERP System Integrators are used to propose also the support for the execution of the System Validation. This strategy may lead to jeopardize the implementation of an ERP System since the following considerations are not adequately addressed: •     the concurrent roles of the System Integrator implies a lack of independence of review: this usually leads to a clear conflict of interests as the controller and the controlled persons are the same entity

•     make a correct comparison between different ERP Computer Systems

•     it’s difficult for a Regulated Company to verify with simple demos if

•     understand the content of what is offered, in terms of functionalities

the ERP best practises are correctly included in the business model or if the System Integrator is simply re-adapting similar projects •     the System Integrators are used to propose to the Regulated Companies solutions based upon the best practises defined for the chemical industrial area since the production flows are considered as similar: this may lead to not adequately address the GMP rules and

included in the fixed price scenario •     understand if the complementary activities (but still crucial for the project success) such as training are properly correctly set or it’s a commercial proposal •     understand if internal organization is ready for the inclusion of a validated ERP

the constraints set forth by the regulations •     the ERP best practises are generally not well documented or well managed, due to the difficulty to maintain the version of add-ons and of the packages •     the implementation model proposed by the ERP System Integrators methodology let out of project all the issues (and they are the most important and tough) determined by the Company organization and

The Validation is not (only) a set of documents to be shown to inspectors, but (mostly) a cost-efficient way to implement an ERP system

the interaction with the Company Quality System •     all differences between the ERP standard package provided by the System Integrator and the Company needs must be considered as

In addition the ERP implementation triggers the following risks:

gaps and adequately addressed in terms of resources, costs and

•     the inclusion of the ERP business model which is not compatible

timeframe.

with organization of the Regulated Company: this means that the operators will maintain in parallel the usual paper information.

Risk connected with product driven project When these concerns are not adequately considered, the Regulated Company may face a risk connected with ERP System selection since it’s a tricky task to: presentation of the System Integrator

1_2010_spf_EN.indd 23

(collect data in paper, insert data in computerized system and verify the alignment between paper and system) •     an under-use of the package: fixed price and short time frame pushes

•     understand effective capability of the ERP system only through the

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System Integrators to go-live, regardless a clear, detailed and shared definition of what the System is expected to do: therefore the

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24 | Polish industry

System Integrators are used to postpone to the post go-live all the

process. The user requirements document describes the system’s

found issues or what they consider as not mandatory for the System

functional, physical, interface, performance, data, security requirements

go-live.

etc as expected by the Company management.

•     The underestimation of the impact of the validation documentation,

This document must be the result of a process mapping of the as-is

which is considered as an activity that can be executed in the post go

processes and the analysis of the to-be scenarios determined to reduce

live phase. This approach forces the Quality deputies to implement

manual controls and to optimize the processes.

a contingency plan to verify the system output which is very time consuming in terms of controls and verifications

It is a document which the System Integrator uses to communicate their understanding of the system back to the users. The completion of the User requirements document allows the

The Validation as a key driver for the ERP implementation process The above listed issues arise when the Validation target is not adequately accomplished but it is executed in a bureaucratic manner (sometimes after Go Live) with the sole purpose to have some paper to be shown to the inspectors. The Regulated Company shall acknowledge that, if properly ad-

following benefits: •     The requests for proposal can be sent to the System Integrators requiring the fulfilment of to-be requirements identified in the document. •     Different proposals from the vendors can be effectively compared based upon the level of coverage of the Requirements. •     The processes identified in the User Requirements can be used as

dressed, the Validation can become a crucial key driver for the success

the list of issues the System Integrator is required to address during

of the implementation process: the GAMP life cycle shall be considered

the demo to allow user to verify all cases

as a methodology to implement the system and not just a mere preparation of useless paper. A number of companies make the mistake to think that project is only an IT implementation (sometimes completely delegated to a System Integrator), but according to the GAMP life cycle, the project starts with

•     The User Requirement document can be used a fundamental component of the contract with the customer, allowing a shared goal of project •     The successful completion of the implementation project is a measurable event through the detailed verification of each Requirement

a controlled vendor/software selection. The difficulty is to define this requirements since the skilled

Define Requirements to select the System and the Integrator A fundamental activity addressed by GAMP is the creation of a complete User Requirement before the initiation of the system selection

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operators or IT guys do not always have the time or competences to define in detail the to-be process flows allowed by the ERP potential functionalities; in addition these resource may be not incline to the changes.

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Benefits of a Risk-based Validation

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The identification of the transaction

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ments for a strict security management which

allows the selection of the appropriate risk

has been enforced in the last years by the

control strategies for the various activities in

Regulatory Agencies.

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Validation activities must be integrated in the ERP project scheduling and must be considered as milestone for the entire project. The implementation of the Validation Life Cycle determines a number of project checkpoints which prevents from the following most frequent errors: •     A lot of documentation but not under control which does not match with the actual SW configuration •     The project documents are not coherent since they are created in different phases and not updated •     The validation team is at the mercy of System Integrator: the validation process is forced to be limited to acquire (without any review) the documentation issued by the System Integration and to execute make some non traceable formal tests. •     The system is not under control and iterative changes are implemented putting at risk the system reliability In the assessments executed so far, PQE has observed that these issues may easily lead to jeopardize the project and to increased costs and project’s duration. Through the GAMP life cycle, powered by PQE methodology ERP system went live and was fully validated in less than 3 month. The cost to maintain validated status can be higher than validation project costs: for this reason the methodology must define a validation approach, that can be easily maintained and kept up to date. Validation documents must be done in a way which enables simplifying of the Change control and permits integration of IT QA competences, avoiding useless verifications. In those cases where the validation is not properly executed, the maintenance of the validated status might imply higher costs than the implementation project.

Conclusions The implementation of an ERP system in a Regulated environ-

Producent urządzeń ze stali kwasoodpornej dla przemysłu kosmetycznego i farmaceutycznego, spożywczego i chemii gospodarczej

ment implies a wide range of additional challenges with respect to

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used as the implementation model in order to minimize either the

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impact on the company organization and the Regulatory exposure. The total effort for the implementation process can be minimized bearing in mind the following concepts: •     The Validation is not (only) a set of documents to be shown to inspectors, but (mostly) a cost-efficient way to implement an ERP system •     The Validation of an ERP is based upon the validation of the

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1_2010_spf_EN.indd 26

the other industrial areas. The validation process can and must be

processes executed through the ERP •     The Validation project starts before software selection and ends after systems retirement. •     The total cost of ownership (TCO) shall be taken into c onsideration and therefore the validation documentation must be structured for optimizing maintenance •     The Validation GAMP driven methodology must be adapted to the ERP characteristics.

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production | 27

Automating the validation of measurement methods Michał Iwaniec, Mirosław Popieluch StatSoft Polska Sp. z o.o.

Validating and monitoring the reliability of methods of measurement are very important factors in assuring the adequate quality of finished products. As with the production process, it is important to learn and understand how a measurement system works, what factors may have a significant effect on measurement results, and what uncertainty there is in the measurement of a given value.

Moreover in the case of manufacturing applications it is necessary

An interim solution might be the creation of a suitable spreadsheet to

to have knowledge about the variability of the measurements obtained

assist calculations, but this approach has several significant defects:

for the method used, to ensure that it is sufficiently small relative to

•     it is not a simple matter to implement statistical methods in

the changes which may occur in the process. Otherwise it will not be possible to detect unfavourable changes, and product quality may suffer as a result. This article presents a methodology which has

a spreadsheet; •     before adopting such a solution it is necessary to conduct a procedure to validate it, which is complex and time-consuming.

been proposed in a Polish standard and provides a full assessment of a method’s usefulness.

StatSoft, taking advantage of its many years of experience not only in the field of statistical methods, but also in the deployment of computer

The hard road from data to knowledge Unfortunately the validation process is time-consuming, and requires that the people conducting it have knowledge not only about methods

systems, has proposed a solution which will overcome the difficulties described above. The solution we supply can be successfully used for the validation of most methods of measurement.

of measurement, but also about statistics. This means that validation causes many problems of a technical and methodological nature. It is thus natural to strive to make the process work better wherever possible.

Statistics in validation, step by step In order to confirm the high quality of measurement systems, it is

In the case of the part of the validation process which involves descrip-

necessary to document their correct operation based on “hard” proof.

tion of the measurement method, the manner of preparing samples,

Such proof is provided by an experiment during which measurement

equipment, etc., efficiency may be improved by adopting an appropriate

data is collected in an appropriate way. In most cases measurement

template, but all operations must be described by hand.

data will carry uncertainty, and hence we have to evaluate the data using

The situation is different in the case of statistical assessment of

statistical methods. Statistics is a subtle field, requiring a certain amount

data from a validation experiment. Firstly, someone who has very

of invention and intuition on the part of the researcher, which means that

good knowledge of the measurement methods he or she uses may

computational technique alone is often not enough – more important

not be fluent in the statistical methods that enable assessment of that

is the right interpretation of the results. Moreover, during analysis of

method. There therefore appears the first obstacle, which relates to

validation data, it is not possible to apply different statistical methods

the determination of appropriate steps in the statistical processing

in a chaotic manner, since the results obtained in some methods often

of data. The next obstacle is the computations themselves, which if

depend on others.

performed manually will be very difficult and have a high probability of causing errors.

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Statistical methods are described below in the order which normally applies in the processing of results obtained from a validation experi-

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28 | production ment. An example will be used which allows illustration of most of the statistical methods used in method validation.

Figure 1. Analysis input data – STATISTICA spreadsheet

Figure 4. Histogram for level 3 obtained in STATISTICA

a table, but the human eye will have difficulty making a preliminary evaluation of a set of raw numbers. Hence to begin with we normally calculate statistics such as mean and standard deviation, which tell us where the “centre” of the data lies and how much it varies. Below is a table of values (Figure 2.). The statistics above are calculated for each level as a whole. Note, however, that when the measurement data was collected it was divided Figure 2. Descriptive statistics produced in STATISTICA

into groups (classes), as is indicated by the “Group ID” grouping variable in the data file. Data within a group may have been collected at different times, for example, which may have introduced additional variation

The example data comes from a determination of sulphur content in coal, and is shown in the table. The values of standards used for the respective levels are 0.7, 1.255, 2.45 and 4.07. For the purposes of the

(uncertainty) into the measurements; it is worth examining the statistics for individual groups (Figure 3.). The table shows that the values of mean and standard deviation in

example we assume that these values have been determined with an

the groups differ only slightly from each other. The question therefore

expanded uncertainty of 0.04 (expanded uncertainty is a value which

arises as to whether those differences are significant. In order to answer

tells us within what interval most of the obtained measurements lie). The

that question formally, it is necessary to perform appropriate tests, as

data is taken from [1].

described in the following section. However, before it is possible to use most of the statistical tests, it must be verified whether the data

Descriptive data analysis The first step is to make a description of the collected data. Of course, the final validation report must contain the raw data in

collected fits a normal distribution. To start with it is useful to produce a histogram – in this case four separate histograms for each level. Below is an example graph for level 3 (Figure 4.).

Figure 3. Descriptive statistics for classes, obtained in STATISTICA

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production | 29 It remains to compare the value of G with a critical value, which can be read off from appropriate tables. If G is too high, the candidate should be considered an outlier. A similar procedure is followed to discover whether the largest standard deviation in the classes deviates excessively from the others. Of course the test statistic is constructed differently; this time it is called the Cochran statistic:

The value of C calculated using this formula is compared with the corresponding critical value from the Cochran test tables. Note that when performing an outlier test it is possible to reject only one value. After rejecting that value, the test must be repeated.

Normality and outliers Notice that the presence of an outlier does more “damage” to the data Figure 5. Normality graph for level 3, obtained in STATISTICA

set the further it deviates from the others. Remember also that outliers have a large effect on normality testing: specifically, the presence of an

The histogram shows the empirical distribution of values, to

outlier will probably cause the hypothesis of normal distribution of a data

which one can fit a theoretical normal distribution density curve.

set to be rejected. This problem can often be observed on a normality

This gives a general view of how well the data set fits a normal

graph, which makes it possible to assess graphically the similarity of

distribution. It should be noted that in the case of a small quantity of

a set to a normal distribution.

data, conclusions drawn as to its normality will often be mistaken. A much better approach is to use a normality graph which is so

In graphical assessment of data normality, and also in the perfor-

created that, for normal data, the relationship between the data and

mance of numerical tests, the quantity of data is significant. The fewer

the expected normality is linear. A normality graph for the data from

elements in the data set, the harder it is to assess normality by graphical

the histogram is shown below.

means and at the same time look for outliers. The less data there is, the

The relationship shown below can be seen to be linear, and hence it can be considered that normality has been positively verified. The

more useful are numerical tests for normality such as the Shapiro-Wilk (S-W) test.

validation report should also contain a “numerical” test verifying normality, such as the Shapiro-Wilk test.

Consider the example shown in Figure 6, where the first graph shows a small data set with close to normal distribution. The second is based

Outliers

on a larger set of data, where one outlier was identified (the point in the

Tests which detect outliers in data sets are in some way connected

green circle). In the first case the test probability p for the S-W test is

with the normal distribution; when seeking outliers it is necessary to take

0.48, while in the second it is close to 0. This means that the data in the

account of normality, and when examining normality it is necessary to

left-hand graph displays similarity to a normal distribution (p > 0.05),

take account of outliers. The tests proposed below are most appropriate

while that in the right-hand graph does not (p < 0.05, and we observe an

for normally distributed data in which an outlying value has occurred. If

outlying value).

the data is expected to have a non-normal distribution, these tests may lead to erroneous conclusions.

Therefore, before proceeding to further analysis of the data set, it

Using the example data, we can assess whether there are outliers

is necessary to examine the outlier. If it was not a data entry error, that

among the means and standard deviations in the classes. In order to

value should be excluded from the set, since it is probably the result of

check whether a data set contains an outlier with respect to mean value,

a gross error and would significantly upset subsequent analysis.

we must first find a candidate, namely the value most distant from the overall mean. Next we take the absolute value of the difference between the mean and the candidate value, and divide by the standard deviation. This gives what is called the Grubbs statistic:

Precision of a measurement method. Assessment of repeatability and reproducibility Up to now we have been discussing the preliminary analysis of data, which on the one hand helps to better understand the data, and on the other enables rejection of suspicious values which might falsify the computations. After checking the normality of the data and rejecting

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30 | production

Figure 6. Examples of normality graphs of different-sized data sets

any outliers, we can assess the most critical thing for a measurement system, namely its variability. The precision of an analytical method is one of the most important parameters characterizing a method of measurement. This is a general concept, describing the variability of the results of repeated tests, and the need to use it results from the impossibility of avoiding various types of error when performing analyses. The concept of variability (sigma) in statistics is one that requires more detailed discussion. In the simplest case, for a data set we can calculate its mean and standard deviation. The mean tells us where the middle (centre) of the data most likely lies; however it is more difficult to understand what information is conveyed by the standard deviation, which is a measure of the variability of the data set. The standard deviation informs us of the average distance of a data point from the mean value. In the case of measurement data, the concept of standard deviation should be considered in relation to a distribution of data which is similar to a normal distribution. By adding and subtracting the standard deviation from the mean value, we obtain a range within which the

Figure 7. Normal distribution density curve

value of a measurement may lie with a certain probability. For example, within a distance of one standard deviation from the mean we can find

a standard value and that the measurement is repeated several times

approximately three-quarters of all measurements, while at a distance

by a laboratory technician in identical measurement conditions, which

of three standard deviations from the mean we can find 99.73% of

include:

measurements, i.e. “almost all” of them. The distribution of probabilities

•     the same measurement procedure;

of the occurrence of measurements within a given range is naturally

•     the same measuring instrument;

related to the normal distribution density curve, and is shown in Figure 7.

•     the same place; and •     repetition at short time intervals.

We now go on to the heart of the matter, namely calculation of the variability for a measurement system, which we use to obtain the

A measure of variability obtained on the basis of these several

results of analyses. It turns out that from the overall observed indicator

measurements, e.g. the standard deviation (s1), tells us how well, in constant

of variability we can separate out certain of its components, such as

conditions, we are able to repeat the measurement – this is a measure of

repeatability and reproducibility. These terms may be understood

repeatability. Next another technician measures the same standard several

differently depending on the context in which they are used, but we will

times, and again we can obtain an estimate of repeatability (s2). We can

attempt here to explain their meaning in general terms.

now compute the repeatability for the measurement system, which will be the sum of variance obtained by the two technicians: xxx . The resulting

In order to separate these two components of variability, the data must be collected in an appropriate way. Imagine that we are measuring

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value is a measure of variability which reflects the best (smallest) variability of the measurement system. However it may be worse, i.e. resulting from

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production | 31 reproduction of the result of the measurement by different operators in the

composed of correctness and precision. Correctness is related to

same laboratory using different apparatus, over a longer time interval, i.e.

the agreement between the arithmetic mean of a large number of

determined in conditions of reproducibility. Conditions of reproducibility also

single test results and the true value or adopted reference value,

cover situations where the measurement is made at different laboratories.

while precision is a measure of the agreement between test results.

Then the procedure is slightly more complex computationally, and is

Precision is composed of repeatability and reproducibility, as

described in detail on page 25 of the PN-ISO 5725-2:2002 standard. It may

mentioned above. In order to assess accuracy fully, we must also

turn out (and this would be best) that the reproducibility was not significant,

determine correctness. Correctness can be referred to when it makes

or more precisely was not significantly greater than the repeatability. This

sense to speak of a true value for the quantity being measured.

would mean that the quality of the measurement does not depend on which

Unfortunately the true (real) value is usually unknown. In many cases

laboratory technician performs it.

it can be determined using a standard, a certified reference material

We have somehow reached the problem of testing the significance

(CRM) or reference material (RM) prepared with an exactness

of differences between values of variability obtained from different data

adequate for the method in question. When a CRM is used (with

sets. Imagine a situation where we want to compare two methods of

a known content of the analysed substance, µ), the accuracy of the

measurement. It is then necessary to make a parallel determination of the

method is determined by performing an analysis with six repetitions,

analysed substance using the tested method and using another method

then taking the mean x and standard deviation s of the results. If the

regarded as a reference, giving reliable and precise results. A suitable

mean is within the range µ-2s<x<µ+2s, this means that the method in

CRM or RM standard is therefore prepared, and a number of repetitions

question is accurate, and its correctness and precision are satis-

of the measurement are made for each method (the number being

factory. When an RM is used, 10 repetitions are performed and the

appropriate to the material used). It can be verified whether the variability

mean x and standard deviation s are computed. Based on the results,

of the results differs significantly, using an easily computed statistical

using the t-Student statistic, the value of t is calculated and then

test based on the

χ

2

distribution.

compared with the critical value read off from tables for the specified number of degrees of freedom and expected level of confidence. If

Correctness of a measurement method In assessing a method of measurement, we speak of its accuracy. According to the ISO 5725 international standard, accuracy is

the computed value of the statistic t < t crit , this means that the method is accurate and there is no significant difference between the mean value and the true value for the content of analysed substance in

Figure 8. Control chart obtained in STATISTICA

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32 | production the difference obtained is accidental, or whether it should concern us. Hence we create a test statistic, which will have an approximately normal distribution. The greater the difference between the standard value and the mean measured value, the worse it is, so the modulus of the difference will be in the numerator of the formula. On the other hand, the larger is σ, the harder it is to determine whether the difference is significant, as it is “lost” in the variability. Hence the value σ appears in the denominator of our test statistic, which finally takes the form:

The value of the statistic N will always be different from zero, so the question remains: what must the value be in order for the difference to be called too large to be accidental? We will answer this question not directly, but by way of a probability for a normal distribution, corresponding to the value of N. Similarly to the case of the Shapiro-Wilk test, until the probability value is greater than 0.05 there are no grounds to state that the difference is statistically significant. However if we show with high probability that the difference is significant, then it is worth considering a permanent adjustment to the measurements being performed.

Linearity In quantitative methods, a particularly important parameter describing the analytical method is linearity. the reference material. Apart from the techniques described, the

This denotes the ability of the method to obtain test results directly

accuracy of a method can also be determined by way of comparative

(or indirectly following appropriate mathematical transformations)

tests between laboratories. It should be noted that this is a costly and

proportional to the analysed concentration. Together with linearity

rarely applied procedure. However for a laboratory, participation in

there should be determined the working range of the analytical me-

interlaboratory studies, particularly for methods where it is difficult

thod, namely the interval within which the method gives results with

to obtain a suitable standard or certified material, may provide much

acceptable precision, accuracy and linearity. Linearity is determined

valuable information on the measurement method and allow the

most simply by successive dilutions of the standard substance,

laboratory to assess its own proficiency in that area.

performed so that they cover 40–100% of the expected working

So how do we assess whether a measurement method is

range. It is most advantageous to make 6–10 solutions (successive

sufficiently correct? Most generally, it is necessary to perform

dilutions of the standard) covering the expected working range,

several measurements of a known value (standard) and calculate the

with an additional measurement on a blind sample. Each solution

difference between the mean measured value and the standard value.

should be analysed at least three time, the result for a particular

Clearly that difference will usually be different from zero. However,

concentration being the arithmetic mean of all repetitions. Next,

consider that we are dealing simultaneously with the variability of

after the results have been obtained and analysed, taking account of

measurement values, which has been previously evaluated as the

errors resulting from the dilution procedure, a graph is plotted. This

precision, namely the sum of repeatability and reproducibility (we

verifies the correlations between the expected concentrations and

denote this by σ). Hence if we have now obtained a difference, say

the concentration values obtained for the samples (with expected

–0.13, then if we again perform a number of measurements of that

concentration on the x-axis and obtained values on the y-axis).

standard, we may obtain a difference of, say, 0.03. This results

The points obtained should form a straight line: y=ax+b. Another

from the fact that σ (the variability) is greater than zero. We should

very important step is the analysis of the resulting line and the

therefore perform a statistical test to answer the question of whether

arrangement of points. If the points have a linear arrangement, as is

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production | 33 confirmed by Pearson’s linear correlation coefficient r 2 – the closer to unity (best 0.97–1.00), the better the proportionality of obtained results to the expected concentrations – then we can conclude that the method is linear over the analysed range. Problems arise when points are observed to deviate from a linear arrangement, which may indicate errors in dilution or absence of repeatability for one concentration, if single points are observed to lie away from the graph. Discussion of this topic can be found in Kalibracja liniowa w zagadnieniu walidacji metod pomiarowych (“Linear Calibration in the Validation of Measurement Methods”) in [5].

Stability The quality of measurement processes, as in the case of production processes, is not frozen within those processes, but must be constantly monitored. It can be monitored within the laboratory, using Shewhart control charts, or (and) by regular participation in proficiency testing. Shewhart charts or modifications thereof can be used for monitoring correctness and precision on one level, or it is also possible to monitor the quality of the calibration function itself.

Figure 9. Example of an automatically generated report

The statistiCa measurement method validation system (www. StatSoft.pl) provides the ability to automatically create reports based on pre-defined MS Word document templates, depending on the structure

In both cases it is necessary to make regular measurements of

of the input data. What the user has to do is enter data in an appropriate

objects of known properties, and after performing the necessary

format on a statistiCa spreadsheet, select variables for analysis, and

calculation, place the results on the control chart(s). A result is

press a button. The program will create a ready-to-print report, which

considered stable if it lies within previously set control limits. An

can be further customized as required.

example of a control chart for average value and displacement is shown in Figure 8.

It should be noted that the report below is complete, i.e. apart from the results of the analyses it also contains (where this is possible and appropriate) the formulae used in the computations, and in the case

The way in which the control limits are determined depends on the type of chart, and will therefore not be addressed in this article. More

of statistical tests the conclusions are automatically recorded, which facilitates interpretation of the entire analysis.

information on that subject can be found in [5]. When considering computer-based solutions, it would be hard not

Automation

to mention the validation of the computer system itself, particularly in

As discussed above, carrying out validation of a measurement method is often time-consuming and expensive. The time required for validation depends on the time needed to describe the method, the quantity and type of measurements (determinations) that need to

relation to [4]. StatSoft can carry out validation of the correct functioning of a computer system during its deployment. Additional information concerning the above solution can be found in [6].

be performed, and on the proficiency of the person responsible for validation in the statistical techniques used to process the collected data. When it is often necessary to validate dozens of measurement methods, improvement of the efficiency of any of these stages will bring a significant profit. The method description and performance of the measurements usually leave little room for manoeuvre, by contrast

Bibliography 1. LAB – Laboratoria, Aparatura, Badania, Teresa Topolnicka, Michał Iwaniec, “Automatyczna walidacja metod badawczych i pomiarowych cz. 1”, year 13, no. 6.

automated. Of course, statistical knowledge on the part of the people

2. PN-ISO 5725-2:2002, Accuracy (correctness and precision) of measurement methods and measurement results. Part 2: Basic method of determining repeatability and reproducibility of a standard measurement method, December 2002.

involved in validation is an essential factor, but nonetheless appropriate

3. PN-ISO 11095, Linear calibration using reference materials, August 2001.

with the statistical processing of data, which can be systematized and

systematization of that knowledge can produce significant improvement to the quality of the analyses carried out. The goal of the system created by StatSoft was primarily to propose appropriate analysis templates which will make it possible to systematize the statistics and automate the analyses. This approach has made it possible to reconcile two

4. Wyrażanie niepewności pomiaru, Przewodnik, Główny Urząd Miar (Central Office of Measures), 1999. 5. Biuletyn Informacyjny Klubu POLLAB, 1/50/2008, Wytyczne do zarządzania kom pu terami i oprogramowaniem w laboratoriach w odniesieniu do normy ISO/IEC 17025: 2005, EUROLAB TR 2/2006.

conflicting aims: to perform the relevant set of analyses without error and

6. StatSoft Poland Internet library: www.statsoft.pl/czytelnia/czytelnia.html.

in a short time.

7. http://www.statsoft.pl/industries/Laboratorium.htm.

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34 | production

Realization of complex projects in pharmaceutical industry Antoni Skolik I.E.S. INTERNATIONAL POLSKA

In last few years many polish pharmaceutical companies have realized complex investment projects within “turn key” formula. The projects have had different technical scopes, different budgets and have concerned different process technologies, but have had one in common: complexity, what results in the necessity of coordinated activities of contractors of different specialties on small area, often simultaneous, or at least limited by very short time intervals devoted for specific branches.

As all the experienced investors know, this problem, disregarded nearly

of the investment under their wing including also specialist supplies and

always at the beginning of the project, turns out to be most frequently

labours, about which the construction companies don’t know a lot and

the basic obstacle in punctual investment finishing and its bringing into

which they must subcontract anyway. Such a situation give rise to lot of

operation.

dangers and often makes up favourable circumstances for searching by

The same experienced investors encounter proposals, most frequently of big construction companies, of taking of the entire scope

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the contractor of cost-sparing solutions, which works at the investor’s disadvantage.

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35

Consortium HVAC48

Consortium HVAC56

Consortium walls

There is a help to remedy such situation. During last 2 years in Polish

operation allows for discretional Consortium configuration and adjustment

pharmaceutical companies several considerable investments have been

of its composition to the needs of certain project, its scope and the

realized in the framework of co-operation within Consortium model.

investor’s requirements level. Good Consortium is an equivalent of a sport

A Consortium constitutes a voluntary association of few, tight co-opera-

team of the best possible membership, tailored for the specific task. In the

ting design, supply and executive companies, having an aim to realize some

situation, when certain investment task doesn’t foresee deliveries or works

complex project. The Consortium is created for the time needed for invest-

in a Consortium branch, due to the flexibility of its configuration, it simply

ment realization and its substantial composition is adjusted to the concrete

doesn’t generate the costs in this speciality and limits its scope of activity

needs and supply of supplies and works connected with a certain project.

to the investor’s expectations. The consortium thanks to lack of limits, has

The principle of Consortium functioning is very simple:

the possibility and uses the knowledge resources of the best European and

•     Investor’s offer inquiry (URS) is analyzed by a Consortium project group

polish design companies, what has considerable innovative significance,

and is transcribed for separate deliveries and services groups according

especially during designing phases at the level of conceptual and technical

to the speciality (design activity, construction works, HVAC, pipes

project. Depending on the state of Investor’s preparing, the Consortium

installations, electrical installations, automatics, pharmaceutical walls,

begins its work from requirements (URS) verification or from qualification

validation package, co-ordination of the entirety of the task).

at DQ level (if any project documentation exists already), or, what happens

•     The companies associated in the Consortium prepare offers according to their speciality considering at this operation the general realization plan and the assumed schedule. •     After collection of this co-ordinated offers, the Consortium passes on a

more seldom, it joins the investment realization (if the detailed, approved by the investor engineering documentation exists). The above described approach to the range of problems connected with the realization of complex, multi-branches projects, bring remarkable results

complete package, what is important – with no financial overheads, to

and in investors’ opinions, who know how to optimise the expenditures,

the investor.

it can be used as a very good tool for investment costs’ reduction while maintaining the highest quality and realization time safety.

The Consortium works flexibly, it means it considers all the additional

Expressing it in a shortest possible way, use of Consortium model

conditions imposed by the investor, such as investor deliveries, inclusion

means that the investment will be realized quicker, cheaper and better

into the Consortium of the companies known to the customer and which

than any other way.

participation is required by the investor, co-operation with the investor’s project groups, executive groups and validation groups. Such a model of co-

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I sincerely recommend this model to the polish investors planning the realization of projects in the nearest time.

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36 | production

Industrial design registration for protecting product appearance Ms. Joanna Pilka PATPOL Patent and Design Department

The external appearance of a product is an important element of promotion and strategy of creating the image of a company as well as the products that it is manufacturing. An interesting appearance increases the value of the product, raises its attractiveness and attracts the customers’ attention, which allows to gain the advantage over competition on the market.

For this reason, designing the appearance of a product that will make

Example of a two-dimensional deign:

the said product noticeable and easy to remember is a very important

•     graphics

element during creation of the product image strategy. Since designing such product appearance involves a lot of effort and frequently considerable expenses, it is worth remembering to secure company’s interest

RCD 000897210-0001

claiming the product appearance in order to prevent copying or imitation

source: www.oami.europa.eu

of the ideas. The product appearance can be protected by a registration The appearance of a product, in order to be validly protected by the

as an industrial design.

registration of an industrial design, must be new and have individual

What is an industrial design?

character. This means that a registered industrial design must be

An industrial design shall be understood as the appearance of the

different and make a different impression on the informed user in relation

whole or part of the product resulting from the features of, in particular,

to the designs previously registered or made available to the public on a

the lines, colors, shape, texture or materials of the product and its

world scale. A very important issue for maintaining the possibility of industrial

ornamentation. Industrial designs can be both three- and two-dimensional. Three-

design registration is keeping it secret before filing the application.

dimensional are the designs relating to the original shape of the product,

An industrial design which is made available to the public, e.g. by

while in case of two-dimensional designs the essential features are for

presenting on fairs, or placing in catalogue or advertising leaflet, cannot

example ornamentation, lines of colors.

be regarded as new. Although the law in some countries (e.g. Poland or

Example of a three-dimensional design:

EU) provides the so called “grace period” allowing to make the design

•     packaging

public up to 12 months before filing the application without the loss of novelty, it should be kept in mind that not in all countries such grace period exists. Therefore, it is advisable not to disclose the design before filing the application. The companies from the pharmaceutical sector protect industrial designs relating to the packaging, labels, logos, pills, blisters, phials, RCD 000853908-0003 source: www.oami.europa.eu

capsules, and many other types of products. A few examples of industrial designs registered in relation to pharmaceutical products have been presented below.

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•     packaging

The holder of a registered industrial design may prevent: •     any third party from using an industrial design, for profit or professional purposes in the territory of the country where the protection was granted, •     making, offering, putting on the market, importing, exporting or using a product in which the design is incorporated or to which it is applied, or stocking such a product for those purposes. RCD 000848668-0001 source: www.oami.europa.eu

A registered industrial design constitutes an important non-material value of the company and an asset increasing the company’s value.

•     pill

Moreover, a registered industrial design can be the subject of sale or license, and by that it may be an additional source of income for the company. The holder of an industrial design registration can grant a third person a license to exploit the industrial design, on the previously RCD 000124284-0001 source: www.oami.europa.eu

mutually agreed conditions, which are defined in details in the license agreement. The license agreement contains the provisions defining the territory on which a licensee can exploit the design or the period of time for which the license is granted.

•      pregnancy test

Disadvantages of industrial design non-registration The entrepreneur who does not protect the appearance of the product RCD 000498761-0003 Source: www.oami.europa.eu

by the registration of an industrial design risks the unauthorized selling by the competitor of the products looking identically or remarkably similar to the company’s product, which can mislead the consumers as

Advantages of industrial designs registration By obtaining the right in registration for an industrial design the

to the origin of the product and reduce the company’s profit. Moreover, if the competitors’ products are of a bad quality, it can damage the company’s reputation.

company acquires the exclusive right to use the design for profit or professional purposes in the territory of the country where the

If an industrial design has not been registered, legal actions against

protection was granted. An industrial design registration gives the

the competitor selling identical or remarkably similar products are much

holder the right to take legal actions against the entity infringing his

more complicated and expensive than those that can be taken when

right. In practice it is the right to combat copying or imitating the

the appearance of the product is protected by the industrial design

design.

registration.

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38 | production

Registration of an industrial design in Poland In Poland one application may contain up to 10 forms of the industrial design. The forms of the design are the designs which have the same essential features. The Polish Patent Office registers an industrial design after conducting a formal examination and founding that the application was filed correctly. The industrial design is registered after the payment of the publication and first protection fees. The procedure at the Polish Patent Office currently lasts about 3 months from the filing date till registration. Reasons for protecting designs in the European Union

The Polish Patent Office may also issue a decision on refusal of registration of an industrial design, if it finds that the appearance of the product, or its part evidently lacks novelty or individual character.

How to register an industrial design? In order to obtain protection for an industrial design the application

The industrial designs registered by the Polish Patent Office are pu-

should be field with the Office appropriate for the territory on which the

blished together with the illustration presenting them in the Patent Office

design is to be protected. The protection resulting from the industrial

Information, whilethe applicant receives the registration certificate.

design registration is limited to the particular territory and it is usually the territory of the particular country or region.

The right in registration is granted for 25 years from the filing date and is divided into 5-year periods for which the successive fees should

The company has a possibility to obtain the protection by registering

be paid.

the design under the following systems: •     national – territory of the specific country (e.g. Poland);

Examples of the industrial design registered by the Polish Patent

•     regional –community design – UE territory;

Office:

•     international – Hague Agreement Contracting Countries territory.

•     capsule

The protection for an industrial design in Poland can be obtained by

Rp-7560

national, regional and international system. If the industrial design is to

source: www.uprp.pl

be solely protected on the territory of Poland, it should be registered in the Polish Patent Office. Optionally, the equivalent protection on the ter-

•     packaging

ritory of Poland can be obtained by registration through the regional and international systems. In the case of regional and international systems, the protection on the territory of other countries can be obtained as well,

Rp-14814

by this one application.

source: www.uprp.pl

The time required to obtain the protection is different in each country, as it depends on the course of the formal and substantive examination, which is conducted in order to estimate whether the application contains any essential deficiencies or defects.

Registration of an industrial design abroad The right in registration granted by the Polish Patent Office protects this design in the territory of Poland only. In order to obtain

In the majority of countries the registration of the industrial design is

the protection for an industrial design outside Poland, in the country

made after carrying out only a formal examination, i.e. it is not examined

in which we plan to market a product, an application for registration

whether the design is new and have individual character. Therefore, it

of an industrial design should be field with the national office of

is advisable to conduct a search before filing the application in order

that country, or the protection should be obtained via regional or

to check whether the design is new and there is no conflict with earlier

international system.

designs. Such pre-filing search is usually conducted by checking the

Obtaining protection for an industrial design in specific countries is

online databases of the appropriate offices, as well as by the market

fundamental in order to counteract in case of potential unfair use of the

research.

design by competition. The cost of registering an industrial design abro-

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production | 39

ad is an investment in the protection of the companyâ&#x20AC;&#x2122;s interest in case of potential court disputes for unfair use of the design by competitors.

The application can be filed in one of the EU official languages, e.g. in Polish. However, if the application has not been field in one of the working languages of OHIM, which are English, German, French,

The protection for an industrial design can be obtained through one of the above presented three systems, i.e. national, regional or

Spanish or Italian, such language should be indicated in the application as the second language for the procedural purposes.

international. The use of regional system enables to file one application, on the

The application can be made traditionally on paper, or electronically

basis of which the protection for the territory of all member states is

by means of the appropriate application form available on the website

granted. The regional office where such application giving the protection

www.oami.europa.eu

on the territory of the whole EU, including Poland can be field, is the Office for Harmonization of Internal Markets (OHIM) in Alicante (Spain).

Unlike the regulations in Poland, in the case of a community design,

The international system also enables to file one application, on the

one application may cover more than one design. However, a special fee

basis of which the protection for the territory of countries designated in

is collected for each additional design.

the application is granted. In such international application Poland can also be designated. The office where the international application can be

The application procedure before OHIM, similarly to the procedure

field is the World Intellectual Property Organization (WIPO) in Geneva

before the Polish Patent Office is a registration procedure, which means

(Switzerland).

that only formal requirements are examined. Novelty and individual character of the new design application are not examined by the Office.

Registration of an industrial design in particular countries In the case of a national system an application is filed with the

The length of the application procedure is usually a few weeks. If all formal requirements are fulfilled, the Office registers the design

appropriate office in the particular country. Since such application

and the information about registration is published in the Community

is usually filed in the official language of that country, and moreover

Design Bulletin.

the required official fees need to be paid, it is advisable and in most countries obligatory to act by the local representative having the appropriate authorization.

The protection of the community design is granted for 25 years from the filing date and is divided into the periods of 5 years, for which successive fees should be paid. The application fee is the fee for the first

Registration of an industrial design on the EU territory

period of protection at the same time.

The community design application should be filed directly with OHIM, or in the case of the applicant from the EU territory - via the national office of the applicant.

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40 | production Examples of the community designs registered with OHIM:

more than one design, however the amount of designs included in the

•    capsule

application cannot exceed 100 in this case. The international application is examined by WIPO with respect to the formal requirements, i.e. novelty and individual character are not RCD 000029855-0001 Source: www.oami.europa.eu

examined by the Office. If all formal requirements are fulfilled, WIPO registers the design and the information on registration is published in the International Designs Bulletin. In each designated country the protection can be granted for different

•    blister

period of time. The length of the protection periods depends on the national law of each country. The periods of protection vary between 10 and 50 years, depending on the country in question. Examples of the registered international industrial designs: •    packaging

RCD 000785746-0002 Source: www.oami.europa.eu

•    Capsule DM/052764 Source: www.wipo.int RCD 000086954-0002 Source: www.oami.europa.eu

•    pill

•    packaging

DM/058532 Source: www.oami.europa.eu

As it can be seen from the presented examples, the industrial designs registered via the above described three systems do not differ RCD 000173885-0004 Source: www.oami.europa.eu

between each other in principle. Only the procedures of obtaining the protection are different. When making a decision on the system of obtaining protection, the needs of a particular company and the markets on which said company intends to sell its products, should be taken into consideration.

International registration of an industrial design The application for an international registration of an industrial

The presented systems, by which the protection of the product appearance can be obtained via the registration of the industrial designs, give the company many possibilities of securing the rights to the

design can be filed directly with WIPO, or via the national office of the

original product appearance. However, it should be kept in mind that

Applicant’s country.

such registration itself does not always constitute a sufficient protection

The international application for an industrial design registration

against unfair competition. Each company protecting the appearance

should be field in English or French, and it can be made traditionally

of its products by the industrial design registration should constantly

on paper, or electronically by filling the appropriate application form

monitor the market and react to the infringement of its exclusive rights,

available on the WIPO website: www.wipo.int. The countries, in which

remembering that the lack of reaction is often regarded as a silent

protection for the industrial design is sought, should be indicated in the

consent. If infringement occurs, claiming one’s rights resulting from

application.

industrial design registration is a necessity and must be a part of

Similarly to the community designs, in the case of an international registration of industrial designs one single application may cover

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1_2010_spf_EN.indd 40

company’s activity, which constitutes a conscious policy of protecting one’s own achievements in the field of industrial property.

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42 | production

Water Quality in the Pharmaceutical Industry

Marian Granops University of Technology and Life Sciences in Bydgoszcz

Water is the basic substratum of all life processes and has an enormous influence on the conditions of a human being’s life. It constitutes around 65% of our mass. The loss of a mere 10% causes serious disorders, and depriving the body of 20% of its water may lead to death. The human body can survive without food for around a month, but only 8 days without food. Water cannot be replaced by any other substance, which is why its presence is so important.

Various mineral components vital for proper development are supplied

water taken from underground contains significant amounts of iron,

to the body along with water, but unfortunately harmful substances may

manganese and ammonium ion.

also enter the body by the same route. Certain substances present in water, in admissible concentrations

Iron and manganese no longer constitute a major technological problem with regard to removing them from water. They can be removed

of course, may be harmful for particularly sensitive people, or the sick.

by aeration and then filtration through a sand or catalytic bed. Not all

Substances also appear in water which may have an adverse effect on

water can be treated in this way, though. Whether or not water can be

health after a long period of ingestion. These include toxic substances

treated depends on the form in which the iron and manganese compo-

with properties which cause them to accumulate in the body, as well as

unds occur, and from the (pH) reaction of the water and the compounds

compounds of a mutagenic and carcinogenic nature.

present in it with properties which reduce e.g. hydrogen sulphide. Then

Any substances may have adverse effects on health if they occur in quantities greater than those considered acceptable. According to suggestions by the health service, long-term exposure of the human

it is necessary to correct the water’s reaction and use an oxidant, which assists the process. Underground water contaminated with humus substances is

body to low concentrations of hazardous impurities probably causes

characterised by high colouring, oxygen consumption and acid reaction.

chronic illnesses, and may also affect genetic mutations.

Humus substances such as multi-particle organic compounds are the

In spite of the aforementioned dangers, drinking water is considered to be a secondary source of health hazards compared to food and air. Water quality in hospitals and the pharmaceutical industry constitute a separate problem. In these establishments, water from public distribution networks should also be subjected to further cleansing and treatment. The truth is that in establishing the highest admissible concentra-

precursors of trihalomethanes (THM). Coloured water should not be chlorinated without first removing the humus compounds. A coagulation process is used for this purpose, e.g. with clay salts or by filtering the water on active carbon. Apart from iron and manganese, common impurities are nitrogen compounds, including ammonia nitrogen and nitrates. Until recently,

tions of hazardous substances, it is the admissible limits of health risks

ammonia was removed by chlorinating the water, but due to the

which are being set (these can sometimes be influenced by the economic

deterioration of the water’s organoleptic qualities and the appearance

factors of a given country, and technical possibilities).

of chloric derivatives of a mutagenic nature, this process is being

This is the sad reality, since our health is our greatest treasure, one which we cannot buy. This is worth remembering, although we often only become aware of it when we take ill.

abandoned. A process of nitrification and ion exchange are often applied (easy to automate). Nitrates are removed from water intended for human consumption by ion exchange, using membranous processes or by biological

Methods of treating drinking water.

methods. The most commonly used methods are the first two. In the

Treatment of underground water

membranous process, the reverse osmosis (RO) method has found wide

Underground water of the highest quality may sometimes be used

application. 95 – 98% of substances dissolved in water can be removed

for consumption and economic needs without treatment. However, most

on a semi-permeable membrane. Water prepared in such a way should

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production | 43

not be recommended for drinking, however, as it lacks the calcium and magnesium salts vital for the human body.

The assimilation of Polish norms with those in force in the European Union (EU) has meant that sporadic cases are still recorded of excessive manganese compounds in water (norm 0.05 g Mn/m3) and of ammo-

Treatment of surface water

nium ions (norm 0.5 g NH4/m3).

Environmental degradation has and still does influence the poor quality of surface waters, which creates difficulties for treating water for consumer requirements. The most commonly used treatment processes are: infiltration, coagulation with filtration and disinfection. Infiltration - the following indexes are improved in the infiltration

Methods of treating water for pharmaceutical purposes If hospitals or pharmaceutical plants have their own water sources, they should first of all treat the water according to the methods described

process: turbidity, colour, iron, manganese and other metals, chemical

above, and then in the next stage prepare it for their pharmaceutical

oxygen demand (COD), smell, taste, nitrogen compounds, micro and

requirements.

macro-organisms are also removed to a large degree, as are compounds

People most often use pharmaceutical water indirectly by taking me-

which are subject to natural oxidation and coagulation. Infiltration

dicine, or in a more general way during dialysis. In both these cases, any

also removes a major amount of the THM precursors of natural origin,

impurities which may appear in the water may enter the blood circulation

in other words those formed during algal bloom. A disadvantage of

and interfere with the workings of the human body. Either way, a chemist

infiltration is its low efficiency.

should have the most chemically and bacteriologically pure raw material

Coagulation - the coagulation process involves removing colloid particles, suspensions, bacteria, living organisms and heavy metals from water. In this process, colloidal impurities in water pass from a soliquid

possible when producing medicines. I think that the existent legislation and water processing technology create such a possibility. In accordance with art. 25 of the Pharmaceuticals Law Act of Sep-

state to a gelatinous state in the form of flocculent, easily settling

tember 6th 2001 (i.e. Journal of Laws No. 45, item 271 from 2008) the

suspensions which can be removed by sedimentation and filtration.

basic quality requirements and testing methods for medicinal products

Coagulation is based on mixing water well with such coagulants as

and their packaging and raw materials in Poland are defined by European

ferric chloride (FeCl3) or aluminium sulphate – Al2(SO4)3 x 18 H2O and

Pharmacopoeia no. 6 (from 01.01.2010 with supplement 6.6).

waiting for floccules to form. Recently, initially hydrolysed coagulants have been in general use, which differ from those mentioned in that they contain hydroxyl groups which cause their increased alkalinity. Disinfection - the aim of disinfection is to render pathogenic living and sporulating organisms harmless and prevent their secondary

European Pharmacopoeia distinguishes three types of water: •     Purified Water – PW This is water used in the production of medicinal products which are not

development in the water-pipe network. Disinfection may be carried

subject to sterility and pyrogen requirements, it is water for direct usage.

out physically or chemically. The general practice in water networks

•     Water for Injections – WFI

is to use the chemical methods of chlorination with chlorine and its

This is water used as a solvent in the process of producing medicines

compounds, and ozonisation, and of the physical methods ultraviolet

for parenteral application, and of dissolving and diluting medicines for

(UV) rays are applied. Products harmful to health may be formed during

parenteral application, the water is produced by distillation.

chlorination, such as: chloramines, chlorophenols, THMs, halogen

•     Highly Purified Water – HPW

acetic acids, formaldehyde and acetic aldehyde. Chlorine dioxide (ClO2), which is a stronger oxidant than chlorine, can be a good disinfecting

This is water used in manufacturing medicinal products which

agent. Its application may result in the formation of harmful by-products

require the use of water of a high chemical and biological quality, except

in the water, namely chlorites and chlorates. The disinfecting agent in

in cases where water for injections is necessary. This is water of the

ozonisation is ozone, which is a very strong oxidiser and disinfectant,

same quality as water for injections, but obtained using methods other

considerably better than chlorine, and similar to chlorine dioxide in that

than distillation.

it does not react with ammonia nitrogen. A disadvantage of ozonisation

The quality of the types of water mentioned above is shown in table 1.

is that its action is short-lived (decomposition), which creates a danger

The term HPW (highly purified water), introduced in European

of secondary development of bacteria in the water pipe network. Because

Pharmacopoeia in 2002, has made it possible to produce it simultane-

of this, water in expansive networks is additionally disinfected with

ously using processes other than distillation, while retaining the same

chlorine compounds.

requirements as for WFI. Development of water treatment technology and

The water treatment methods outlined above should ensure that

the increasing demands of the pharmaceutical industry, both in terms of

water meets the requirements stipulated in the decree of the Health

the amounts water needed and its quality, has meant that HPW is now

Ministry of March 29th 2007 concerning the quality of water intended

generally produced.

for human consumption (Journal of Laws No. 61, item 417). Water with

There are many factors which affect the choice of choice of

the parameters defined in this decree should be the raw material for

equipment for water treatment stations (WTS). The most important of

producing water for pharmaceutical purposes.

these are: the composition of the raw water, its source (spring, deep or

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44 | production Parameters

Determination

Qualitative requirements of water PW

Organic substances as total organic carbons (TOC) Conductivity

WFI

HPW

ppm C

0.5

0.5

0.5

200C µs/cm

≤4.3

≤1.1

≤1.1

Dry residue

max %

-

0.001

0.001

Nitrates (NO3)

max ppm

≤0.2

≤0.2

≤0.2

Heavy metals

max ppm as Pb

≤0.1

≤0.1

≤0.1

CFU/100 ml

≤100

≤10

≤10

EU/ml

-

≤0.25

≤0.25

Total number of bacterial colonies Endotoxins

Table 1. Overview of water quality in the basic parameters defined in monographs of European Pharmacopoeia Note: ppm= mg/l, CFU – total amount of bacteria, EU = IU unit of toxin measurement

surface water), any seasonal variations in its composition. The quality

problems. A better principle is to design two technological pipelines

and quantity of the water to be produced in m3/h and m3/d and the

rather than one pipeline with double output, as in the event of any fault

hourly water demand index. This is often at level 3. Whether the source

or periodic inspection of one pipeline the other still produces water, and

of water supplying the WTS may change while it is operating. The

production is thus only limited instead of halted.

information above makes it possible to adapt the system of installations

Here I present the available and most commonly used technology for

in the WTS to specific situations.

treating WP and HPW for pharmaceutical needs (source: BWT).

When the designers of WTSs for pharmaceutical purposes

This table presents the processes most commonly applied in

consider that the water supplied does not or periodically cannot

producing water for pharmaceutical purposes, and these are reverse

fulfil the norms for water for human consumption (Journal of Laws

osmosis (a semi-permeable membrane which retains rigidly defined

No. 61 item 417 from 2007) they equip the WTS with equipment for

impurities depending on the pore size), reverse osmosis combined with

initial water treatment. This is most usually sand filters for removing

electro-deionisation (EDI) of the water, distillation and ion exchange

mechanical impurities (which often appear in water pipe networks)

involving the exchange of ions (cations and anions) usually for hydrogen

and iron and manganese compounds. Biological impurities are

and hydroxide ions, i.e. chemically pure water.

eliminated chemically or using UV lamps.

Materials are very important when building the station. The

To protect other components of the station, hard water is often

necessity to sanitise stations or pieces of equipment and the intro-

softened using the ion exchange method on strongly acidic cation

duction of running water for this purpose at temperatures above 700

exchangers, periodically regenerated with a sodium chloride

C means that tanks, pipes and most of the equipment and machinery

solution.

is made of high quality stainless steel. It should be remembered,

A well designed station should ensure the supply of the required

though, that this has previously been cleansed and prepared for the

amount of water with the most continuous possible operation of

transport and storage of purified but aggressive (corrosive) water. In

machinery with the lowest possible output. Thus the size and role of the

the case of the circulation of mill water from the tank to the customer

storage tank for the water produced is of great importance.

and in transporting the excess back to the tank in a circulation loop

Many existing pharmaceutical water production plants are excessively large, and apart from high construction costs this leads to operational

Processes/criteria Investment costs Operating costs

by the inflow of water into the tank, disinfection is carried out by UV lamps, and filtration is also sometimes applied.

Two-stage reversed osmosis

Reverse osmosis + EDI Septron

Distillation

Exchange ion

++

+

--

= do +

+

++

--

+

= do +

+

++

-

Safety chemical/physical

+

+++

+

= do –

Requirements concerning space/ infrastructure

+

+

--

--

Initial treatment/effects of raw water fluctuation

-

+

=

++

Safety microbiological

Official regulations

++

++

+

--

Total points

++

+++

--

-

Table 2. Processes applied in treating water for pharmaceutical needs and the criteria for their use Key: -- very bad - bad = average + good ++ very good

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+++ excellent

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advertisement

Construction of stations is best entrusted to a company with experience, and this can additionally be contracted to carry out maintenance services for a year, a period in which design and construction faults may become apparent, and the investor’s service staff master the technique of operating the WTS.

Literature: 1. European Medicines Evaluation Agency. Note for guidance on the quality of water pharmaceutical use. London. CPMP/QWP/158-01. 2. European Pharmacopoeia. Web site for the publishers of the European Pharmacopoeia Published annually, see http://www.usp.org. 3. Granops M., Opalinski St., Technologie fizyko-chemicznego uzdatniania wody miejskiej w Kolbuszowej i Rzeszowie dla potrzeb sztucznej nerki, Z. N. P. Rz. Nr 2, Budownictwo i Inżynieria, 1985. 4. Granops M., Małe i indywidualne stacje oraz urządzenia uzdatniające wodę do picia i celów medycznych, Z.N. P.Rz.,T.160, Z.28, 1997. 5. Granops M., Jakość wody, a zdrowie człowieka, Mat. International Scientific Conference, PAN in Kraków, Rzeszów – Lwów,1999. 6. Kowal A. L., M. Świderska – Bróż, Oczyszczanie wody, Wyd. Naukowe, PWN, Warsaw, 2007. 7. Decree of the Health Ministry of March 29th 2007 concerning the quality of water intended for human consumption (Journal of Laws No. 61, item 417).

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46 | production

Innovative concepts

for sterilizing-grade gas filtration Process design for optimum safety, efficiency and ease of use PALL POLAND Sp. z o.o. Dr. Jörg Schubert, Dr. Dirk Sievers

Safe sterilizing-grade filtration of gases is essential in numerous production processes in the biopharmaceutical industry and food technology. The latest GMP guidelines call for far-reaching quality assurance measures, particularly when gases come into direct contact with the end product.

Hydrophobic filter membranes are generally used for the sterilizinggrade filtration of gases, since their water repellent characteristics make them difficult to wet.1 The US Food & Drug Administration (FDA) has issued corresponding recommendations: Gas filters (including vent filters) should be dry. Condensate on a gas filter can cause blockage during use or allow for the growth of microorganisms. Use of hydrophobic filters, as well as application of heat to these filters where appropriate, prevents problematic moisture residues.2 The principal membrane materials used are polytetrafluoroethylene (PTFE) and polyvinylidendifluoride (PVDF).

Careful selection of suitable membrane filter materials is only one

This reduces the risk of a filter blockage caused by water ingression

aspect of designing a safe and efficient concept for the sterilizing-grade

into the membrane pores, which would drastically reduce the throughput

gas filtration. It is also important to pay close attention to the process

rate. In case of some filter types the potential wetting of the sterilizing-

conditions during sterilisation and use, which occasionally reach the

grade gas filter membrane carries the risk of bacterial contamination due

limits of the filter specifications. In addition, the filter system should be

to a reduction in the retention performance of these filters in liquids.1 In

designed for ease of maintenance, so that filter integrity tests can be

practice membrane wetting can occur, for example, with vent filters on

performed easily without first removing the filter and filter changes can

bioreactors due to foaming of the fermentation broth. This would result

be effected easily even in large multi-round housings.

in serious process disruptions and therefore, to ensure the required maximum process safety, sterilizing-grade gas filters should also be

Emflon® PFR

Emflon® CPFR

Politetrafluoretylen Politetrafluoretylen (PTFE, (PTFE, hydrofobowy) hydrofobowy)

Material of the membrane

Emflon® II

Polivinylidenodifluoryd (PVDF, hydrofobowy)

scenario of a (partial) membrane wetting.

Steam sterilisation as a critical process step Modern membrane filters for sterilizing-grade gas filtration (tab. 1) are highly resistant to repeated steam sterilisation cycles (steam-inplace, SIP). Steam sterilisation is widely used before and during filter

Compatibility towards gamma rays

nie

nie

tak

Protective and drainage layers

Polipropylen

Poliaramid

Polipropylen

tak

tak

tak

use with many applications which require the filters to be sterilised along with the entire unit. The steam is usually fed into the system via the filter. In addition to the thermal stress the filter must be capable to withstand the increased differential pressure in particular at the beginning of the

Validated as the sterile filter in liquids Load bacterial test

Brevundimonas Brevundimonas diminuta, Bacillus diminuta, Bacillus Brevundimonas diminuta subtilis przetrwalniki subtilis przetrwalniki

Load bacterial tests with bacteriophages

PP7 (25 nm), MS-2 PP7 (25 nm), MS-2 (23 nm) (23 nm)

Tab. 1. Filter selection criteria for the sterilizing-grade filtration of gases

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validated as sterilizing-grade liquid filters, based on the worst-case

sterilisation process. The maximum permitted differential pressures and the maximum achievable cumulative sterilisation times that the filters are capable

T1 (50 x 100 nm)

of withstanding under these conditions do not depend solely on the membrane material. Both, filter construction and filter style also affect these parameters and must be taken into account when choosing a filter.

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47 For example, it is important to ensure the compatibility of the plastics when using gamma-irradiated filters in pre-sterilised single-use systems. Filters with PTFE membranes that are widely used for the sterilizing-grade filtration of gases are not generally suitable for this purpose since they do not necessarily have the required resistance to gamma irradiation. Filters with PVDF membranes offer an alternative.

Sterilizing-grade gas filters for optimum safety The effectiveness of a sterilizing-grade gas filter should already be demonstrated by the manufacturer on the basis of a meaningful generic validation. An example is the detailed study of the retention performance of Emflon  PFR filters, which includes both a challenge with liquids and a challenge with gases. Validation is based on a liquid challenge with Brevundimonas diminuta at >107 cfu/cm² in accordance with ASTM standard F838-05. In addition, aerosol challenge tests were performed with Brevundimonas diminuta and Bacillus subtilis as part of a 30-day long-term study to simulate typical process conditions for vent filters, with PP7 bacteriophages and MS-2 coliphages, and with sodium chloride particles. The aerosol challenge tests in the long-term study were performed on steam-sterilisable NovasipTM capsule filters which were exposed to ten

Fig. 1. Cross-section of an Advanta AGT filter housing with effective condensate drainage for the sterilizing-grade filtration of gases

60-minute SIP cycles at 125 °C prior to the begin of the study. Moistened air with >90 % humidity was passed over the filters for eight hours each

Materialforschung und -prüfung (BAM) using a specially developed test

working day. Rest periods over night and at weekends simulated realistic

method. As well as containing more robust hardware components made

conditions. The challenge was performed once each working day. The

from pigmented polypropylene, these filters use a specially impregnated

filters were not re-sterilised during the 30-day test period. The filtrate

polyaramid for the drainage and support layers which makes them

samples in all cases were found to be sterile.

significantly more resistant to oxidation.

The low pressure drop of modern sterilizing-grade gas filters permits

The filters satisfy the requirements for pharmaceutical applications

the use of small systems with low installation costs. High cumulative

according to the US Code of Federal Regulations (CFR) and the United

sterilisation times and long service life ensure low total filtration costs.

States Pharmacopeia (USP). The filter components have been additionally tested for biological safety and meet the requirements of class VI

Sterilizing-grade gas filters for highly oxidative conditions

plastics (extraction at 121°C).

Selection and installation of filter housings

The use of a sterilizing-grade gas filter under highly oxidative conditions makes stringent demands on the filter components. Examples

The use of filter housings in pharmaceutical processes places

of such applications include the venting of water systems that are

particularly high demands on the quality and surface finish of the

ozonised or permanently operate at virtually 100° C, and the filtration of

stainless steel. AdvantaTM AGT (fig. 1) and Advanta AVL are current

oxygen for special fermentation applications. The drainage and support

examples of filter housings specifically designed for sterilizing-

layers of the filter in particular, which, like the filter membrane, have a

grade gas filtration. They fulfil all criteria for aseptic design and

very large surface, are critical components under these conditions. The

can be cleaned simply and efficiently in accordance with regulatory

polypropylene typically used in conventional filters cannot continuously

requirements. Alternatively, NovasipTM capsule filters (fig. 2), which

withstand these highly oxidative conditions and can lead to spontaneous

were primarily designed for use as inline steam-sterilisable vent

combustion in extreme cases. The material of construction is subject

filters on storage tanks, can be used.

to severe embrittlement resulting in the emission of material particles. Consequently, alternative plastics with lower sensitivity to oxidation must be used to achieve longer filter service life.

The filter housing should be fitted with standard connections for process monitoring sensors and for performing inline filter integrity

For safety and regulatory reasons it is advisable to perform a

tests. In addition, a suitable condensate drainage for inline steam

detailed test of filters used for gaseous oxygen as an oxidising chemical

sterilisation of the filter system is essential. Electrical trace heaters can

to verify their suitability for this highly critical application. Emflon

be used with the filter housing to minimise the formation of condensation

CPFR filters have been validated in this way by the Bundesanstalt für

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on filters used on hot water tanks.

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World

48 | production Various different methods can be used to perform an integrity test, including the water intrusion test (WIT), the forward flow test, also referred to as the diffusion or pressure decay test, and - in exceptional cases - the bubble point test. The WIT, which was developed specifically for testing hydrophobic filter membranes, has proved popular in more recent systems because it is very much easier to use inline than other test methods. Furthermore, WIT does not require alcoholic solutions for membrane wetting. Unlike other integrity tests, this method only requires pharmaceutical grade water as a test liquid. The use of modern integrity test equipment enables all stages of the filter testing process to be automated. The AquaWIT System (fig. 3) does not require any operator involvement on the downstream side of the filter, which means that integrity tests can be performed reliably and safely even straight after steam sterilisation and therefore immediately prior to using the filter. In addition to the integrity tests described above, visual examination of the filters can be useful to early detect any deformation, discolouration or embrittlement of the plastic.

Process monitoring Process monitoring requires particularly careful control of the temperature and the pressure at the inlet and outlet side of the filter, whose difference corresponds to the differential pressure across the filter membrane. These parameters have a significant impact on filter service life. Steam sterilisation deserves particular attention, since the plastic Fig. 2. Novasip capsule filter for use as inline steam-sterilisable vent filter on storage tanks

filter components are highly sensitive to high differential pressures or pressure peaks due to the prevailing process temperatures.

The housing should also be easy to maintain and easily accessible for filter changes. Careful thought should be given to the installation height to ensure that the housing bowl can be removed with ease to allow for a filter change. The filter system (filter and housing) should be sized in accordance with the manufacturer‘s data on differential pressure and throughput rate, with particular regard to specific process conditions. For example, the breaking of the vacuum in the cooling phase following the steam sterilisation of a vessel frequently requires a significantly higher throughput rate than the normal filtration process.

Detailed knowledge of the operating conditions enables targeted fault analysis in the event of an error occurring during filtration. It also makes it easier to identify the root cause if the filter is found to be damaged after filtration. In addition, only an accurate process understanding enables the individual filter qualification for each planned application.

Summary A comprehensive overall concept for safe and effective sterilizinggrade gas filtration which meets the increasingly exacting requirements placed on this essential process step should take account of every

Integrity testing as an opportunity for cost optimisation

aspect listed in this article. The choice of the filter and the associated

The efficiency of a sterilizing-grade filter and therefore the longterm process reliability can be comprehensively documented only by

housing is just as important as the integrity test method and the process monitoring to ensure the desired degree of safety and efficiency.

meaningful filter integrity testing. For this reason the FDA calls for regular integrity testing: We recommend that filters that serve as sterile boundaries or supply sterile gases that can affect product be integrity tested upon installation and periodically thereafter (e.g., end of use). [...] filters should be replaced at appropriate, defined intervals.2 Similar wording can be found in the EU GMP guidelines: the integrity of critical gas and air vent filters should be confirmed after use. the integrity of other filters should be confirmed at appropriate intervals.

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3

PDA Technical Report No. 40 – Sterilizing Filtration of Gases, Supplement to PDA Journal of Pharmaceutical Science and Technology, Volume 58, 2005.

1

FDA Guidance for Industry – Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, 2004.

2

EU Guide to Good Manufacturing Practice, Annex 1: Manufacture of Sterile Medicinal Products (EUDRALEX, Volume 4 – Good Manufacturing Practices – Medicinal Products for Human and Veterinary Use), 2008.

3

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S


World of the Pharmaceutical Industry 210x297

21-01-2010

11:50

Pagina 1

THE WORLD

of pharmaceuticals meets. Only CALEIDOS-NEXXUS.IT

AT PHARMINTECH It’s the only event in Europe specifically dedicated to the pharmaceutical industry. It’s where you’ll find the latest technology and the most innovative solutions, from raw materials to distribution. It’s a meeting place for delegates from 22 different countries. It’s established as part of an international community that leads the evolution of the pharmaceutical industry. Only at Pharmintech.

BOLOGNA, ITALY May 12-14 2010

BolognaFiere, piazza Costituzione entrance Opening times: 10.00 am - 5.30 pm

Supported by:

Organizing secretariat: Ipack-Ima spa - corso Sempione 4 - 20154 Milano - Italy tel. +39 023191091 - fax +39 0233619826 - ipackima@ipackima.it

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50 | production

New trends in solid dosage forms production Dr Harald Stahl Senior pharmaceutical technologist GEA Pharma Systems

The operation of a high speed tablet press has two main requirements on the feed material: it needs to flow well to assure a homogeneous filling of the dies; plus it needs to compress well. These requirements can be achieved in two different ways.

It is possible to use expensive raw materials with special physical

the materials deform under pressure by brittle fracture. This method can

characteristics allowing a direct compression of the mixture, but this

also be expensive if large amounts of materials need to be produced.

method doesnâ&#x20AC;&#x2122;t work for all formulations, especially if very high or very

The alternative is to use wet granulation. This requires a significant

low drug content is required or if the API deforms during compression

up-front investment however cheaper raw materials can then be used

(mainly caused by plastic deformation). In some cases the application of

as they will be converted into the desired physical state by the process.

a roller compaction step can improve the situation but itâ&#x20AC;&#x2122;s unsuitable if

Wet granulation has been around for decades but over recent years some exiting new developments have taken place that will be described in this article. The use of a high shear granulator with a fluid bed dryer is still the most widely used combination. Its advantages are obvious: it combines the most productive and versatile granulator with the most effective dryer. For large volume products and long campaigns this gives unbeaten productivity. Downsides are the high upfront investment, the large space required plus the long downtime for product changeovers.

Recent alternatives addressing these issues are: Single Pot technology A mixer/granulator that dries granules in the same equipment without discharging is commonly called a single pot. The granulation is done in a normal high shear processor; there are various options for drying in single pots. The traditional heat source comes from the heated dryer walls; the heat transfer is related to the surface area of the walls and the volume of product Integrated High Shear Granulation and Fluid Bed Drying Suite

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treated. This direct heating method is therefore only effective for small scale use.

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51

Single-Pot R&D solid dosage suite

Introducing stripping gas into the pot allows large scale operation.

FlexStream™ Fluid Bed Processor

and sampling - such as split butterfly valve systems - substances such

A small quantity of gas is introduced in the bottom of the equipment

as hormones or oncology products can be processed without the need

which then passes through the product bed, improving the heat flow

for PPE (Personal Protection Equipment). Additionally, it offers very high

from the wall into the product. The gas also improves the efficiency of

yields as a result of the minimal surface area in contact with the product,

vapour removal. However, as the heated wall is the only source of drying

a huge advantage when processing expensive products.

energy, linear scale-up is not possible. This problem is exacerbated if the material to be processed is heat sensitive (as this limits the wall temperature); if water is used as a granulation liquid (it has a high boiling

FlexStream™ – tangential spray system Granulation can be performed using fluid beds fitted with spray noz-

temperature under vacuum and a high heat of evaporation); and if used

zles. For many years the top spray position was preferred, but now the

for larger-scale production the surface/volume ratio deteriorates as the

advantages of tangential spray systems have become obvious. The main

volume increases.

advantage is the location of the spray nozzle, in an area with significantly

Microwave energy can be used to overcome these limitations. This

higher shear forces that allows the processing of formulations that could

provides a further source of energy and has the additional advantage,

previously only be granulated in high shear processors. Additionally the

with organic solvents, that only pure organic vapours will be treated

introduction of the new FlexStream™ range of fluid beds also eliminates

on the exhaust side, and not a mixture of solvent and large volumes

the problem of scale up.

of process gas, as would be required in most other wet granulation

In recent years fluid beds have improved dramatically in response to competition from single pot technology. It is possible to have completely

technologies. Single pot technology offers various advantages depending on the

closed material handling by linking with upstream and downstream

product mix. The machine can be cleaned in less than 2 hours – even for

equipment. Also, fully automatic cleaning (CIP) in fluid beds using

substances that don’t dissolve easily in water – so it’s a highly pro-

stainless steel filters has now reached a level that compares favourably

ductive tool for short campaigns that require a high number of product

with what is possible in a single pot.

changeovers. As a one pot operation it is perfectly suited for the handling of potent substances. By using appropriate technologies for loading, unloading

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Another advantage of the FlexStream™ range - recently introduced by GEA - is that for drying, granulation and coating only one product

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52 | production

Continuous Processing Technology Center

container is required. Tests with more than 100 different products prove

While the reduced footprint and the reduced need of operators makes

that the performance of the FlexStreamâ&#x201E;˘ processors are always at least

it very attractive from an investment point of view, it offers many other

equal, and in most cases superior, to conventional top spray granulators

advantages.

or Wurster coaters. These advantages make it the most versatile and cost effective solution.

The only scale up parameter is time, which means scale up problems that are often seen with conventional batch equipment no longer exist, allowing research orientated companies to shrink their development times while generic companies can start their development programs

Continuous Tableting Line As a result of various FDA initiatives there is a huge interest in con-

later. With the unit installed in the GEA test centre, a typical product

tinuous processing. In response to this, GEA introduced ConsiGmaâ&#x201E;˘

changeover is done in less than six hours. This makes the technology

Continuous Tableting Line. A typical installation consists of continuous

not only attractive for large volume productions but also for a wider

raw material feeding, a continuous granulator, a semi-continuous

product mix. An additional advantage here is that there are no fixed batch

dryer, an evaluation unit, a blender for the addition of the outer phase

sizes required allowing the production of flexible amounts as required by

and a tablet press. For raw material feeding there are three options: a

the market.

pre-blend of all components can be used; up to four components can

Finally the system offers a unique solution for effervescent produc-

be fed individually; or a pre-blend of all excipients and the API can be

tion. As a result of the ultra short residence time the pre-effervescent

fed independently. The last option is of particular interest if potent APIs

reaction happens much less than with any other wet method.

are involved as the overall residence time in the system is less than 30 minutes. One main advantage of such a system is that it can, by adjustment

Conclusion Wet granulation is a very important technology in the process train

of the process parameters, compensate for variations of the input

of tablet production. Exciting developments over recent years have

parameters, for example different raw material properties, leading to an

boosted the performance of the technology significantly allowing optimal

end product of consistent quality.

solutions to be identified for product mix and production scenario.

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54 | packages

Rapid Rapid launch launch of aofnew a new medicinal medicinal product packaging product packaging – feasible – feasible andand cost-effective cost-effective Andrzej Zielaskowski A-tech

The introduction of a new packaging must be considered in terms of the new possibilities and benefits offered and the costs of the entire operation. Reasons for packaging changes in the pharmaceuticals market may be very varied. Primarily they are the result of laws, for example those relating to safety markings or the use of closures which are childproof and friendly to elderly users. No less significant, though, are marketing-based arguments – the need to differentiate a product from competing ones through a new image.

Manufacturers are using very modern forms of packaging, introducing

the early stage of design, this will ensure that the development process

accessories which make it easier to measure out and administer

goes through smoothly. Sometimes a minor omission of one of the

a product, and launching packagings which emphasize the features of

significant factors (such as the temperature of the technological process)

the product in question.

may lead to major complications, increase in project completion time,

Many matters must be considered and decisions taken before the process

and in extreme cases the failure of the entire project.

of developing a new packaging can begin. Key issues will include the limitations of production lines and manufacturing technology, the requirements of the particular pharmaceutical product, and finally financial and time factors, as well as requirements relating to the registration of a medical product. This article aims to describe how to estimate the costs and time needed in order to launch a new plastic packaging produced using a micro-injection method. This technology enables significant cost savings on the design and introduction of packagings, even when the quantity needed is relatively small. An example might be the market launch of a new spoon for measuring and administering a medicine, completed within six weeks, including the

New spoon for measuring and administering a medicine - version 1

time needed to design the item. The cost of such a project is between 10 000 and 20 000 zloty, not many tens of thousands as it would be using a conventional method.

How is this possible? The most important thing is to determine and understand the customer’s expectations at the very beginning, which means the collection and verification of starting data. It is particularly important to supply the design firm with all information relating to the final use of the packaging, conditions of manufacture of the final product, temperature of the technological process and other factors which seem obvious to a medicine manufacturer, but may not be known to the packaging designer. If the requirements applicable to the packaging are defined at

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New spoon for measuring and administering a medicine - version 2

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55

Project of production tools for new spoon for measuring and administering a medicine

Modern design is essentially based on CAD and CAM three-dimensional

After one or more submitted proposals have been selected, three-

computerized techniques. Even at the preliminary design stage visualizations

dimensional models are created using a rapid prototyping method. This

are produced of different versions of the new product, in order to give a reali-

technology makes it possible, on full scale, to evaluate the productâ&#x20AC;&#x2122;s

stic representation of the planned packaging. At this stage further questions

functionality, touch it, see how it will fit in the multi-packaging, check

arise relating to the technology for manufacture of the final product, and the

its compatibility with the production line, etc. A model can be created

customerâ&#x20AC;&#x2122;s expectations are specified more precisely. Depending on the

within two or three days. At this stage final verification and acceptance

complexity of the project, this stage may last from several days to several

of the design takes place, and a decision is taken to begin making the

weeks. It is very important that the customer should be involved and should

production tools.

respond quickly to proposals for the new packaging when sent.

The concept of micro-injection technology is based on minimizing the costs of making the production tools. Solutions with a single machine group or several groups are used, optimizing production requirements to meet the expected annual need for the product in question. This means that the cost of this stage is several times smaller than with a traditional production method. Also significant is that the input data from the CAD system is sent directly to the CAM systems in the toolshops, which minimizes the chance that an error will occur at this stage of the project. At last we reach the final moment in implementation of the project â&#x20AC;&#x201C; production of the packaging.

New spoon for measuring and administering a medicine - version 3

The micro-injection method makes it possible to optimize production costs, thanks to the many times smaller consumption of energy, as well as minimization of the production space required and the time needed to prepare for production. It is a great deal easier to fulfil orders for colour versions, with a lower threshold of minimum quantities. The method described makes it possible and cost-effective to produce single batches of as few as 1000 pieces of a given product, with a maximum monthly output of 2 500 000 pieces, depending on the item being produced. These quantities relate to a single machine group. It is worth noting that micro-injection technology has already been brought into use and is applied successfully in Poland. We

New spoon for measuring and administering a medicine - final product finalny

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use it to produce items of packaging, dosers, droppers and other medical items.

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56 | packages

The Internet

and the pharmaceutical branch Aneta Baberowska Noise department of Noise Technology

With this article we would like to initiate a new thematic series that will show the possibilities that the Internet offers to the sector of the pharmaceutical market. It is possible that at times it might contain quite obvious information, however, its main goal is to show you certain tendencies and ways of thinking when it comes to the Internet. Often the Internet will be referred to as the strong purchasing, marketing and promotional instrument.

We will show you how your product is seen by an Internet user, who

Internet. According to the Megapanel PBI/Gemius research each Polish

as a matter of fact, often for the first time and thanks to the Internet

Internet user spends approximately 46 hours 29 minutes on the web. The

encounters the product, its package and opinions about it on forums.

index of the number of page views grew as well. It is not enough for the

This way we will help you understand that the marketing life of the

professional organisations just to be on the Internet. More relevant is

product begins exactly on the Net and then it is continued in the retail

how the company is perceived by the users. More often we deal not with

and wholesale outlets.

static www services but with applications or services which use more

We will do our best to lead you through problematic issues concer-

advanced technologies. In the present day, the interactive agencies and

ning e-marketing, most optimal technologies or questions regarding web

their clients encourage to interact with the recipients through developed

design with reference to the pharmaceutical branch.

innovative web solutions.

We will show you what kind of promotions are the most effective on

Our observations of the market show that the companies which offer

the Internet, how to chose the most trustworthy interactive agency and

and present the â&#x20AC;&#x2DC;productâ&#x20AC;&#x2122; notice that the essential instrument is to begin

tell you how to work with tools available on the web.

communication with the client not only through presenting the product,

Taking into account the fact that the chief element of promotion

but also providing the information about its quality. To achieve such

when it comes to pharmaceutical business as well as cosmetic

goal various procedures are used, from loyalty programmes or discount

business, is the product, we will prove how important its presenta-

systems to banner campaigns.

tion is with the Internet services.

Product services are worth mentioning here. Contrary to corporative

For the last two years the dynamics of the Internet users growth

services, they are not based on the schematic sitemap. The companies

decreased. However, people spend remarkably more time using the

and corporations associated with the pharmaceutical branch tend to invest more willingly in the product services and this is the first step of the advertising campaign whose aim is not only to popularise the product on the Internet and increase the sales in e-shops, but also the emphasis and response in retail. Therefore, in the pharmaceutical division product services are first and foremost a part of the marketing strategy of the product. As a consequence, the key to success is the creation and then web technology adjusted to the advertising form. Technological solutions in the form of CMS (Content Management System) are a good tool integrated with the web solution, as they allow its actualisation. According to the www.esteticapolska.pl service, CMS associated with it is the most common instrument as regards the communication with the client. Thanks to the available administrative panel the manager of the service can easily update news, add new

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57 descriptions or control the banner system. Regularly updated webpage,

As far as the graphic design is concerned, it has to be aesthetic and

not only company page but also the page of the product, is a crucial

consistent with the presented products. In such projects the ‘simplicity is

source of information and knowledge to the Internet user. It is necessary

strength’ principle is followed and that is why too sophisticated graphic

to mention that what the recipient sees, i.e. the creation is the most

designs are not popular. As a consequence, they can blur the clarity and

important when it comes to the product presentation.

message of the presented products. The graphic projects are mostly

Of course, any company can adopt the e-marketing strategy

based on the colours of white, light blue or pale green. Vivid colours are

focusing on the promotion of a given product through its distinction

to be avoided as they are not associated with the pharmaceutical branch.

and creation of a dedicated system. Such corporation actions should

It should be also mentioned that the emphasis of the message is laid on

be consistent with marketing-mix which refers to the actions of

professionalism and specialisation and those ideas cannot be covered by

general product lining. Promotion, product, price and distribution

‘pictures.’ It does not mean, however, that we should neglect the visual

strategy in such case should be reflected in the web marketing

side of the page like the photographs of the product or the way in which

actions. However, for the web marketing strategy to work well and be

the substantial content appears. As regards the technological tools,

trustworthy we should take care of the foundations – proper brand

zooming mechanisms or magnifying glasses are used in the services.

presentation and product lining on the Net.

They help to magnify the product and to read the information placed on

There are many ways to reach the client through the Internet tools.

the package. According to the infoplus24.pl service which advertises

Product service is the point of reference. The next step is to properly

the products of such companies as Plane System or Isispharma we can

advertise that product. It can be done thanks to such tools as SEO/

define the good practices of the product advertisement on the web. As

SEM which focus on positioning and contextual advertising of the

mentioned before, the service was designed with the use of the colours

service. The next stage that the companies invest in are the Web 2.0

of white and light blue. From the technological point of view, the whole service was based on the Flash technology and is managed with the friendly CMS system. adWertisement

tools. Internet forums or thematic blogs maintained by branch experts assemble the clients and invite them to buy the product. In many cases competitions thematically connected with purchasing the advertising product are organised. Such competitions often require the application of appropriate tools which help to register one’s profile on the page and monitor the prize drawing. Gathering the information about people is a valuable source when it comes to further advertising actions not necessarily performed by the web. All things considered, advertising campaigns, as well as the loyalty systems on the Internet, are a means to build the relation between the client and the product, which is reflected in the profitability of the project. Another activating method used to reach the client successfully is the creation of the distribution network built with the use of e-commerce. The topic of the Internet shops will be touched upon in the next publications.

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58 | reports, projects, plans

Pharmaceutical distribution market in 2010 Consolidation, privatisation and development of new forms of distribution Monika Stefańczyk, Agnieszka Stawarska Pharmaceutical market analysts

In recent years the pharmaceutical distribution market in Poland has seen many changes. The wholesale distribution segment has experienced consolidation, including combinations between leading players, as well as the privatisation of State Treasury outlets. New forms of distribution have also been developed, such as direct/DTP distribution1.

New consolidating trend on distributor market According to our latest report “Distribution on the pharmaceutical market

companies. Hence we do not rule out acquisitions in the coming years between some of the biggest players on the market.

in Poland 2010. Development forecasts for 2010-2012”, during the period 2008-2009 the pharmaceutical distribution sector in Poland saw further consolidation, both among distributors and among retailers. The most

State shedding wholesalers In April 2008 the State Treasury published a list of pharmaceutical

important event in the wholesale distribution segment was the buyout of

distributors to be privatised in the coming years. In July 2008 Cefarm

Prosper by Torfarm, another leading distributor on the Polish market, in April

Krakow was privatised (the shares were acquired by PGF). In December

2009. After the fusion, the two companies together control more than 30% of

2008 the state surrendered its stake in Cefarm Wroclaw (36.31% of the

the market of distribution to pharmacies in Poland.

shares were purchased by Farmacol, one of the leading distributors to

The takeover of Prosper by Torfarm was one example of a new trend

pharmacies). In July 2009 Farmacol also took over another wholesaler

that is becoming visible on the wholesale market in Poland – conso-

– Cefarm Bialystok for PLN 71.5m (€16.6m). Cefarm, which is active in

lidation among the largest players. Prior to this, the takeover targets

north-eastern Poland, also has a chain of pharmacies numbering nearly

tended to be smaller, regional entities. In February 2008, for instance,

50 outlets. In November 2009 the State Treasury announced its intention

PGF acquired 57.3% of the shares in the Aptekarz wholesaler, based in

to sell its shares in Cefarm Rzeszow. One of the likely potential buyers of

Rzeszow, for PLN 26m (€7.4m). In July 2008 Torfarm bought a 100%

these shares is ACP Pharma, which already has over half of the shares in

stake in the distributor Promedic for PLN 700,000 (€200,000).

the Rzeszow-based company.

Following the acquisitions on the Polish market in recent years,

In 2010 the privatisation of the last state-owned distributor – CF

there are few entities left as potential takeover targets. One of them is

Cefarm – is scheduled to complete. In mid-January Farmacol, Eko-Berry

the Legnica-based wholesaler Legfarm, the last of the Apofarm group

and Polfarmex, following the completion of the due diligence process,

1

According to the definition adopted for the purposes of the report, in the DTP distribution model the manufacturer supplies pharmacies using a logistics operator. In the direct sales model the manufacturer sells its products directly to pharmacies (using its own resources and/or a logistics operator), as a way of supplementing the traditional distribution channel via wholesalers.

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59

submitted their binding offers for the acquisition of 85% of the shares in

in another ordinance, prepared the criteria for the classification of

the company.

medical products for non-pharmacy sales.

Increase in significance of direct distribution

submitted, for social consultation, an ordinance pertaining to the lists

At almost the same time, on 19 February 2009, the Health Ministry In recent years new forms of distribution have developed on the Po-

of medicinal products suggested for non-pharmacy trade. The deadline

lish pharmaceutical distribution market. In March 2009 Sanofi-Aventis

for the submission of comments passed on 25 February. However, this

launched its Retail Pharmacy Supply Service for its cardiovascular drugs

ordinance waited for the sign of the health minister almost eight months

Clexane and Plavix and the drug Rilutek, used in patients with amyotro-

(it was signed at the beginning of October). The document, presented

phic lateral sclerosis. It is designed as purely an interventionist measure

on websites in February, contained many shortcomings and mistakes,

(in case of problems with purchasing these drugs from the pharmacyâ&#x20AC;&#x2122;s

pointed out by several dozen companies and other organisations. There

regular supplier). As its partners in this programme, Sanofi-Aventis

were many mistakes in the spelling of the names of drugs, the doses and

selected ACP Pharma, Farmacol and Prosper (now part of Torfarm), but

forms. Some products placed on the lists were no longer on the market,

sales to all the wholesalers with which it normally cooperates remain

because of the lack of harmonisation of their documentation, among

unaffected.

other things. Many companies and other organisations proposed the

In May 2009 AstraZeneca rolled out a Direct Sales System for all its

addition of other products.

drugs on the Polish market. In November 2008 it chose the wholesalers

One of the items removed from the list is Aviomarin, the

PGF, Torfarm and Prosper (Prosper was later taken over by Torfarm) as

popular motion-sickness drug. However, the list of medicines

its partners in the system.

allowed to be sold in shops has been expanded as the previous

Our survey among the biggest pharmaceutical corporations in Poland

version of 2006 contains 109 items (however, various pack sizes

indicates that around a third of pharmaceutical companies on the Polish

were presented as one item) plus simple herbs (removed in the

market currently use a direct distribution system to some degree.In the

current version), while the list of 2009 has 525 items. The new

relevant question, direct distribution was defined as supply of drugs

list contains also many more versions and doses of popular

by the manufacturer to pharmacies or hospitals directly, bypassing the

medicines, e.g. 13 of Apap, 17 of Aspirin, 16 of Panadol or 20 of

wholesaler, though in fact wholesalers often become involved and offer

Paracetamol. At the same time, retailers have been given until

manufacturers their services.

6 April 2010 to sell out their existing stocks of the medicines removed from the list.

Non-pharmacy distribution of drugs: a controversial issue in Poland and Russia The outlook for sales of OTC medicines outside pharmacies

Most of the proposals to add other products were justified by the fact that such products meet the conditions of the 2 February Ordinance. This means that these two ordinances do not complement each other,

differs from one Central and Eastern Europe country to the next.

as intended by the legislature, but are sometimes even contradictory.

Poland is one of the countries in which there is a very long tradition

Furthermore, the previous ordinance pertaining to the lists of medical

of selling drugs in general stores. The new list of drugs approved

products was overturned in October 2008. As a result, the market has

for sale was approved in October. Meanwhile, the Health Ministry,

been left without a relevant act for an almost a year despite the fact that,

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60 | reports, projects, plans in accordance with an amendment to the 2007 Pharmaceutical Act, lists

many Russian pharmacies, as such products are an important source

should be updated once a year.

of income for many of them. Estimates suggest that the total turnover of pharmacies could fall by 10-15% as a result of the liberalisation of the

Russia considering non-pharmacy OTC drug sales Russia is one the countries which have, in the recent past, seriously

market[1]. Taking into account the DSM data for the overall pharmacy market, the value of non-pharmacy sales of OTC drugs could reach

considered permitting the sale of OTC drugs at general stores. However,

approximately RUB 24-35bn (€500-800m). This could, therefore, be a

in Russia such a move could carry much more risk than in other

very attractive sales channel, assuming that sales of pharmaceuticals in

countries, according to Pharmexpert, a market research company.

Russia grow despite the crisis (in RUB).

First of all, there are safety issues. Many drugs which have an Rx status in other countries, for example, Diclofenac, Nystatin and Korvalol, are available without prescription in Russia. Some include potentially dangerous substances, the distribution of which needs to be controlled

Consequences of allowing non-pharmacy sales in Russia According to a PMR analysis of the effect of allowing sales of OTC drugs

by qualified persons such as pharmacists. Secondly, the approval of

in Russian general stores, the opening of non-pharmacy channels will not, in

OTC drugs for non-pharmacy channels would lead to the bankruptcy of

fact, increase the overall growth rate of the market – this will change only the channels of distribution of such products but will not have a positive effect on demand for OTC drugs. Of course, the situation is different in the case of particular OTC manufacturers. In other CEE countries if non-pharmacy sales are allowed they are restricted to a specific list. It is, therefore, probable that the Russian government will also approve a closed list of products for sale at grocery stores. Those manufacturers who succeed in placing their products on such lists will gain a substantial share of the market. The categories which could be affected the most by such changes depend on the products placed on this list, but we expect analgesics to be to the fore. These are the subject of so-called “impulse” purchases at grocery stores, kiosks and petrol stations. To a certain extent sales of cold and cough remedies and digestive medicines might also develop well in stores.

Do non-pharmacy sales present opportunities for market entry? Although Russia is one of the most promising OTC markets in the region, with considerable growth potential, the complex regulations and lengthy registration procedures can hinder the entry of new companies onto the market. Deadlines are not adhered to by Russian officials, and drug registration, which should take up to six months, may, therefore, take a few years. In addition, Russia’s national pharmacopeia and quality control methods are not harmonised with the regulations which are in force in the US or the European Union countries. This situation may also reflect the political turmoil Russia has experienced in the last few years. For example, during the last four years, three different people have been head of the Health Ministry, with each new appointee undoing his predecessor’s work. Despite those obstacles the OTC market is performing very well even in the times of crisis – in H1 2009 the growth dynamics was double-digit (in RUB). On the other hand, it is worthy of note, particularly from the perspective of foreign companies, that most changes in the value of the euro and dollar were negative in H1 2009. more information on the distribution of drugs in Poland and other Central european countries can be found in Pmr’s reports: “distribution on the pharmaceutical market in Poland 2010. development forecasts for 2010-2012” and “distribution on the pharmaceutical market in Cee countries 2010. development forecasts for 2010-2012” which are to be published in 2010.

4/2009

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