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contents

interview

4

Changes on the medicines market? A conversation with Leszek Borkowski

Changes at Polfa Łódź A conversation with Marko Dolžan, founder and owner of Sensilab

Daniel Gralak, Marcin Kołakowski

Full control over the implementation and quality of a logistical process Bartosz Jacyna

Counting, sealing and labeling Grzegorz Dziewanowski

Marcin Weksler

6

7 10 12

mgr farm. Maciej Szerszenowicz, mgr inż. Mirosław Jasiński

Wet granulation of milled lactose Brenntag

15

The monitoring and evaluation of the phenomena occurring during the studies on the release of medicinal substances 20 Przemysław Dorożyński

Let the braille be visible!

DRUK-PAK S.A.

22

Impact of GAMP®5 what does this mean to Polish Life Science industry 23 Paul Irving, Sion Wyn

Zbigniew Fijałek

HAZOP in pharmaceutical industry? 49 Marzena Sokołowska, Pat Swords

FSP GALENA Adamed in foreign pharmaceutical markets Adamed

Polfa Warszawa S.A.

Polpharma and Bioton together Robert Miller

conferences, fairs, training

Diet Supplements Workshops 2008

31

Cleaning Validation

33

PLIVA

Quality Masters

Confocal Raman Microscopy Harald Fischer

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57

Adamed

Tomasz Butyński

PLIVA – an ideal employer

55

Klopidogrel in the international market 58

26

Jerzy Lasota

53

New board elected at Polfa Warszawa S.A. 56

Tomasz Butyński

Direct compression

41

Counterfeit medicines – myth or reality? 45

Piotr Didkowski production

38

Polish industry

Increasing qualification effectiveness within the investment process

logistics

Logistics in pharmacy Part 2

Learning from Booklet Labels

Medicine Refunding 2008

59

60

61

reports, projects, plans

Supply chain management PMR Publications

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From the editors:

In spite of the holiday season, there is no sign of a slowing of pace in the Polish pharmaceutical industry. Quite the reverse – there is a great deal happening. The deadline has passed for the Medicines Registration Office to accept harmonization applications; Polfa Łódź has finally found an investor after many years of searching; Adamed is constantly expanding into new markets; Polpharma, instead of merging with Gedeon Richter, is taking over Bioton…

List of advertisers: BEATRONIC Sp. z o.o. BEMA Sp. z o.o. BOCCARD POLSKA Sp. z o.o. BUJALSKI Sp. z o.o.

We are not slowing down, either. Due to the significant number of international fairs within the pharmaceutical industry approaching, we are putting at Your disposal a special, bilingual edition of the “Świat Pr zemysłu Farmaceutycznego” quarterly.

DAMASZ Sp. z o.o. DRUK-PAK SA ECOLAB Sp. z o.o.

I wish You pleasant reading

ERWEKA POLAND Sp. z o.o. Editor-in-chief „World of the Pharmaceutical Industry”

FAUBEL & Co. Nachf. GmbH GRUNDFOS

Programme Board: Leszek Borkowski DPharm

Chairman of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Andrzej Szamański President of ISPE Poland, Quality Director at Polpharma SA Pharmaceuticals

Zbigniew E. Fijałek director of the National Institute of Medicines Marcin Kołakowski head of the Supervision Department of the Central Pharmaceutical Inspectorate.

HLP HYDROLAB POLSKA I.E.S. International Polska Sp. z o.o. IKA-TECHNIK Sp. z o.o. i ZMR S.C. IRtech Kraków J.S.HAMILTON POLAND LTD.

Irena Rej President of the Polish Pharmaceuticals Chamber of Commerce

KOMENDER TECHNOLOGIES LABART Sp. z o.o. LIMAREX

Quarterly, published by FARMACOM Wodzisław Śląski 44-300 ul. 26 Marca 31/11 farmacom@farmacom.com.pl www.farmacom.com.pl Editor-in-chief Robert Miller tel./fax +48 032 455 31 61 tel. kom. +48 502 084 101 robert.miller@farmacom.com.pl Subscription and distribution Publisher FARMACOM Wodzisław Śląski 44-300 ul. 26 Marca 31/11 tel./fax +48 032 455 31 61 prenumerata@farmacom.com.pl Issue price „ŚPF” – 10 zł Annual subscription price – 35 zł

Payments may be made to the account: ING Bank Śląski O/Wodzisław Śląski 56 1050 1403 1000 0023 2091 8119 Editors Tomasz Butyński, Teresa Kubsz-Miller tel./fax +48 032 455 31 61 redakcja@farmacom.com.pl

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LOT-Oriel Polska MIKROLAB MMR CONSULT Sp. z o.o.

Proofreading: Maria Gniłka

POL-EKO-APARATURA sp.j.

DTP: Wiktor Adamiec wiktor.adamiec@farmacom.com.pl

POLYGEN Sp. z o.o.

Printing: Drukarnia BIMART. Number of copies printed: 2 500 Partner:

SCHWARTE-MILFOR Sp. z o.o. Stangl Polska Sp. z o.o. StatSoft Polska Sp. z o.o. TESTO Sp.z o.o.

www.ispe.org.pl

TRADE&CONSULT Sp. z o.o.

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 pharmaceuticals-related 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.

www.farmacom.com.pl

Linde Gaz Polska Sp. z o.o.

UNILOGO

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interview

Changes on the medicines market? A conversation with Leszek Borkowski

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

dr Leszek Borkowski

The harmonization process is continuing, but the Office for Registration is no longer accepting new applications…

• June 30 was the deadline for harmonization applications to be submitted to the Office, but some firms had posted applications or submitted them to other offices, so we had to wait for those documents to arrive. In total we have about 7300 documents submitted, out of the 8766 which the Office ought to have received. We therefore know how many medicines have not been harmonized and will be taken off the market. We have divided these into two groups: refunded medicines and non-refunded medicines. Of the refunded medicines, 406 have dropped out. About 180 medicines in this category are of importance in therapeutic application, counting all their various forms. The medicines whose registration documentation have not gone through the harmonization procedure will not vanish from the market immediately. They will disappear gradually as their validity dates expire. The only condition is that they be placed on the market before 31 December 2008. The question arises here as to what “placed on the market” means. Does the release of a batch by a Qualified Person count as placement on the market? In my opinion it does not, as the release of a batch is an element of manufacture. For me, placement on the market occurs when

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Did the Office for Registration expect such a high dropout rate?

• No. When we made a request to responsible entities for initial information on the subject of the number of medicines to be harmonized, they returned a number of around 9500. With hindsight it can be seen that the Office’s request for data was not treated seriously by the responsible entities, which replied without much care and just to “get us off their backs”. However the Office tried to plan its work based on those surveys. Luckily we did not act solely on the basis of those results, but also took account of our own market research, and we were thus able to avoid problems.

There are those who say the days of cheap medicines are over. Is this true?

• I think these views represent a kind of artificial hysteria. There are large changes in the prices of medicines. Many factors affect the level of medicine prices. They are mainly influenced by competition among manufacturers, the market situation, whether or not a particular medicine is subject to refunding, and so on. For this reason I believe that all claims of this type are untrue, and that the medicines market, even though it is regulated, is governed by similar mechanisms to other markets. •

interview

a document is produced – maybe an invoice, maybe a warehouse transfer document – confirming that the medicines have been moved from the manufacturer’s warehouse to a wholesale warehouse. In the case of medicines coming off the market as their validity periods expire, there may exist a paradoxical situation where a harmonized and non-harmonized medicine remain on the market for the same length of time, since a non-harmonized medicine can remain valid for five years, the same as a harmonized one. Only after five years is it possible to apply for indefinite validity of a medicine.

The Health Ministry has prepared a new draft law on registration, making a number of changes in the way the Office functions. The draft is currently undergoing a process of social consultation, and ought to be placed before parliament in September, once it has been approved by the government…

• True. Discussions are currently under way. We will see what the results are. We have to remember that there have been two similar previous proposals, but they failed to get through parliament. For that reason I take a somewhat sceptical attitude to this. We will see what comes of it this time. Interviewer: Robert Miller

Maciej Głowacki, Chairman of the Board Polfa Warszawa for „World of the Pharmaceutical Industry” on the harmonization process Without doubt the process of harmonization has been and remains essential. Its ultimate objective is the good of the patient, who ought to receive safe and effective medicines that fully comply with European quality standards. Accepting that objective, we took a decision to harmonize the documentation for the vast majority of the medicines produced by Polfa Warsaw. This decision inevitably led to high costs being incurred, more than 50 million zloty so far. Over that time we have also taken decisions not to go ahead with the update of certain of our medicinal products. The reasons for not harmonizing these products were varied. Sometimes it was because it was impossible

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to bring the existing documentation into line with the requirements of the Pharmaceutical Law. This applied in particular to older-generation medicines, which pharmacologists had asked to be withdrawn from the market due to their low effectiveness, insufficiently documented therapeutic indications or safety of use. Other reasons included technological problems with the production of a substance, problems with the documentation of certain ingredients, and non-compliance with the company’s product strategy. Economic factors (usually low sales of a particular product) were among the reasons behind decisions not to go ahead with the harmoniza-

tion of certain medicines. However it seems unfair to claim, as has been done recently in the media, that in taking decisions not to harmonize some medicines the pharmaceuticals companies have been guided by financial considerations alone. At Polfa Warsaw that was certainly not the case. I emphasize that it was one of the factors, but certainly not the decisive one. Polfa Warszawa SA is and will remain a manufacturer of medicines accessible to all patients. In 2007 we were the fourth largest firm in the market in terms of number of packages sold, but only seventeenth in terms of their value. These figures speak for themselves.

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interview

Changes at Polfa Łódź A conversation with Marko Dolžan, founder and owner of Sensilab

After years of searching, Polfa Łódź has finally found an investor – the Polish-Slovenian firm Sensilab. What was it that made Sensilab interested in Polfa Łódź?

• The Polish pharmaceuticals market is expanding extremely rapidly. From virtually the very inception of the free-market economy in Poland after 1989, I have had the opportunity to be part of the transformations taking place in that market. Much still remains to be done. There are firms in the market, like Polfa, which need a strategic partner if they are to be able to compete with both foreign and local pharmaceutical concerns. Mergers of mediumsized companies are an inevitable element of increasing operational efficiency. This year Polfa Łódź is celebrating the 75th anniversary of its founding. This means many years of tradition, and huge loyalty among patients, pharmacists and doctors.  But Polfa Łódź is not only a well-known brand. It also has vast experience in manufacturing products to the highest standards. Such a company makes an ideal partner for Sensilab, which can boast flexibility in operations, access to foreign markets, and a well-known brand of specialist dietary supplements. •

What expansion plans do you have? Will the plant’s production portfolio be expanded? What is going to change?

Our plans are ambitious. We plan intensive expansion of the portfolio, although in the short term we want to realize the potential of existing products – under both the Polfa Łódź and Sensilab brands, both in and outside Poland. Naturally we plan to develop manufacturing operations by purchasing new production lines. We are also in negotiation with foreign partner firms which would like to have us manufacture their products under contract manufacturing arrangements.

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Will Polfa Łódź be introducing its products to new markets?

Of course! This is an element of the synergy I mentioned at the start. Sensilab has a presence in 10 rapidly developing markets. One of our priorities is to launch Polfa Łódź’s products on those markets too. Naturally, with regard to new products, we are analysing other markets where we have or will have a presence. Interviewer: Robert Miller

Marko Dolžan Has been working in Poland since 1991. From 1991 to 2005 he headed the company Lek in Poland. Over this period the company’s sales increased from 10 to 100 million US dollars (a 10-year CAGR of 35%). In 1991, as the first foreign investor in the pharmaceuticals industry, he opened the Lek Poland factory in Pruszków. In spite of the many obstacles, since 1997 Marko Dolžan has been pushing through the idea of further expansion and development, leading in 2001 to the takeover of the Łódź-based pharmaceutical company Argon SA, and then the opening in 2003 of a second Lek factory in Poland, at Stryków near Łódź. At the end of 2005, Marko Dolžan and several colleagues founded the company Farmicom in Slovenia, and soon afterwards in Poland the company Sensilab Sp. z o.o., which manufactures and sells specialist dietary supplements. In June 2008 Sensilab took over the Polfa Łódź pharmaceutical manufacturer. The merged companies are now facing up to new challenges and making ambitious plans. In 2001, Marko Dolžan was awarded the honorary Cavalry Cross by Polish President Aleksander Kwaśniewski. Age: 57 Education: Master of Pharmacy.

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logistics

Logistics in pharmacy part 2 Daniel Gralak

GIF Manager of the GMP Inspection Department

Marcin Kołakowski

GIF Manager of the Department of Supervision

The first part of the article on logistics in pharmacy was devoted to issues related to the process of good distribution practice (GDP). The present article, which is a follow-up to the first part, will focus on a few key problems pertaining to good manufacturing practice (GMP).

B

ased on the analysis of the Pharmaceutical Law act of 6 September 2001 (Dz. U. of 2008, No. 45, Item 271), particularly the record of Article 1, Section 1, Items 2 and 4, and the record of Article 65, Section 1, it should be concluded that the legal mechanisms regulating pharmaceutical logistics have been specified by the legislators, both in the main text of the act and in its executive supplements. Nevertheless, logistics concerning raw materials, substances, and finished products, is an extremely difficult and complex matter, taking place both on the EU territory, and outside. The key element of pharmaceutical logistics is transport. It is a component of both GMP, and

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GDP. Nevertheless, it is worth noting that transport itself is not subject to GIF licensing. What is more, in addition to transport itself, permissions do not cover logistic reloading units, present in large corporations. In practice, it is often the case that manufacturers and importers transport API, semi-finished, or finished products, by means of outsourcing. In such events, the only document protecting the client is an appropriately and reliably drawn contract, guaranteeing not only the preservation of product quality by the shipper, but also the possibility of

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logistics

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claiming one’s rights if improper handling of goods should directly influence third parties, which is very probable in the case of medicinal products. It should be remembered that transport concerns both medicinal products “awaiting” release for trading, and those already released; therefore, none of these products will be further subjected to quality checks by the manufacturer. Transport of the product released for trading is not only possible between the manufacturer and the wholesaler, or the consignment store, but also between different manufacturers (e.g. in the case of a contract for production with regard to storage and distribution). The history of pharmaceutical inspection has known cases of an incredible lack of imagination of the “professional personnel” of the transport companies, i.e. the drivers. The problem with pharmaceutical logistics is that the consequences of irrational behaviour influence the priceless value of health and life of a patient, and the estimable value of product brand and manufacturer brand. That is why every forwarder transporting medicinal products must be fully aware of the responsibility. The question of transport in pharmacy can be divided into two basic threads. The first one concerns the actual supervision of the fleet and assessment of its key elements (e.g. cleanliness, technical condition, duration of the ride, duration of the stops, temperature/humidity levels and their monitoring inside the transport chambers). The second one pertains to appropriate security of documentation of the producer and the importer using the services of outsourcing partners. What is particularly important in the process is completing an appropriate set of documents confirming or denying the propriety of transport conditions for a given batch of goods.

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Unplanned stoppages in transport or breakdowns of refrigerators are calculated in the risk of transport. However, a question remains how the forwarder is quickly going to restore the original situation. In case of a crisis, it is also important that the driver knows what load they are handling. It should be the shipper’s duty to inform the receiver of any unexpected situations that had happened during the transport. This fact should be recorded in the transport documents. This might be of crucial importance for the personnel receiving the goods to the store, and for the qualified person who will release the batch for trading or further distribution. However, in the case of importing a medicinal product, determining the responsibility is not as simple. This is because the procedure embraces, first, transport from the third-party country to the customs house, and then transport from the customs house to the importer’s store. The transport contract and the distribution of responsibility are complex. One cannot speak of sole responsibility of the key importer’s personnel for the whole transport, assuming that the customs house remains outside its quality-control system. Transport in the sphere of import is regarded as one of the most difficult to implement, and the most difficult to control. This also stems from the fact that, in many cases, various the means of transport are used (aeroplane, ship, and car), and that the product often passes through different climatic zones. Risk evaluation in such transport must take into account at least a few basic elements, such as the following: the country of export, the number and type of means of transport, the type of the medicinal product (e.g. high-risk products, such as insulin, or vaccines), and the season of delivery (summer/winter). The notion of transport in import is inseparable from the transport of medicinal product samples, which are subsequently intended for research. The samples should be representative of the batch and should be examined within the territory of the European Economic Area. If the samples are received from a third-party country, they should be transported in the same conditions as the batch that they represent, by means of determining and monitoring the storage and transport conditions. The above-mentioned record of Section 6.4 of Appendix 16 – Certification and releasing the batch by a qualified person – which is annexed to the ordinance of the Minister of Health of 2 October 2006 on the requirements of GMP (Dz. U. No. 194, Item 1436 of 26 October 2006), obligates a qualified person to compare the key elements of transport.

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logistics

The first one should be based on the monitoring of sample transport, and the other form is for the monitoring of transport of the rest of the batch. The purpose of the analysis is gaining certainty that, in both cases, the transport was conducted properly and in identical conditions. Only then can it be affirmed that the results of sample analysis are authoritative of the whole batch. Unfortunately, in practice, the process of admitting a medicinal product for trading often proceeds differently. The qualified person admits the medicinal product for trading solely based on laboratory tests of the sample, without waiting for the transport of the remaining part of the batch to the place of destination. Such action not only disagrees with the requirements of Appendix 16 but also exposes the qualified person to grave consequences. Although a negative evaluation of the transport conditions may result in detaining the transport in the importer’s store, a formal decision on admission for trading is issued regardless of the key element, which, in the case of import of medicinal products, is the assessment of transport conditions. Such action violates the provisions of Appendix 16. Another question to be discussed is the “return” transport of the medicinal product from the distribution network to the manufacturer, resulting from an administrative decision of GIF to withdraw the product from trading. In 2007, out of 118 decisions of withdrawal, GIF reversed about 7.6% of them. In the first 6 months of 2008, this index amounted to 13%. Therefore, there has been an increase in the number of medicinal products that were returned to distribution, having been previously withdrawn from trading. This is why every responsible agent, importer, and manufacturer should be aware of proper supervision over the product at the logistic stage of returning it to the main store. Documents certifying the supervision of transport conditions should be included in the documentation of the withdrawn batch and may be subjected to inspection after a possible decision on the readmission for distribution.

Moreover, it should be remembered that, in such cases, full product examination is not always repeated, because it is conducted before the original decision of release for trading. Assuming that the only manufacturing operation on the withdrawn batch often is the process of re-packaging, it is absolutely important to monitor the conditions of the return transport and storage of the medicinal product in a withdrawn products’ store. A qualified person must be sure that the product re-released for distribution is absolutely safe and effective. Until recently, the existing regulations did not simplify closing the balance of withdrawal. The products returned to the factories at various times and in various quantities. The ordinance of the Minister of Health of 12 March 2008 on the specifics of withholding and withdrawing medicinal products from trading significantly allays this problem, because Paragraph 5, Section 2, Item 7 orders the manager of a pharmaceutical wholesale firm to return the accumulated stock of the product to an authorised party, or to the manufacturer within no more than 90 days of the date of receiving the decision on withdrawing the product from trading. This regulation should simplify the process of withdrawal and consequently facilitate the supervision over transport conditions of the products returned for trading. There is one more important element of the logistics in pharmaceuticals to be emphasised. It is the possibility of tracing the path of the batch during the whole length of its market life. The process of batch tracing is extremely important from the point of view of every competent institution. Not only does it enable an efficient evaluation of the quality and quantity of the traded product, it also provides assurance that all participants in the trade are authorised entities. Taking into account the disturbing news from Europe on counterfeited medicinal products, appropriate control of the batch documentation is not only in the interest of competent institutions, as GIF, but also, or perhaps most of all, in the interest of all participants in the product path, on its way from the original manufacturing place, and consecutive manufacturers, importers, or wholesale firms, and finally to the patient. The contract should specify the scope of the responsibility of both parties. It should describe the behaviour of the forwarder in case of a crisis, the type of documents that they are obliged to hand over to the client, and the manner of forwarder’s personnel training. To sum up, the success of pharmaceutical logistics on the part of the manufacturer and the importer of medicinal products is always inseparably bound with two elements: a well-construed contract with the forwarder, and a proper system of quality checks, guaranteeing the existence of relevant documentation within the company.

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logistics

Full control over the implementation and quality of a logistical process Process efficiency is most important – technology and systems should support it Bartosz Jacyna Logisys Sp. z o.o.

At one of the largest pharmaceuticals distributors in southern Poland, a project was carried out to deploy palmtop terminals for use in order preparation. The cause was a noble one: to increase control and improve human productivity. However the effect was just the opposite, and the project failed spectacularly. How, then, can we effectively improve the efficiency and accuracy of logistical operations without unnecessary investment risk?

Bartosz Jacyna Business Relations Partner, Logisys Ltd. Representative, RFID Konsortium

An ERP system does not ensure logistical efficiency Fork-lift operator Andrzej has had a bad day. He has just finished making up an order for a customer, and in the place where there should have been a palette ready with an order for a warehouse in Piaseczno, there was just an empty space! “That’s the third time this week...” he sighed. “Another hour’s searching, and the driver’s already waiting.” In the modern business, the management of production, warehousing, distribution and other aspects of operations is supported by computer systems. However, management systems of ERP, MRP and SCM (including WMS) types do not eliminate all the problems. Many discrepancies arise, the data are often not up-to-date, sometimes the information is incorrect or incomplete. These problems normally arise where there is contact between the system and humans, namely where things are constantly being done on the basis of printed sheets or from memory. Most sensitive to such errors – from the costs standpoint – are logistical processes within the firm and between firms. Erroneous dispatch of goods, palettes left in the wrong place, and the inability to reward wareho-

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use staff for productivity and accuracy, lead to higher costs in connection with corrective actions and with obtaining reliable information about the true state of affairs. This is the case because even the best and most expensive systems are physically separated from the processes – both in terms of space (when information is conveyed only on a printed sheet or in an employee’s memory) and time (information reaches the system only after a delay), and in terms of the level of detail of the information. The Distribution Manager has just hung up the phone. A customer was angry that once again he had received something other than he had ordered. The difference was not great, but anyway no payment will be received until the matter is cleared up. The Finance Director will be displeased once again. Sending the correct order will produce an additional burden on the distribution budget. It is not even possible to check who made this costly mistake. Any bonus for this quarter has probably gone to the devil. The Distribution Manager felt powerless... For this reason there is a need to give the system “eyes and ears”. Examples of answers to that need include marking key elements or packages with bar codes or RFID tags

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Ergonomic operation supports productivity and reduces unit operating costs Because the processes within firms and their specific features are so varied, every project to integrate systems with devices is different. Even the number of types of devices and portable computers which might be used is very large. Finding an optimum solution (favourable from the standpoint of the logistical process) for integration is not a simple matter. The complexity of technologies of communication, integration, data exchange and architecture provides an additional challenge in projects of this type. A wrong decision in choosing hardware, or non-optimum unreliable communication, can significantly reduce the positive effects of an investment project. The shape of the solution is often decided by IT specialists, which in consequence means that all of the functions will indeed be implemented, but in a very inconvenient and slow fashion. We hear more and more often of deployments which significantly SLOWED DOWN work, even though everyone had expected it to be speeded up. This turns the balance-sheet of deployment upside-down. This happened in the case of the distributor mentioned at the outset, where the firm chose a device without taking account of the specifics of practical operation (this is very easily done when devices are tested only for half an hour in the office, rather than for eight hours in battlefield conditions). Another reason for the failure was that the IT supplier was inexperienced in logistics matters. Although the distributor had been using the services of that firm for many years, in this project it had to establish everything by trial and error. This teaches us a valuable lesson:

Beware – IT experts don’t know logistics! The proposed solution should be dependent on the parameters of the process and the speed and accuracy of its execution. More importantly, the solution should take account of many domains and factors: organization, ergonomic operation, risk and adaptability. The IT system and devices come right at the end! The design and implementation of integration obviously requires not only specialist middleware, but also a searching analysis of the process itself and development of a strategy for integration with the main system, so that the project can not only fulfil present needs, but also take account of predicted future needs.

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Full control and statistics Main ERP and WMS systems collect statistical data, but these are usually not precise enough to give full control over the process. Because the integration of devices is based on middleware, it is possible to collect very detailed data about individual operations, including the time taken to complete them. Waldemar was making an inventory of a transport load. Although two large W65-type packages were missing, on Waldemar’s sheet everything seemed in order. “Who could be bothered wasting time investigating the difference?” he asked himself rhetorically. At worst someone else will come up against the problem; Waldemar will in any case have no reason to worry. Such data can, on analysis, provide a full picture of events, making it possible to assign precise responsibility to individual employees and machines and to optimize (and verify the optimization of!) the steps in a process.

logistics

(ensuring unambiguous identification), reading the codes at appropriate points in the logistical process, enabling operational staff to access the system at exactly the place and time where it is needed using mobile computers, application of marking standards which can be used throughout the logistical chain, etc. A sophisticated and sufficiently well-designed integration of processes and their supporting devices with the main system enables an accurate flow of data in real time and the collection of detailed operational data giving many analytical possibilities. The binder to create an infrastructure for such integration is comprised by the specialist software known as middleware.

Security is fundamental Interrupting a logistical process due to computer system problems is very expensive. For this reason much attention has been paid to the security and stability of integration solutions. On one hand the applications on the mobile terminals should be resistant to loss of battery power (reinstallation takes time), and also to destabilization by an employee. On the other hand – if there is to be real employee responsibility and data security – the application and data should always remain accessible to authorized users only. For this reason three-level authorization on logon is used.

System – and hardware-independence brings savings In the long term, needs and processes evolve. This is particularly visible in the pharmaceutical industry, where markets expand at a rapid rate. For this reason the middleware should offer a high level of flexibility, to make later adaptation of the integration solutions simple and inexpensive. It is important in the medium term to enjoy independence from the type and make of hardware. This enables uncomplicated expansion and replacement of devices, and avoids dependence on a particular supplier. This makes it possible on one hand to make use of existing devices, and also to negotiate better prices for new ones. Also important is independence from the automatic identification medium. For example, in the process of marking goods for issue to a group of customers, firm A currently uses barcodes, but perhaps a larger customer will have a requirement for parallel marking of logistical units with an RFID tag. The operational logic of the middleware does not change – it is simply necessary to introduce a different type of marking device. Benefits of independence from the main system include both improved quality of the solution and the ability to make unlimited changes to the main system in the future – or even to replace the whole system. This provides a very important saving – the costs already spent on investment in integration will not have to be incurred in full once again.

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logistics

Counting, sealing and labeling Error-free counting of products at various stages of the production process is no easy task when we are faced with a tray filled with vials, inserts or ampoules. And if after counting the tray has to be sealed in such a way that while in quarantine no unauthorized person can open it, and the tray has to be marked so that all necessary information is legible for later stages of production – and we want to achieve all this using one machine – then it becomes a challenge. This was the challenge faced by UNILOGO when, in cooperation with specialists from Bioton SA, it designed a device for counting insulin vials and inserts. Grzegorz Dziewanowski UNILOGO

A

fter many months of thorough testing, selection of sealing materials and software design, the device was made and installed at Bioton’s plant in Macierzysz. At one ergonomically designed working position the device combines three functions: counting, sealing and labelling. During the machine’s work cycle the operator moves the tray manually between positions.

Counting in 3D

counting, cutting off access to light. To enable the counting of different products on trays, such as vials, flasks and inserts, for each product an algorithm is defined for processing the image obtained. This algorithm takes account of the height of the package, the diameter and colour, and also the size of the tray. After scanning, the image is converted so as to cut off areas located at a given height (e.g. caps of bottles), thus producing “patches” of defined area, which are very easy to count. The probability of a counting error, if the packages on the tray are well arranged, is practically negligible.

The counting function is performed by a one-of-akind 3D video camera, which moves above the product tray. This is a visual system based on a very fast CMOS processor operating in three dimensions (x, y, z) with a maximum possible rate of 5000 profiles per second. The device uses a triangulation method to create an image of the object. This uses illumination, perpendicular to the camera’s direction of movement, of a product tray lying under the camera, with successive laser line images being stored in the camera’s memory. From these successive scans (profiles) a 3D image The camera Image processed Inset the product tray scans – blue “patches” is created. In this way it is possible to are counted scan differently shaped and sized objects. Moreover the camera, having its own illumination A compact seal (a laser), can function practically regardless of the colour After the products have been counted the tray is scheme of the object. To minimize the likelihood moved to the sealing position, where it is sealed with two of disturbance of the camera by outside factors, ultrasound-welded 30mm-wide bands of polypropylene. the housing closes automatically for the time of At the next position a seal label is printed containing essen-

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UNILOGIC – and everything’s under control The device’s operation is managed by original Unilogic software, specially developed for the purpose of this application. It operates under the Windows CE operating system. Great attention was paid to the convenience and simplicity of use of this software, as well as its functionality, taking into account the possibility of future communication with a master system such as SAP. The device is operated via a convenient touch panel and function buttons. The operator logs into the system, and then enters the data necessary for the later generating of a label, including the product type, batch number and expiry date. The entire cycle of the machine’s operation is then started using a function button. Unilogic ensures that all stages are performed properly and in the correct order. When the operator selects a product, Unilogic selects the appropriate image processing algorithm for that product. If the operator provides a different product

for counting than was set, an alarm is activated. After the products have been counted, the count result from the camera is read by Unilogic and is used, together with the data previously entered by the operator, to produce an individual label for each tray. During sealing the machine checks whether the tray cover is properly in place and whether the bands are applied in the correct order – any error activates an alarm. Next the seal label is generated, printed and stuck on. The uniqueness of each seal label is ensured by a 128 code containing the batch number, tray serial number and the quantity on the tray. It is also verified that the seal is correctly printed and affixed. This is done using a scanner, which reads the 128 code from the label after application. Only when confirmation is received from the scanner is the information on the packed tray recorded in the device’s database and the cycle closed. The labels generated by the software include not only seals for individual trays, but also additional labels per carton (if the tray is later packed) and per palette of trays. The palette label is printed at the time it is needed. To enable to device to generate and print carton labels, the operator scans the 128 code previously placed on the tray. Also, when work is complete, it is possible to print out a batch report containing all information necessary for production auditing – number of packed trays, number of products on the trays and number of palettes.

logistics

tial information such as the number of products on the tray, the batch number, the date of packing, and an individual barcode for each tray. The label is then stuck over the crossing-point of the two bands. The material of the label is chosen so that it is not possible to remove it from the bands without damaging the label. This makes sure that the contents of the tray will not be interfered with by unauthorized persons during quarantine.

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production

Wet granulation of milled lactose Brenntag

Lactose is commonly wet granulated with microcrystalline cellulose in the preparation of pharmaceutical tablets. The studies reported in this article examine the effects of lactose / MCC ratio, lactose particle size and polyvinylpyrrolidone concentration on granule and tablet properties.

I

t was found that the breaking force of tablets made by high shear granulation of lactose and MCC is most affected by the lactose / MCC ratio and the particle size of the lactose. Harder tablets are achieved by reducing the proportion of MCC, and by use of finely milled lactose. In comparison, the PVP level had only a small effect.

Lactose is a disaccharide obtained from the whey of milk. It may exist in a number of distinct forms depending upon the crystallisation and drying processes employed. The forms can vary in he contents of crystalline and amorphous lactose, the amounts of α-lactose (O-β- d galactopyranosyl-(1→4)-α- d -glucopyranose) and β-lactose (O-β- d -galactopyranosyl-(1→4)-β- d -glucopyranose), and in their hydration states. The α-form of lactose exists in either the anhydrous (C12H22O11 = 342.3)

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or monohydrate (C12H22O11,H2O = 360.3) state whereas the β-form exists only in the anhydrous state. Some pharmacopoeias include separate monographs for anhydrous lactose and lactose monohydrate. Ph.Eur. 5.5 (Lactose Anhydrous). It is β-lactose or a mixture of α-lactose and β-lactose. A white or almost white, crystalline powder. Freely but slowly soluble in water; practically insoluble in alcohol. Ph.Eur. 5.5 (Lactose Monohydrate). It is the monohydrate of α-lactose. It may be modified as to its physical characteristics and may contain varying proportions of amorphous lactose. A white or almost white, crystalline powder. Freely but slowly soluble in water; practically insoluble in alcohol.

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Lactose is widely used as an excipient in pharmaceutical manufacturing. In the production of capsules or tablets it may be used as a diluent, bulking agent, or filler, and in powders as a bulking agent. Lactose is also used as a carrier for drugs in dry powder inhalers. Characteristics such as particle size or flow characteristics make different grades of lactose suitable for different applications. Mostly as a bulking agent for productions of granules or tablets. In opposition to recently opinions lactose is still important excipient for tablets and capsules productions, wide use in a wet granulation process even as a mixture with MCC.

Product characteristics

Wet Granulation Process

The three main types of wet granulation process are: • low shear granulation, (planetary mixer), • high shear granulation, (high speed mixer with an impeller and chopper) • fluid-bed granulation, (fluid-bed drier).

The most widely used excipients for granulation are microcrystalline cellulose, lactose and dicalcium phosphate. Process Principles Wet granulation is a process in which a mix of powders is agglomerated with a liquid binder forming larger particles or granules. These granules normally have a size distribution in the range of 0.1 - 2 mm, and are mainly used for tablet compaction and capsule filling.

Wet granulation is typically used to improve the flow, compressibility and homogeneity of the mixture used to produce solid dosage forms.

Powder particles • • • •

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Classical process. Build-up of granulates from powder. Comparison. Wet granulates are generally denser and more mechanically stable particles than fluid bed granulates. Product advantages. Fast build-up of granulate. Compact and stable structure. Grain sizes between 0.1mm – 2 mm even 10 mm possible depending upon the downstream sieve.

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Wet granulate • Dust free • Good flow • Easy to dose • Good dispersibility • Good solubility • Highly suitable for making into tablets • Compact structure • Low hygroscopic condition • High bulk density

Wet granulation (high shear granulation/high shear mixing) in a vertical or top-drive granulator is the classical method for building up granulates from powder. In this process, powder is fed to a product container and then moistened or sprayed with molten material in order to

increase the cohesive forces. The liquid can be water or an organic solvent, if necessary with a binder. At the same time, the ingredients are mixed together vigorously. Denser granulates are formed than in the case of agglomeration/granulation in the fluid bed. • Dust-free, high-density granules. • Uniform pellet-shaped particles. High throughputs. • Mixing/granulation in the shortest possible time. • Economic process. Low air/ gas requirement. • Processing of different starter products. This study (1) describes how some formulation and process factors affect the properties of granules and tablets made by the high shear granulation process.

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Granulation and Compaction Materials: milled lactose (Pharmatose 150M, 200M, 350M and 450M, DFE (former DMV International)), microcrystalline cellulose (MCC) (Pharmacel 101, DFE (former DMV International)), polyvinylpyrrolidone (PVP) (polyvidone K30, Bufa bv), sodium starch glycolate (SSG) (Primojel, DFE (former DMV International)) and magnesium stearate (Bufa bv). Granulation: All granulations were performed on a laboratory scale high shear granulator (Formate 4M8, Procept nv, Zelzate, Belgium). After 5 minutes dry mixing (lactose, MCC and PVP), water was added to the mixing vessel during 8 to 10 minutes. After water addition the granulation was wet massed for 2 further minutes. The granules were dried in a Fluid bed dryer (Retsch TG-1, Retsch GmbH, Haan, Germany), passed trough a 500 µm screen using a sieve shaker (Retsch Vibro, Retsch GmbH, Haan, Germany) and stored in plastic bags. Compaction: After conditioning the granules overnight in a climate chamber (HC2020, Heraeus Instruments, Hanau, Germany), at 30%RH and 20°C, the granules were mixed with 0,5% w/w magnesium stearate in a Turbula Mixer (T2C, W.A. Bachofen AG, Basel, Switzerland) for 5 minutes at 90 rpm. The mixtures were compressed on an instrumented rotary press (RLE 15 AM, Kilian & Co. GmbH, Cologne, Germany), at 10, 15 and 20 kN, and a targeted weight of 250 mg (± 3 mg). The tablets were stored in air tight containers. Granule and Tablet Testing Granule Testing: The poured bulk density was measured by the weight of the granules in a 250 ml cylinder and expressed in g/l. Tablet Testing: Tablet hardness and dimensions were determined 24 hours after compaction using an Erweka hardness tester (TBH 300 MD, Erweka GmbH, Heusenstamm, Germany). For each batch 10 tablets were tested. Disintegration times were determined using an Erweka disintegration tester (ZT-3). Six tablets were tested (using no discs). Friability was determined by taking a sample of whole tablets corresponding to 6.5 gram, using an Erweka friability tester (TA-UZ) operated according to the USP procedure.

Results and discussion The results and discussion are divided in four separate parts: • The effect of the lactose / MCC ratio on granule and tablet properties. • The effect of particle size of milled lactose on granule and tablet properties. • The effect of the amount of binder on granule and tablet properties.

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The effect of lactose / MCC ratio Microcrystalline cellulose is frequently used in combination with lactose in wet granulation processes. Lactose compacts predominantly by brittle fracture while MCC exhibits plastic deformation. The ratio of these two filler binders can affect tablet properties, and these experiments studied MCC proportions in the range 0-50% of the total granulation mass as shown in Table 1.

Component

% w/w

Pharmatose 200M Pharmacel 101 Polyvidone K30

48-98 0-50 2

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Experimental Section

Table 1.

Granule formulation to study the lactose / MCC ratio

In these batches the amount of water used for granulation was 0.83 times the amount of MCC, except the 0% MCC (4% water added).

MCC (%)

Density (g/l)

Strength (N)*

Friability (%)*

0 5 10 15 20 30 40 50

570 505 497 485 477 616 618 655

109 103 103 96 88 63 66 35

0,12 0,14 0,12 0,12 0,13 0,12 0,10 0,29

Table 2.

Effect of % MCC on the poured bulk density and tablet properties. * At 15 kN compaction force

As shown above, and in Figure 1, the breaking force of the tablets decreases with increasing MCC content. Above 20% MCC the granule density also increases steeply. It is known that wet granulation of MCC leads to granule densification and loss of compactibility(2), and this mechanism is also thought to be responsible for the observed changes in breaking force when MCC is granulated with lactose. To test this theory, granules were prepared according to the formulation in Table 3 but using different amounts of granulating water (28%, 56% and 83% of the amount of MCC,). These granules were blended with 2% SSG (Primojel)(3-6) in addition to 0.5% magnesium stearate before compaction.

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production

Effect of particle size of milled lactose From published data(7) it is known that the breaking force of lactose tablets increases with decreasing particle size of the lactose crystals. The four milled lactose batches used in this study have different particle size distributions listed below in Table 5. Pharmatose

D10 (µm)

D50 (µm)

D90 (µm)

150M 200M 350M 450M

4.6 3.4 2.9 2.7

54 35 28 21

159 108 79 49

Table 5. Figure 1. Effect of lactose/MCC ratio on the compactibility profile Component

In order to study predominantly the effect of lactose particle size on granule and tablet properties, the formulation used contained only 10% MCC as shown in Table 6.

% w/w

Pharmatose 200M Pharmacel 101 Polyvidone K30

68 30 2

Table 3.

Granule Formulation to study the effect of granulating water quantity The results in Table 4 and Figure 2 show that decreasing the granulating water quantity causes a decrease in the granule density and an increase in the breaking force of the tablets, in accordance with the proposed explanation. Tablet disintegration times (15 and 20kN compaction forces) increase with increasing granulating water, again as a consequence of increased granule density.

Water 28% 56% 83%

Density (g/l)

Strength (N)*

Disintegration time (sec) *

510 586 682

96 62 27

33 38 54

Table 4.

Effect of the amount of liquid binder on poured bulk density and tablet properties. * At 15 kN compaction force

Figure 2.

The effect of the amount of water (added to a 30% MCC mixture) on the compactibility and disintegration time.

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PSD of used milled lactose’s by Sympatec dry powder laser diffraction at 3.0 bar

Component

% w/w

Pharmatose Pharmacel 101 Polyvidone K30

88 10 2

Table 6.

Granule formulation to study the effect of lactose particle size. In these batches the amount of water used for granulation was 0.86 times the amount of MCC. The results are shown in Table 7 and Figure 3. Pharmatose 150M 200M 350M 450M

gęstość (g/l) 563 538 545 517

wytrzymałość (N)* 65 101 110 132

Ścieralność (%)* 0,15 0,13 0,14 0,13

Table 7.

Effect of PSD of lactose on the poured bulk density and tablet properties. * At 15 kN compaction force

Figure 3.

Effect of lactose particle size on the compactibility of granules.

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Effect of amount of binder on compaction A binder such as polyvidone K30 is usually added in concentrations from 2-5%(9). Table 8 shows the formulations used to study the effect of binder concentration. Component (%w/w)

1

2

3

4

Pharmatose 200M Pharmacel 101 PVP K30 Water

89 10 1 10

86 10 4 10

69 30 1 27

66 30 4 27

With 10% MCC in the granules MCC, increasing the PVP from 1% to 4% has a small beneficial effect on tablet breaking force, but this effect is not evident with 30% MCC granules.

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Granule density is not greatly affected by lactose particle size distribution, but there is a strong effect on tablet breaking force. The effect of the lactose particle size on the breaking force can be explained by the fact that smaller crystals have a higher surface area available for bonding within the tablets(8).

The data are also in general agreement with Figure 1, where it is shown that a higher amount of MCC gives tablets with a lower breaking force.

Conclusions From the data presented here, the breaking force of tablets made by high shear granulation of lactose and MCC is most affected by the lactose / MCC ratio and the particle size of the lactose. Harder tablets are achieved by reducing the proportion of MCC, and by use of finely milled lactose. In comparison, the level of PVP K30 used as a binder had only a small effect.

Table 8.

Granule formulations to study the effect of binder concentration

References Figure 4 and 5 show the effect of the amount of PVP on granules with 10% and 30% MCC.

K. Kussendrager, J. Langridge, (Nörten Hardenberg), B. Walsma, (Veghel) own research and information DMV-Fonterra Excipients,

S Westermarck, AM Juppo, L Kervinen and J Yliruusi, Microcrystalline cellulose and its microstructure in pharmaceutical processing, Eur. J. Pharm. Biopharm., 1999, 48(3), 199 – 206.

E Schotten and GS Leonard, Effect of intragranular and extragranular disintegrating agents on particle size of disintegrated tablets, J. Pharm. Sci., 1993, 82, 1170 – 1174.

HV van Kamp, GK Bolhuis and CF Lerk, Improvement by superdisintegrants of the properties of tablets containing lactose, prepared by wet granulation, Pharm. Weekbl. Sci. Ed., 1983, 5, 165 – 171.

MS Gordon, B Chatterjee and ZT Chowhan, Effect of mode of addition of croscarmellose sodium incorporation on tablet dissolution and friability, J. Pharm. Sci., 1990, 79, 43 - 47.

I Khattab, A Menon nad A Sakr, Effect of mode of incorporation of disintegrants on the characteristics of fluid bed wet

Figure 4.

Effect of % PVP on compaction of lactose/MCC tablets (10%MCC).

granulated tablets, J. Pharm. Pharmacol, 1993, 45, 687 – 691. •

JT Fell, and JM Newton, Effect of particle size and speed of compaction on density changes in tablets of crystalline and spray-dried lactose, J. Pharm. Sci., 1971, 12, 1866-1869.

AH De Boer, H Vromans, CF Lerk, GK Bolhuis, KD Kussendrager, and H Bosch, Studies on tableting properties of lactose III. The consolidation behaviour of sieve fractions of crystalline α-lactose monohydrate, Pharm. Weekbl. Sci. Ed., 1986, 8, 145-150.

V Bühler, Kollidon, polyvinylpyrrolidone for the pharmaceutical industry, 6th edition, BASF, 2001, 73.

Figure 5.

Effect of % PVP on compaction of lactose/MCC tablets (30%MCC).

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The monitoring and evaluation of the phenomena occurring during the studies on the release of medicinal substances Przemysław Dorożyński

P

A is defined as the quantity of a medicinal substance, measured in in vitro conditions, which is released from the dosage form and dissolved in the surrounding liquid, and the speed at which this process progresses.

Pharmaceutical availability (PA) is one of the more important parameters characterising the quality of a medicinal product, because it describes many of its properties. This is why this parameter is an essential element in assessing the pharmaceutical equivalence of many medicines.

Research on the release of medicinal substances is accompanied by a broad range of information concerning the analysed preparation. First, the research results are characterised by numerous physical and chemical properties of the dosage form. This is because many changes occurring within the analysed preparation are reflected in the changes of the release profile of the medicinal substance. These changes may be intended, concerning the composition or methods of production of the medicine, or they might be changes resulting from the inappropriate course of medicine production, or finally, resulting from the ageing of the product (e.g. decrease or increase in tablet hardness). Another important direction of studies is the comparison of release profiles of various preparations, which may take place during development research, when an optimum preparation formulation is sought or in the initial stage of bioavailability studies. In the case of solid oral dosage forms, a PA study is conducted as a starting element for assessing the bioavailability and bioequivalence of the medicinal substance, and in some special cases, it may wholly replace them. This is because, in the case of oral dosage forms, it is relatively easy to determine the relations between the released quantity of the substance, and its biological availability. In the case of

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other dosage forms (e.g. ointments), the study of pharmaceutical availability is an important element of quality control of the preparation. Consequently, it is possible to analyse the influence of changes in the production process on the properties of the product and to make quick and efficient assessments of the repeatability of production series. The general assumptions for conducting research on the release of medicinal substances were described in pharmacopoeial monographs. Whereas, detailed questions concerning the study of the release of medicinal substances can be found in specialist book publications, numerous publications in professional journals, and in the Internet resource bases, e.g. http://www.dissolutiontech. com, http://www.tabletdissolution.com. In early November of 2005, FDA launched a database presenting the recom-

Figure 1.

Removing the coat of a tablet coated with membraneforming substances in the early stage of release

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Figure 2.

A coated tablet sticking to the bottom of the glass during a drug release study

mended specifications of medicinal substance release research. Access to this webpage and its search engine is available at: http://www.accessdata.fda.gov/scripts/cder/dissolution/ Multi-directional possibilities of using the obtained research results on PA make it very difficult to determine the conditions for their conduct and to justify one’s choices afterwards. As it was already mentioned, the drug release profiles, apart from routine quality checks, may be used in diversifying the preparations during development studies. On the basis of them, important decisions are made regarding further research, and the final properties of the prepared medicines. Advice given in detailed monographs of some pharmacopoeias (e.g. FP 6, USP) on the conditions for conducting drug release research mainly concerns the routine methods of quality checks, and it is difficult to apply in experimental research and development studies. Especially because an incorrect choice of drug release method may give incorrect results, and consequently, lead to faulty conclusions on the properties of the analysed preparation. Practice shows that, before deciding on the choice of research conditions, it is beneficial to conduct preliminary

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tests, during which the occurring phenomena accompanying the drug release are observed. This is also indicated in the General Monograph No. 1092 USP 30 “The Dissolution Procedure: Development and Validation,” which emphasises that visual observation and monitoring of drug release and disintegration processes, and they are very useful in identifying the variables affecting the properties of preparations. The following figures present examples of phenomena observed during PA studies, which may affect their results. In the case of coated tablets, it is often observed that the coating is dissolved unevenly, which increases the variability of the results (Fig. 1). Another frequent problem is the sticking of tablets to the bottom of a glass (Fig. 2). This phenomenon results in a decrease of quantity of the released substance. Also, the formation of a small heap of the tablet mass on the bottom of the glass may cause underrated result values of drug release (Fig. 3). Another effect to be observed is the limited solubility of soft gel capsules. This kind of dosage form contains a solution or suspension of a drug,

Figure 4.

The contents of a soft gel capsule after dissolution of the coating which may remain unmixed and undissolved in the solution used for drug release analysis (Fig. 4). Such observations may constitute valuable information allowing for correct choice and optimisation of the method of PA analysis. For example, in the case of tablets sticking to the bottom, the shovel method may be replaced by the rotating basket method, while the formation of a heap of tablet mass may be avoided by increasing the mixer revolution. The presented examples of monitoring the phenomena occurring during the PA analysis prove that observations of this kind may be a valuable addition to the research, allowing for the identification and better understanding of the phenomena occurring during the drug release studies, as well as their influence on the release profile. Photographic documentation may also be the basis of justifying the choice of the method of PA analysis.

Figure 3.

The heap of tablet mass, forming on the bottom of the glass after tablet disintegration

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sponsored article

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Let the braille be visible! DRUK-PAK S.A.

The EU Directive containing instructions concerning pressing of descriptions in Braille on pharmaceutical packages evoked much controversy with regard to the correctness of the methodology of pressing of such inscriptions and labels.

Mr. Marek Jakubowski, a tactile graphics designer, in cooperation with the Polish Association of the Blind have undertaken the task of organising and arranging the issue of pressing of the Braille code on the packages with drugs and medical preparations. High costs notwithstanding, Kujawskie Zakłady Poligraficzne DRUK-PAK S.A. from Aleksandrów Kujawski offered their partnership by making available a modern stock of machine tools, experience and recommendations of numerous pharmaceutical companies. Up till now the company has produced over 500 types of pressed packaging on almost 70 million pieces

Example of correct stamping on cardboard packaging – DRUK-PAK Aleksandrów Kujawski: Studia Tyflografiki collections The ever growing number of packaging with pressed Braille writing not always meets the highest quality standards. Quite often the voices of the visually impaired people can be heard complaining about the correctness and legibility of the Braille code. Therefore, it was important to conduct tests and verifications. Those would not be possible without the assistance form DRUK-PAK company. The very strict and demanding standards concerning the quality of the pressings that the manufacturer applied with regard to its products guarantee a good quality of the pressed tactile graphics. In order to press the description in Braille correctly it is necessary to use a proper kind of matrix and counter with convex dots forming the proper touch-readable inscription. The matrixes and counters used are deep etched, milled and cast of noble metals and magnesium components. Polymers are also commonly used. DRUK-PAK has its own, based on its experience, method of pressing of the Braille symbols on printing sheets, which guarantees high readability of the text.

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One contentious issue is the height of the pressed Braille signs. It is impossible to combine a flat fully coloured print with deep pressing of the Braille alphabet on the packaging face which would be devoid of micro-cracks and interruptions. However, these flaws perceived by the sighted are caused by a deep pressing of about 0.5 mm, which gives a very good readability of the signs. The bottom value of readability proved to be the height of 0.13 mm. During the tests conducted at DRUK-PAK facilities the desired height of 0.5 mm was achieved without any difficulty. However, the structure of the cardboard box with a fully coloured print was always damaged. The box lost some of its aesthetic value, but the inscription was flawless according to the performed measurements and in the opinion of the blind consultants. When pressing the Braille inscriptions on drug packages, we must reconcile two groups of recipients. The sighted, who value the aesthetics and readability of the visible information and the blind, who need the Braille information to be clear and readable. The compromise would be to lower the height of the pressing of the Braille dots for the blind and to accept the micro-cracks in the places of the pressings by the sighted. Various experiments conducted by DRUK-PAK on numerous types of cardboard proved that 0.13 mm is the boarder beyond which the micro-cracks appear – in most cases not visible with the naked eye and not spoiling the aesthetics of the packaging.

Examples of microcracks on market products, significantly magnified: Studia Tyflografiki collections The social responsibility of both pharmaceutical companies and manufacturers as well as the society as their customers should aim at accepting the micro-cracks and minor damages on the surface of the packaging. Printinghouses will be able to press Braille with full responsibility in parameters higher than the current ones without the risk of being accused of neglecting aesthetic values when manufacturing the packaging. Let the Braille be visible!

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Impact of GAMP®5 what does this mean to Polish Life Science industry Paul Irving, Sion Wyn As a new emerging market Poland as part of Central and Eastern Europe, needs to be in touch with global industry standards and approaches. It is as an experienced practitioner, that the author of this article truly embraces the spirit and application of the concepts detailed in the new GAMP® 5 Guidance for industry.

T

hrough many years of working in the industry and in cooperation with the regulators it is felt that this guidance and recommended industry best practices, will help companies in Poland form an agile and innovative approach to the implementation of computer systems in a compliant and cost effective manner and help: • protect the safety of the patient • improve product quality • improve time to market by reduction of bureaucracy and optimizing quality assurance • focus the qualification/verification/validation efforts on the areas of greatest risk and potential impact • I strategic, project and program management Going forward in years to come, guidance such as ISPE GAMP, will compliment regulatory requirements, and enable Pharmaceutical Life Science industry better interpret the predicate rules and ensure that they are in compliance with those same underlying rules.

What is new in GAMP®5 GAMP (Good Automated Manufacturing Practice)®5 has been updated to align with the concepts and terminology of current industry and regulatory developments. These regulatory and industry developments focus attention on patient safety, product quality and data integrity. This is a key driver for GAMP 5. The main body of the document encompasses the following topics, which are described as fundamental KEY CONCEPTS: Key Concepts • Life Cycle Approach Within a QMS • Scaleable Life Cycle Activities • Process and Product Understanding • Science-Based Quality Risk Management • Leveraging Supplier Involvement

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Sion Wyn

Director, Conformity Ltd., is an acknowledged expert in computer system validation and compliance and international regulations in this field

Paul Irving

has extensive experience as a Compliance and Validation Consultant with most of the major international Pharmaceutical companies.

Life Cycle Approach The Life cycle approach see Fig 2 defines activities in a systematic way from understanding requirements to system retirement. It enables management control and a consistent approach across systems. It is fundamental to GAMP® 5 and embodies each of the other key concepts. The life cycle should form an intrinsic part of the company’s Quality Management System (QMS), maintained up-todate as new ways of working are developed. The QMS should enable continuous process and system improvements based on periodic review and evaluation, operational and performance data, and root-cause analysis of failures. Identified improvements and corrective actions should follow change management.

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Fig. 1.

Figure shows the relationship of these important key concept

Scalability of Life Cycle Activities Scalability life cycle activities should be based on the following: • System impact on patient safety, product quality and data integrity (risk assessment) • System complexity and novelty (architecture and categorisation of system components) • Outcome of supplier assessment (supplier capability) • The strategy should be clearly defined in a plan, and follow established and approved policies and procedures. Process and Product Understanding Companies need to have an understanding of the business processes that systems touch. This is fundamental for determining system requirements and as a basis for making science and risk based decisions to assure that the system is designed and verified to be fit for its intended use. Efforts should focus on those aspects of systems that are critical to patient safety, product quality, and data integrity with these critical aspects being identified, specified and verified.

Companies should focus their effort on systems that support critical processes: • Generate, manipulate, or control data supporting regulatory safety and efficacy submissions • Control critical parameters in preclinical, clinical, development, and manufacturing • Control or provide information for product release • Control information required in case of product recall • Control adverse event or complaint recording or reporting • Support pharmacovigilance There should be a focus on risk to Patient Safety, Product Quality, and Data Integrity. There is a need to understand the risks that are associated with a business process before the risks associated with specific functions of computerized systems can be assessed Specification of requirements should be focused on critical aspects. The extent and detail of requirement specification should be based on the associated risk, complexity, and novelty of the system.

Fig. 2.

The Life cycle approach

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Leveraging Supplier Involvement Supplier involvement should be maximised throughout the system life cycle in order to leverage; Knowledge, Experience and Documentation (Subject to satisfactory supplier assessment). For example the, the supplier may assist with: • Requirements gathering. • Risk assessments. • Creation of functional and other specifications. • System configuration. • Testing and other verification. • Support and maintenance. • Documentation should be assessed for suitability, accuracy and completeness. • There should be flexibility regarding acceptable format, structure, and documentation practices. •

® Benefits of GAMP 5

As we have seen in this article, the concepts and layout of GAMP® 5 embody all the regulatory initiatives for the 21st century, innovation and practical application to aid companies who have to implement computer systems using a risk based quality systems approach. It is very important to realise that work that has gone into the new GAMP 5 guidance should be seen and welcomed

by the Polish Pharmaceutical Industry within the CEE as an enabler that brings great BENEFITS, while also reducing BUREACRACY and RED TAPE. Being able to have a defined process, this delivers systems that are fit for: intended use, on time, and within budget. Systems that are well defined and specified are easier to support and maintain resulting in less downtime and lower maintenance costs. The following benefits are just some that may be realised within your organisation: • Reduction of cost and time taken to achieve and maintain compliance, • Early defect identification and resolution leading to reduced impact on cost and schedule, • Cost effective operation and maintenance, • Effective change management and continuous improvement, • Enabling of innovation and adoption of new technology, • Providing frameworks for user/supplier co-operation, • Assisting suppliers to produce required documentation, • Promotion of common system life cycle, language, and terminology, • Providing practical guidelines and examples, • Promoting pragmatic interpretation of the regulations.

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Science Based Quality Risk Management Quality risk management is a systematic process for the assessment, control, communication, and review of risks. It is an iterative process used throughout the entire computerized system life cycle from concept to retirement. The application of Quality Risk Management enables effort to be focused on those critical aspects of the system in a controlled and justified manner. Figure 3. shows the high level process steps involved, GAMP 5, section 5.3 further describes the five step process in more detail.

Summary

GAMP® 5 is one of the most welcomed guidance for Industry in recent years. It helps Pharmaceutical companies from countries such as Poland, who may be supplying markets such as the US/UK for the first time, adopt an industry standard approach which is welcomed by the regulators, companies and vendors alike. It allows companies to focus their efforts and resources where they really matter, whilst using known techniques to justify there actions. The author strongly recommends its use throughout Poland and it does not stop the use of forms and procedures that were contained in previous versions such as GAMP® 4. Gamp has proven to simplify and standardise the process and approach of implementing and qualifying computerised systems in a compliant and efficient manner.

References GAMP® 5 – A Risk Based Approach to Compliant GxP Computerised Systems. 2008.

Acknowledgements Thanks to Sion Wyn, Conformity Ltd for providing valuable review comments.

Fig. 3.

Shows the high level process steps involved, GAMP 5

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Direct compression – a technology still to be discovered Jerzy Lasota

Pharmacists often refer to tablets as a difficult dosage form. If this is the case, it usually happens because of a contribution of mechanics, which plays a significant role in the compression process. Persons with an academic degree in pharmacy or chemistry find it difficult to understand the laws governing the high-volume industrial process in which the leading role is played by dynamically produced powerful pressures.

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he subject becomes even more difficult when it comes to • Supporting the production process itself, that is enadirect compression, but this is exactly the means of produbling a fast formation of the tablet and its easy removal cing tablets – directly out of powder, without wet granulation. out of the mould. This method is exceptionally economically advantageous Modern rotary tablet presses (Fig. 1) produce up to a and often important for product quality. million tablets per hour, which gives only a few milliseconds It is the dream of many industrial pharmacists and company for one tablet to be formed. The pressure sometimes reaches managers. A series of articles is intended to bring this interethe force of 80 kilonewtons (8 tonnes), but usually it is much sting problem closer to the reader. smaller. Fulfilling the rigorous quality requirements is aided by Examples of dosage forms include: syrups, gels, creams, electronic controllers, used since the 1950s, and gradually injections – liquid and gas (e.g. ozone), drops, aerosols, converted into specialised computers able to take full control plasters, suppositories, capsules, and tablets. The latter ones, over the production. as ready-made, easy-to-take portions of medicinal substanIt is not hard to see that the tablet as a dosage form is ces, are the most popular of all existing forms. The history of characterised by a large input of mechanics in its production tablets dates back to the Antiquity, if we count hand-rolled process, the greatest out of all known dosage forms. Thepills as their prototypes. The first information on the presence refore, it is no wonder that good compression technologies of tablets in Poland comes from Cracow. It is there in 1887, an apothecary by the name of Wiszniewski produced tablets using a machine with wooden stamps [3]. Modern tablets do not resemble the ancient pills anymore, and sometimes they are even referred to as “therapeutic systems,” given their complex structure [4]. They are constantly being improved, e.g. for the purpose of better drug dissolution, or such modification of it, so that the patient only has to take the tablet once a day for the sake of convenience. All kinds of positive modifications are possible due to the progress going on in the realm of auxiliary substances [5, 7]. Added to a medicine, they perform Fig. 1. A tablet press with removed covers, without the filler. The diagram presents an extentwo important functions: sion of the line of stamps, which together with the rotating table, move in relation to • Helping in the drug’s distribution large nip rolls, performing only the rotary movement. Orange-coloured elements are in the body, e.g. maintaining an fixed cams, forcing the vertical movement of the stamps. Red colour denotes the comappropriate concentration for pressed substance, applied gravitationally to the moulds a long time,

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are created especially in those centres where pharmaceutical science skilfully combined with the knowledge of mechanics, and it is exactly in direct compression that it is most evident. The term refers to producing tablets directly out of powder, with the omission of wet granulation.

Comparison Though the compression itself is performed almost identically both in the case of wet granulates and dry powders, there are fundamental differences in the manner of substance preparation. It is clearly shown in Fig. 2. Since it has been 15 years since that implementation, a decision was made to reveal its details in order to prove that the described effects are true. Fig. 3. These include the following: Comparison of tablet compression methods • The avoidance of a few expensive machines, • A radical decrease in energy introduced in the process, often rendered as drawbacks. The chart presented in Fig. 3 • A significant decrease of demand for human labour, compiles the main “pros and cons.” It should be explained • Vital improvement in tablet quality, that the notion of fluid granulation refers to the production • The reduction of stress among the staff, and of a granulate in a single machine, in which a liquid binder • Saving time. is sprayed into a body of dry products, suspended in the air. Consequently, spherical granules are created, which are A question arises, if there are so many advantages to ready to be compressed immediately, or after a short seasodirect compression, why is it not as popular as it should be? ning period. Sometimes one can encounter cases of fluid This is because certain characteristics of the process are granulation done so clumsily that it requires further processing, particularly sieve granulation. This is a proof of insufficient process mastery. The technologists may only be excused by the fact that fluid granulation is often a difficult process, dependent on many factors, of which about 20 can be named. In comparing the two compression methods, one could point to a very significant fact regarding the machinery. In recent years, due to an increasing interest in the dry technology, the tablet presses were so modified as to be able to apply a much stronger initial pressure. Evidence of that (Fig. 1) is identical diameters of both pairs of nip rolls and their similar mounting on solid arms. Thus, the first pair of rolls (applying initial pressure, which used to be much smaller in the past) may press with a much greater force. It is a very important element, in many cases even essential to the process [6]. Therefore, it may be stated that the best machines for direct compression are tablet presses with a strong initial pressure.

Threats

Fig. 2.

The first implementation of direct compression technology in “Polfa” Grodzisk Mazowiecki. 1993, Dopanol. An example of very good co-operation of a pharmacist (G. Prekaniak), and a mechanic (author) [8]

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As the analysis in the chart implies, the direct compression method is sensitive to the physical form of the substance. It is its greatest drawback,

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with which many pharmaceutical producers cannot cope. Here is an example of a substance constituting a large share of a tablet, as filler and binder (Fig. 4). The chart presents the results of mechanical examination of three substances with the same trade name and chemical composition. For some time, they were treated as interchangeable equivalents. Only the analyses of density revealed what is absent in chemical reports: that each of these substances is compressed differently. Not knowing that, if we bought the latter of these substances (Fig. 4), solely based on chemical research results, then during compression we might encounter some unpleasant surprises. The tablets will be frail, and they might crack (so-called capping) or be otherwise defective. Similar problems appear when transferring a technology (one’s own or commissioned) for implementation, when the substances used for research and for production are only identical in name and chemical composition. The sole possibility of occurring allotropes or even differences in the size and shape of particles may result in extremely different compression outcomes. What turns out as a very important factor here is the type of substance processing by the producer, i.e. shaping it into the final form. It obviously concerns the final stages of the process: tumbling, drying, crystallisation, grinding, etc. It is generally considered that the best substances for use in dry compression are the spray-dried ones [6]. However, that is not a rule, and it generally concerns only the looseness of the substance, while there are many more requirements to be met. One’s own mechanical examination is essential in such cases, and its results are invaluable. Another example is a substance by the name of Sucralfat, present on the market in the form of crystals (irregular, sharp shapes), and in a spraydried form (small globules). Chemically speaking, these are

two identical substances, but from the point of view of direct compression technology, the differences between them are fundamental. The spray-dried substance is easily compressed, while the crystalline one is not. This time, it is not a question of different density, as in the previous example, but of inappropriate mould filling, which results in differences in tablet weight, exceeding the tolerable norms. The situation is only rescued by the use of a specially designed filling device. Here is still another example: if starch (e.g. cornstarch) used in the formulation does not come from the same producer (and even that may be insufficient, because different batches may also vary), it may result in inappropriately long time of disintegration [1]. Such situations should be anticipated based on individual experience. One could mention numerous examples. Basically, each newly-purchased substance introduces the risk of trouble in the production process. Pharmacists are often very afraid of that. In order to avoid such risk, they choose the wet method, which is relatively well described in publications and properly mastered, especially by the older generation of professionals. Therefore, new formulations are often prepared by strictly following the literature, and applying for registration without conducting a detailed analysis of all mechanical properties of the product. Consequently, a substance, which might have been exquisitely dry-compressed, is “wasted” in the wet method, solely for the sake of tradition and working “by the book.”

Suggestions The above-mentioned threats may be avoided. In addition to chemical analysis, each substance should be examined from the point of view of mechanics. The analyses should

Fig. 4.

Comparison of calcic phosphates

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Wherever the direct compression method is treated progressively, performing one’s own mechanical tests is necessary. Systematic research allows for solving more and more difficult problems of dry compression. Because of its extremely attractive technology and its advantages, it certainly is worth the investment.

Real-life examples It is best to follow the best. In ADAMED, a company which owes its present position to the diligence and reason of the owners, one of the accurate decisions made at the

very beginning (1994) was a switch from wet compression of Furaginum tablets to dry compression (in which the author had his contribution). The idea was at that time regarded by pharmacists as impracticable. But in ADAMED, the designers and contractors of equipment for the production hall, newlybuilt in accordance with GMP standards, were both surprised and disappointed upon hearing the following decision: “We are giving up the wet line. If some tablets are impossible to be dry-compressed, we will not produce them at all.” Therefore, it might be stated a bit pathetically that the today’s famous position of ADAMED was built on the foundation of dry technology. It is an extremely positive example. What can we say about other pharmaceutical producers? Here are authentic opinions of some managers on the direct compression method: • Why do I need to save on drying, if the boiler house has to operate anyway, because steam is needed for other processes? • What do I do with people who now work on tablets? • I have a tradition-loving technologist, he is an honoured employee, and I do not want to upset him.

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be conducted quickly and on small samples. This allows for making better purchase decisions. The idea of such studies is presented in Fig. 5. It shows a part of a laboratory tablet press (built by the author of this article in the 1990s) in which the pressures are applied gravitationally. A constant development of this device and the research conducted has led to defining the notion of “ tabletability,” meaning the measurable ability of a substance to be compressed into a tablet [8]. This parameter can be determined with considerable precision. Based on a long experience, it seems correct to assert that a comprehensive analysis of each new substance should also include sample compression. Therefore, pharmacist should be able to perform appropriate tests under the following conditions: • at any given time, regardless of the rotary press, • on a very small substance quantity (no more than 3-5 grams), • in a controlled manner, knowing the forces used for pressure and removal from the mould, • quickly and effortlessly.

No comment can be given on the above. However, it is worth noting that, in the courses conducted by the author, the questions on why it is that direct compression is still unpopular are asked… by the technologists themselves. The author’s reply is that a lot of research should be made, and there should be cooperation with a mechanic from their early stages. The research is not easy, and the effects are not visible right away. The importance of mechanical studies in formulation is shown in Fig. 6, which presents the conclusions

Fig. 5.

The hitherto practised (left) and suggested method of analysing substances used in direct compression

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A beneficial effect of combining pharmaceutical and mechanical knowledge of a study several dozens of pages long. The details are and will remain a secret of the pharmaceutical company who had asked for help in this matter. The effects shown here in no way depreciate the efforts of a technological team, acting with care and respect for the art of pharmacy. They are only an example of positive cooperation. It is not by chance that, in the search for a new formulation designer for one of the pharmaceutical firms, the advertisement said: “pharmaceutical education not required.” It is highly symptomatic! The essence of tableting itself – it should be clearly stated – is not as much pharmacy as mechanics. This remark does not undermine the leading role of the pharmacists, but only directs their co-operation to mechanics. There should be no fear that the white-coat professionals will lose their prestige. Unfortunately, pharmaceutical studies provide no knowledge on mechanics whatsoever; however, in the laboratory and designing, direct compression technology, such knowledge is indispensable. Therefore, there is no dishonour to ask a mechanic for assistance and engaging in regular cooperation in performing responsible duties is an even better solution. Compression consists in applying forces of high value, with all its consequences for the substances, tools, and machines. Thus, a pharmacist is absolutely justified to say that a tablet is a difficult dosage form, and it probably proves their inadequacy in the rules of mechanics governing the compression process, which they are fully entitled not to know. If they are aware that they do not know them, it is good. It is worse if they are not aware of their lack of knowledge, and still worse if they know it but push forward anyway, treating the mechanical matters as unimportant, because of their fear of losing their authority. In conclusion: Where there is good cooperation between the mechanic and the pharmacist already in the research stage, there is room for advanced

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formulation projects for direct compression and their implementation. Where such co-operation is missing, many ideas will be described as impracticable, and a certain amount of intellect will be wasted on convincing the management that it is true. Mechanical (dynamic) analyses of pharmaceutical substances, combined with chemical studies, and performed as basics, fundamentally organise the matters relating to the direct compression technology. Surely, it will not be able to oust the wet methods completely, but owing to its many advantages, it will remain an important argument in the strategy of “being the leader” in good and cheap production.

References

1. Farmakopea polska V. 1995-1999. Warsaw: PTFarm. 2. Fiebig, A., S. Janicki, W. Żebrowska. 1980. Technologia stałych postaci leku (Dosage form technology). Gdańsk: A. M. 3. Krówczyński, L. 1994. Zarys technologii postaci leku (An outline of dosage form technology). Warsaw: PZWL. 4. Müller, R. H., G. E. Hildebrand (eds.). 1998. Technologia nowoczesnych postaci leków (Modern dosage form technology). Warszawa: PZWL. 5. Rybacki, E., T. Stożek. 1980. Substancje pomocnicze w technologii postaci leku (Auxiliary substances in dosage form technology). Warszawa: Wyd. Lek. ZWL. 6. Schmidt, P. C. 1987-1989. Preskraft-und-Weg-Zeit-Charakteristik von Rundlauftabletten-pressen. Aulendorf: Die Pharmazeutische Industrie, Editio Cantor. 7. Wade, A., P. J. Weller. 1994. Handbook of Pharmaceutical Excipients. Washington: APhA. 8. Lasota, J. “Polfarmed” course materials: • Produkcja tabletek (Tablet production) (2000) • Szczegóły formulacji (Formulation details) (2004) • Tabletkowalność substancji (Substance tabletabili ty) (2006) 9. FETTE company brochures.

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PLIVA – an ideal employer PLIVA

PLIVA ranked in the top 10 of this year’s Ranking of Ideal Employers in the sphere of pure and natural sciences. The ranking was based on the Polish Student Survey – a survey on the career expectations of young Poles – conducted by Universum.

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n this year’s poll, nearly 10,000 students were surveyed from all over the country. The list of assessed employers covered 130 companies. In the category of pure and natural sciences, PLIVA came in ninth. Universum, an international firm specialising in employer brand-building, has conducted analogous research in 30 other European countries. PLIVA is a European manufacturer of generic drugs. It belongs to the Barr Pharmaceuticals, Inc., a global pharmaceutical company, operating in over 30 countries all over the world. The Barr group specialises in development, production, and sale of generic and original drugs, biopharmaceuticals, and active pharmaceutical ingredients (API). Founded in 1921, PLIVA is one of the largest pharmaceutical companies in Eastern Europe and has its seat in Zagreb, Croatia. The company offers over 550 products, available on the markets in Croatia, Czech Republic, Germany, Poland, and Russia. The wide range of products includes: varied dosages of drugs in the form of tablets, capsules, injections, creams and ointments, OTC drugs, cytostatics, and API. PLIVA is also becoming an important participant in the generic biopharmaceuticals market. In Poland, PLIVA is the second largest pharmaceutical investor, and one of the largest producers of original and generic drugs of supreme quality, confirmed by prestigious certificates of FDA and MHRA, allowing export to the United States and Western Europe. PLIVA Kraków is a subsidiary of PLIVA d.d. It offers about 300 preparations. Its main products include anti-infection drugs, used in cardiology, pain therapy, central nervous system diseases, and anti-cancer drugs.

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Cleaning Validation Quality Masters

Cleaning Validation (CV) might be simply defined as a set of actions whose purpose is to prove that a medicine being used is not contaminated with any other medicine which may at a given moment have adverse effects on the patient.

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ccording to the literature, CV involves making a documented proof of the fact that a device being cleaned according to an approved procedure is suitable for the processing of medicinal products. All of these documented proofs are legal requirements imposed on pharmaceutical firms by acts of parliament, ministerial orders, EU directives, the FDA handbook and PIC recommendations. The guiding principle of CV is “no product contamination means safety for the patient”. When CV can be carried out: • best during scheduled production • during periodic (campaign) production • always when a new product with a new active substance is added to a line of products

To begin validation, the following steps should be taken first: • review the SOP relating to “Cleaning process validation” in terms of compliance with current GxP requirements; • review the cleaning instructions for individual devices included in the line being validated, in terms of their correctness, feasibility and currency; • review the certification of the process devices, ventilation, premises (confirm on the basis of certification of the correct monitoring of devices for assurance of constant working parameters). Earlier, if not already done, it is advisable to perform PQ for the washing of the devices contained in the line being validated, e.g. tests with fluorescein, riboflavin; • make a list of active and auxiliary substances and the detergents used.

Sample photographs of a cleaning test using fluorescein.

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The first step in the intended validation will be to create validation documentation, such as plans, schedules, schemas and of course the main validation protocol, which will describe step by step all of the actions which are to be performed during cleaning validation. The CV protocol should contain: • the range of responsibility of persons involved in CV • detailed description of the actions performed during CV, and information on what instructions and procedures are being followed • plan of CV completion dates • validation data such as: –– dedicated cleaning and disinfecting agents (certification of agent suppliers is important here) –– dedicated cleaning equipment and devices –– dedicated process devices with identification of critical points. It is a good idea to take photographs and mark points on the photographs, to make it unambiguous for the person taking samples. –– identified critical substance (active substance, auxiliary substance or detergent) –– defined method of labelling residues –– defined method of taking samples –– defined sampling recovery level –– defined acceptance criteria –– sampling plan

In some cases an analysis must also be made of auxiliary substances, which at a certain concentration may also exert an adverse effect on the patient. In the case of toxic substances, such as certain cleaning agents, account must also be taken of the toxic dose expressed as an LD50 value (the fatal dose for 50% of a population of experimental animals). In identifying a critical substance one should preferably aim to carry out one validation test for the line in question, such as can be considered a worst case. There are many methods of determining the residue; everything depends what you want to detect and with what accuracy, and on what equipment is available. Every method is good if it gives incontrovertible and repeatable results. Methods for determining residue include among others: • determination of active carbon (TOC) • determination of total nitrogen • titration • chromatographic determination of content (HPLC, GC) • spectro-photometric determination (IR, VIS, UV, fluorescein, MIR, NIR, NMR) • measurement of conductivity and pH • visual assessment (assisted by UV lamp, dyes), low cost, compliant with GMP, high sensitivity, but unfortunately somewhat subjective. By visual assessment we can only prove that there is less than 4 µg/cm2 of a substance on

Dedicated cleaning and disinfecting agents must be safe for the surfaces being cleaned; a specification should be made of their composition, method of use, the operational parameters of an agent, and the method of detecting residues following the washing process. Production devices and cleaning equipment should be certified. In the case of manual cleaning it must be taken into account that washing is dependent on operators, who do not have repeatable operation like machines – the effectiveness of washing will depend on them and will be different each time. For this reason particular attention must be paid to operator training. In semi-automatic devices the human factor is negligible, as only operator supervision is required . These include mobile CIP and SIP systems; automatic systems are stationary CIP and SIP systems assigned to particular devices. Semi-automatic and automatic systems provide incontrovertible washing results, enable repeatability of the cleaning procedures, and are the most appropriate for CV. When specifying critical points account must also be taken of those places which are not easily accessible, and are therefore the hardest to clean. Process devices should nonetheless be designed with a minimum number of nooks and hard-to-access places, joints should be detachable, the walls of (for example) tanks should be slanting, without “dead zones”. Before validation it is also worth checking the roughness value of contact elements and confirming that value on revalidation. It is accepted that the value for roughness (Ra) should not exceed 0.4 µm. In identifying a critical substance for a given production line it must be determined which of the active substances used: • is most difficult to dissolve in the washing substances used • has the strongest pharmacological dose

the area being checked. In the selected analytic method the threshold of detectability should be sufficiently low to ensure detection of an established acceptable limit of residue or contamination.

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In selecting a sampling method, account must be taken of the type of surface from which a sample is to be taken, accessibility of the surface, construction of the device, the adopted analytic method, invasiveness or noninvasiveness in the process, the effect of a given sampling technique on the results of analysis, and what is desired to be sampled from the surface. The best-known methods include: • Swab/tampon method (a sample is taken using tampons or swabs). These may also be moistened with water or solvent. It is very important that instructions be available for the taking of samples by this method, specifying among other things the number of movements, the direction, and the method of wetting. • Last rinse method. In this method the pH or conductivity is measured, depending on the nature of the rinse liquid. • Visual assessment – ability to detect 4 µg/cm2 of a substance. • Component method. In this method an element being in contact with the substance is replaced by another element, which is then analysed after production. During sampling it is good to use ready-made templates with the appropriate value of area to be smeared: 25 cm2 templates are most commonly used.

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• • •

0.001 to 0.0001: products for injection and for the eyes 0.00001 to 0.000001: products for testing

Recovery is defined by the following formula:

• • •

MAC = maximum allowable carryover B = batch (smallest batch size of next product) R = largest daily dose of any product produced using the same production device

The computed recovery value must be greater than 50%.

ADI = NOEL x AAW x SF

Cleanliness criteria must be defined in the chemical sphere (active substances, decomposition products which may have an adverse effect on the patient, auxiliary substances, disinfectants, detergents, pyrogens), and in the microbiological and mechanical spheres (dust, fibres of cleaning agents, substances such as oils and lubricants used for device maintenance). Everything depends on what kind of product it is (sterile or non-sterile) and whether any of the contaminants might have an adverse effect on the patient. The defined limits must be achievable and verifiable. It must be remembered that a device rarely displays absolute cleanliness; in such a case one can question the correctness and reliability of the selected analytic method. In many cases absolute cleanliness is simply not necessary. The acceptance criteria contained in the validation protocol should have a complete, logical, convincing and comprehensible scientific justification. In order to compute residue limits, data such as the following are needed: • batch size of the next product • safety factor of the next product • therapeutic dose of the product being analysed • the largest daily dose of the next product

• •

ADI = acceptable daily intake AAW = average adult weight (average weight of an adult person) SF = safety factor

In determining residue limits, account must be taken of: • whether it is an product in the category of antibiotics (penicillin, cephalosporins), cytostatics, strongly acting hormones or products containing substances within the scope of the Act on prevention of drug addiction (these must always be numerical limit values) • the sensitivity of the analytic method Useful formulae for determining acceptance criteria: MAC (maximum allowable carryover) MACAPI = (TD x BS x SF) / LDD • TD therapeutic dose (of the analysed product) • BS batch size (of the next product) • LDD largest daily dose (of the next product) • SF safety factor (of the next product) SF: • 0.1 to 0.01: products for external use • 0.01 to 0.001: product taken orally

• • • • •

MAC = (ADI x B) / R

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The efficiency of sampling, otherwise known as recovery, is dependent both on the method of sampling and on the method used to determine the residue.

NOEL = LD50 x empirical factor NOEL = no observed effect level LD50 = fatal dose for 50% of a population of experimental animals Empirical factor for detergents = 0.0005

Residue limit: Cresid ≤ MACresid x Recovery resid x (Asample/ Atotal) x (F/V) • • • • • •

MAC = maximum quantity of residue on the device Recovery resid = combined recovery of sampling and

testing for a given residue Atotal = total area of device [cm2] A sample = sampled area of device F = sample concentration coefficient before analysis V = volume of original sample [dm3]

To be remembered during validation: • Validate the time within which the cleaned device is still clean. This is very important for the economics of the process. Take samples as often as possible so that the interval is as long as possible. • Determine the time in which a contaminated device may be contaminated. • The minimum for proof of correctness of a validation method is at least three consecutive cleaning operations. • Pay special attention during validation to the moment at which contamination occurs, before, during and after cleaning. • Document all parameters of the washing process (pressures, temperatures, flows). When all of the validation actions have been completed, remember that they must be repeated in a year’s time.

Quality Masters provides consulting and services to the pharmaceutical industry. It specializes in preparing documentation and carrying out certification of devices, premises and systems and validation of processes and cleaning. More information is available on our website. www.qualitymasters.pl, info@qualitymasters.pl

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35 2008-09-05 21:40:58


sponsored article

production

Confocal Raman Microscopy – Imaging in Pharmaceutical Research Harald Fischer L.O.T.-Oriel

In the pharmaceutical industry, it is important to know as much as possible about the structure and distribution of the active components within surface coatings of medical devices or a variety of other forms. An often employed technique for these investigations is fluorescence microscopy, which requires that the sample be treated with specific dyes before the images can be acquired using a dye-specific excitation laser. Whenever such a staining, which often leads to the sample being rendered useless for further studies, is not appropriate, Confocal Raman Microscopy provides the ability to non-invasively map the chemical properties of such samples at the highest resolution and to acquire depth profiles.

Instrumentation and Experiment The Confocal Raman Microscope WITec alpha300 R combines a highly sensitive confocal microscope and a high-transmission Raman spectroscopy system. In the Spectral Imaging Mode, a complete spectrum can be acquired in 760 µsec. with a resolution down to 200 nm. The number of image points (spectra) is limited only by the computer memory. A typical image consists of 10,000 (100 x 100) to 65 536 (256 x 256) spectra. By integrating over a specific Raman line or a region in all spectra of this multi spectrum file, an image is generated. A variety of properties such as peak-width, center of mass or the peak position of certain Raman lines can additionally be analyzed. For depth profiling measurements, the focal plane can be moved in the z-direction when performing either x-z scans or generating x-y image stacks. Large area scans can be performed using the alpha500 Confocal Raman Imaging systems. This allows large samples to be imaged in order to produce an overview of the distribution of the chemicals across the sample. The experiments presented here examined a tablet of Acetylsalicylic acid, commonly known as ASA or Aspirin. Using an alpha500 system, spectra were recorded with true confocal (diffraction

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Fig. 1a.

Large area Raman scan of a ASA tablet. Scan range: 18 x 9 mm, 200 x 100 pixels

limited) resolution at every image pixel. The tablet was imaged with 200 x 100 pixels and the total scan range was 18 x 9 mm. In Fig. 1a the ASA component is shown in red, while the excipient is color-coded in green. The blue part may be an ASA in a different configuration. The corresponding spectra are shown in Fig. 1d. After acquiring the large area overview scans the alpha500 additionally allows to define an arbitrary number of sample positions on the tablet for automatically image these positions at the highest

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production

Fig. 1d.

Corresponding Raman spectra

Fig. 1b.

Zoom-in of the marked area in Fig 1a, 1x1 mm, 150 x 150 pixels resolution. Figs. 1b and 1c show such zoomed in images of the marked areas. In Fig. 1b the scan range was 1 x 1mm, in Fig. 1c it was 80 x 80 µm, at 150 x 150 pixels. In a second experiment, a depth profile of a capsule within a scan range of 50 x 12 µm and 100 x 80 pixels (=8000 spectra) was acquired. In both cases, a 532 nm frequencydoubled Nd:Yag laser was used for excitation. The acquisition time for each spectrum was 50 ms. Figure 2, top, shows the depth profile of the capsule with the distribution of agent (red and blue) and a coating (green) surrounding the capsule to ensure easy swallowing. On the bottom in fig. 2 the corresponding spectra are shown. The software also offers the possibility to measure distances within the image. In this case, the coating of the capsule is around 2 µm thick.

Fig. 2.

Raman depth profiling image (top) and Raman spectra (bottom) of a capsule surrounded by a coating

Conclusion With its imaging and depth profiling capabilities, Confocal Raman Microscopy enables the visualization of drug distribution in a variety of substrates.

Fig. 1c.

Zoom in of the marked area in Fig 1b, 80 x 80 µm, 150 x 150 pixels

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Harald Fischer Marketing Director WITec GmbH Hoervelsinger Weg 6 89081 Ulm Germany tel. +49 (0)731 14070-0 fax +49 (0)731 14070-20 e-mail: Harald.Fischer@WITec.de www.WITec.de

L.O.T.-Oriel Ruda Śląska 41-700, Szyb Walenty 32 tel./faks +48 (0) 32 2482048 e-mail: polska@lot-oriel.com

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37 2008-09-05 21:41:01


sponsored article

production

From space-saver to multi-purpose all-rounder, Marcin Weksler at Faubel charts the developments made in pharma labelling.

Learning from Booklet Labels Marcin Weksler Faubel

When the self adhesive label was developed in the 1930s, nobody could imagine how successful it would prove to be, or how many different technical solutions would derive from it. Today, self adhesive labels are ubiquitous in everyday life and feature in almost every branch of industry. Beside the ordinary self adhesive label, a whole range of technically advanced solutions, sometimes designed for extreme conditions (for example, deep freeze storage, sterilisation, and so on), has become particularly popular with the pharmaceutical industry.

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AN ALL-ROUNDER AMONGST LABELS

Always in the right shape

The booklet label is the epitome of a modern information support, combining a number of advantages. First, the booklet label is a label and a package insert in one; indeed, it is now possible to apply an 81-page product or patient information leaflet to almost every container in a durable and user-friendly way. The basic structure of a booklet label consists of three different components: the base label, the package insert and a plastic film as covering material. During processing, a leaflet (package insert) is placed on a self adhesive label (base label) – in paper or foil – and fastened by means of a transparent plastic film. There are alternative and more economical solutions, which involve the package insert being directly glued onto the base label without any plastic film cover (see Figure 1). Booklet labels are used every time additional information space is required on containers, or when product information is needed in several languages. Meanwhile, some manufacturers are able to process booklet labels of up to 81 pages, the usual volume being 20 to 40 pages.

Booklet labels can be applied to any container, irrespective of the material or shape used. Through embossing they can be adjusted to the unique shape of containers and visually highlight the appearance of a product. Yet enhancing product packaging is not the only purpose of embossed booklet labels. It is possible, for example, to create enough space on complicated shapes offering virtually no room for labelling by adapting booklet labels to various container shapes.

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Patient-friendly information packaging Being easy-to-use and handle, booklet labels are particularly popular with the pharmaceutical industry as package inserts for drugs. Manufactured like books, resealable and printed in the right font size, they can improve patient compliance. Userfriendliness in medicines is a key aspect

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production

Marcin Weksler Studied English at The Teacher Training College and at Wrocław University; he completed specialist courses in sales, client service and marketing. Before he joined the Dutch Company TRANSPOSAFE SYSTEMS BV, where he helped create its Polish branch in Wrocław and dealt with sales development, he had gained 4 years of experience in IT sales and project management in Poland. He has been specialising in sales establishment and development, including the IT sector and printing, for 12 years. Since July 2007 he has worked for Faubel, a provider of packaging solutions specialising in special label solutions. He is responsible for the realisation of sales and CEE market development strategy, especially in the pharmaceutical sector.

for senior citizens – one of the main groups using medicinal products – as well as for people with disabilities. When combined with special materials and embossing, booklet labels can also help to seal medicines in blister packages that are child-resistant. Another advantage is positioning: the package insert is directly adhered to the medicine. Package inserts as we know them are generally removed from their boxes, unfolded, quickly browsed through, and more likely to be directly disposed of with the packaging rather than replaced in it. Booklet labels, on the contrary, are directly applied to the primary packaging of the drug – separating patient information from the drug can only occur deliberately.

Braille coding It is stipulated by law that names and indications of drugs are printed in Braille on the outer packaging. This can be incorporated using booklet labels: the information is directly screenprinted on the sealing laminate using a special varnish before it is checked electronically. This method ensures compliance for dot position in line with the requirements of the European standard ‘Packaging – Braille on packaging for medicinal products’ currently in preparation.

Flexible distribution – late stage customisation Reacting quickly to market requirements while keeping stock to a minimum is their objective: from day to day the demand for products may rise or fall dramatically following a particular TV-programme or the wrong weather forecast. Late stage customisation refers to the process of adapting/

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optimising an object according to its purpose or use. More often than not, this process only takes place shortly before the product concerned is delivered. Indeed, in the case of certain nicotine substitutes aimed at secondary markets such as Scandinavia or the Baltic States, it is common practice to fill and stockpile standard packages. As soon as demand arises in a particular market area, the folded boxes are equipped with booklet labels tailored to the destination before being dispatched, therefore it is no longer necessary to keep a small number of items of various kinds in stock, producing a more efficient and costeffective approach to storage management.

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production

Label as containers

Versatility and adaptability The versatility of the booklet label is becoming increasingly clear. As illustrated by two examples from the pharmaceutical industry, labels with peel-off sections allow full and uninterrupted documentation. The documentary parts – one or more – of the labels that are attached to the drug are directly stuck on the patient’s medical record or on his/her vaccines record card, facilitating the work of the doctor and helping to prevent errors occurring. Thanks to their built-in clips, booklet labels can also be used to hang infusion solutions. Such integrated clips can prove useful in cases of emergency where adequate suspension devices are rarely available.

Drug safety Today, drug safety is not simply a case of finding the right dosage or proper use: counterfeit drugs or packaging with fake contents are increasingly making the headlines. To protect users and drug manufacturers from serious health risks, it is now possible to integrate a variety of security features and non-tamper evidence in a booklet label. Security features can be implemented by using certain types of finish and/or colours together with special materials, but also by applying RFID tags to trace back drugs along the entire supply chain. According to a current initiative by the EU Commission againstproduct piracy, it will become compulsory for drugs to carry a seal within the EU. It shall serve as non-tamper evidence and display corresponding security features – a sort of certificate of authenticity – which can be incorporated into a booklet label, amongst other things.

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The latest arrival on the market is the container label, designed to convey large amounts of information and incorporate additional elements if requested. Indeed, with this model, manufacturers can offer their customers and patients aids and/or samples, such as control strips, product specimens or magnifying glasses.

Applications in clinical trials Booklet labels are ideal in terms of quality and versatility, especially for clinical trials which are generally conducted worldwide. Printing in several languages gives drug companies more leeway in terms of distribution and logistics, even in such a critical sector. In addition, it is possible to print variable data (randomised data for example) on booklet labels. The combination of printing and camera monitoring systems allows for the optimisation of delivery times, processes and operational safety.

Future prospects Development in labelling is making fast progress, and the trend for development continues unabated. If today’s companies are seeking to achieve new formats, shapes and dimensions in terms of the number of pages in booklet labels, printed electronics and functionality will certainly be items on tomorrow’s development agenda. In integrated data storage, sensors (for example, temperature sensors) or solutions related to tracking and tracing, there is a new world out there for traditional labels, including booklet labels in combination with new technologies.

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Polish industry

Increasing qualification effectiveness within the investment process mgr farm. Maciej Szerszenowicz, mgr inż. Mirosław Jasiński LSMW Sp. z o.o. Total Life Science Solutions, Poland

A traditional approach to qualification frequently means: • cursory impact assessment and risk analysis • tests doubling • multiplication of documentation • excessive scope of qualification. Do we have to proceed so? Do we have time and money for such an approach?

Legal requirements In accordance with the legal pharmaceutical requirements all manufacturers are required to carry out a validation of the critical stages of manufacture of medicinal products. In Poland, the need to implement the process of validation as part of the requirements of Good Manufacturing Practice (GMP - Good Manufacturing Practice) is amended by the Minister for Health of 2 October 2006 In the European legislation in force is the European Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of Good Manufacturing Practice for medicinal products for human use and medicinal products in the research stage for use in humans. In the light of these legal requirements in terms of its pharmaceutical qualifications all critical systems, facilities, equipment, both newly built and the existing, which made significant changes are subject to qualification.

mgr farm. Maciej Szerszenowicz Validation Project Manager Holds a MSc degree in pharmaceutical sciences from Medical University, Gdańsk. For several years he works for pharmaceutical and cosmetic industry. Since 2005 he has been working for LSMW. He is a member of multidisciplinary project teams, responsible for qualification and validation works.

mgr inż. Mirosław Jasiński Validation Engineer Holds a MSc degree in chemical engineering from Technical University, Gdańsk. Since 2004 he has been working for LSMW. He is responsible for qualification of pharmaceutical systems and equipment. He is member of multidisciplinary project teams, responsible for qualification and validation works.

Advantages and disadvantages of today qualification Regulations’ concerning GMP shown in the introduction, give us the basis for the implementation of qualifications, but does not describe how to carry out this certification. This often leads to misunderstanding of the purpose behind these regulations and the individual interpretation of rules. As a result, for many pharmaceutical companies qualification is expensive and time consuming procedure. In some cases it can cause a delay of transmission of facilities such as systems or equipment as well as the final start of the production. This situation can affect real business results.

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Polish industry

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Certain aspects of the qualifications are “value added” in the sense of assurance that the revised property, equipment or systems are ready for repeatable manufacture of medicinal products, which is one of the necessary preconditions for the validation process of manufacturing the therapeutic product. However, other practices can be found simultaneously (including documentary), which reduce the effectiveness of the qualification. These practices emerged over the years, as an attempt to adapt to the requirements of controlling pharmaceutical manufacturers, rather than to meet the GMP intentions. This has led in some cases to a situation where systems (such as ventilation and air conditioning) have not functioned properly, despite the fact that qualification was completed with a positive result. One of the ways to eliminate unnecessary practices and improve efficiency throughout the qualification process is to implement the recommendations contained in the guide association ISPE concerning final acceptance and qualifications (ISPE Baseline Guide: Commissioning and Qualification), as well as guidelines ICH Q8 (Pharmaceutical Development), Q9 (Quality Risk Management ), Q10 (Pharmaceutical Quality System). They define the approach to qualifications based on scientific grounds and on risk analysis, which consequently allows to reduce the scope of qualifications, focusing only on the really critical aspects of the quality of product, leaving other areas of Good Practice of Engineering (GEP - Good Practice Engineering). Terms of GEP have been presented in more detail way in the ISPE guide. A brief description one of the possible procedures for identifying the elements that should be subject to the qualifications have been described below. We want to point here that the new approach to the qualifications should based on understanding of the process and the product and it should separate the genuine requirements of GMP from “traditional” practices and perceptions that existed for the past 20 years. It should also cover the use of more efficient ways to ensure that the systems, installations and equipment meet the requirements of Good Engineering Practices. Any strategy to adopt, as a result of our production systems must conform to their goals - be able to support the reliable production of high quality and safe for the patient.

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Commissioning and qualification Acceptance philosophy (commissioning) and qualifications used today is based on the above mentioned Good Practice of Engineering (GEP) and the evaluating process of the impact (Impact Assessment). The impact assessment allows you to assign systems and installations to different groups depending on the nature of their impact on quality of product. This classification is based on the examination of the physical components and their functions in relation to the manufacturing process and quality of the final product. In accordance with the recommendations contained in the guide ISPE systems, installations and equipment can be divided into groups with direct and indirect impact and not having such an impact. Systems classified in the last two groups have only non-critical components and as such are reviewed only in accordance with the GEP by acceptances. Direct impact Systems both may have critical and noncritical components. Non-critical components are verified in accordance with the GEP, and critical are subject to qualification practices described in the GMP.

Activities related to acceptance tests and qualification tests are designed to verify and document that an object, a system or a device is able to meet the established requirements. The essence of acceptance operations is subject to assumptions and design requirements. Whereas qualification is based on verification of all aspects of the installation, systems and devices, which may affect the quality of the product. In some cases the ranges of the qualifications and the acceptance overlap each other. Through the plan, conduct and evidence of these activities the same tests can be avoided and thus focus on the qualifications solely on critical aspects of the safety and efficacy of the medicinal product.

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Problems for the implementation of investments The Ongoing pharmaceuticals projects should ensure compliance with the GMP requirements, which is a specific condition as distinct from other types of investments. Regular reviews for compliance with the GMP guidelines should be done on the early stages. They should be conducted in parallel with the design. It is very important that all discrepancies have been previously discovered so that the cost of repairing them will be relatively low. During the implementation phase of the investment the Project Manager should implement qualification procedures and / or engage people who are trained in Type: Direct Impact (D) or Indirect (I)

Normally GMP Important

Documentation and Commissioning

Purified Water and WFI

D

Yes

Enhanced

CIP/COP Systems • Final • Pre-Final

D I

Yes No

Enhanced GEP

Clean Steam

D

Yes

Enhanced

Nitrogen and other Process Gasses

D

Yes

Enhanced

Instrument Air

I

No

GEP (=Good Engineering Practice)

Depends on use

Yes In Classified Manuf. Areas

Depends on Application and Area Classification

No

No

GEP

Process Heating/Cooling

I

No

GEP

Process Vacuum

D

Yes

Enhanced

Controlled Potable Water

D

Yes

Enhanced

Non-Process Potable Water

I

No

GEP

Depends on use

Depends on use

GEP Depends on use

I

No

GEP

System

HVAC Breathing Air

Mechanical Seal Fluids Chilled Water

Polish industry

To lead in such a way our investment it is necessary to implement our management risk program of analysis (in accordance with the guidelines ICH Q9). This program allows for early identification of possible threats, and consequently focuses on its elimination (for example, through appropriate action eligibility).

qualifications. It happens sometimes, that the investment of a new pharmaceutical production is led by a person with low awareness of the principles of the GMP. In fact, the Construction Manager should oversee the entire time the quality of the work and executive companies must be aware of their role in the building process of a pharmaceutical plant or an object. To fully ensure the quality of work regulations during the implementation it is indicated for the participation of a team with expertise in matters related to both the technical acceptance and subsequent qualification object. This team is able to identify and minimize the risks associated with the implementation of the pharmaceutical investment since the beginning of its life. The participation of the supervise team to the investment for compliance with the GMP can be implemented in two ways. The first solution, much cheaper for the Investor, is participation of a trained person in preparation of the User Specification Requirements (URS). The specifications should contain a list of necessary documents, the proposed regulations and test, which must be supplied and manufactured for the particular system installation, in order to achieve compliance with the GMP. Such specifications should be transferred directly to person responsible for the execution of the construction. However, the first solution may prove insufficient, and only the seemingly cheaper, since the implementation of the User Specification Requirements by the subcontractors of the particular systems and installation is not always coincide with the expectations of the authors of this specification, and may entail the need for subsequent amendments

Source: ISPE Baseline Guide Biopharmaceuticals, Industry Review Draft December 2002

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Polish industry

regulations. In contrast, the presence of the company or the team responsible for qualification, verification work in progress, it gives investor confidence that all problems related to the completeness of documentation and work regulations will be identified and addressed on an ongoing basis. This will save time and money at a later stage of qualification.

Benefits of cooperation with outside companies Cooperation with the external companies so-called outsourcing is based on their expertise and the experience and is used to do implementation the necessary processes for the functioning of the company faster and cheaper. Outsourcing has been in the past dozen years, an excellent tool by which many companies reduce operating costs. “If there is something we can not do more efficiently, cheaper and better than competitors, it does not make any sense to do it. We should employ to perform this work someone who does it better than us” – Henry Ford, 1923 Employment third-party provider of services in the validation action brings with it many advantages including: • Guarantee high quality services performed • Using the external company’s experience with validation of the various pharmaceutical plants • Persistent implementation of the latest solutions and expertise • Ensuring the continued provision of services arranged on the highest level of quality • Support the development of corrective action • An objective look at the pharmaceutical investment • Engaging qualified personnel and special equipment is not necessary The quality of services provided is associated with conducting validation of actions by trained and skilled workers. Staff trained in the validation can show not only knowledge of the specific requirements of the law on pharmaceuticals, but also mandates norms and standards concerning eligible installation, systems and devices, which combine the experience and practical knowledge of ongoing projects. One company assigned to handle the investment familiar with the specificity of his client is able to provide services at a higher level than the ever-changing teams. It is also important from the point of view of confidentiality. Each company wants to make sure that there is a limited number of people having an access to the company’s classified data. It is also important the experience of a third-party validation company while validating various pharmaceuticals objects. Flexible and comprehensive approach to emerging problems and the support with development of corrective action is undoubtedly the advantage of cooperation with the external companies in field of qualification. The use of this experience, as well as workers practical knowledge in the field of measurements qualification combined with a developed know-how makes that the customer is sure that the taken qualification action is carried out according to the latest technologies, current requirements, standards and rules of law.

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There is no doubt that while selecting outside company, opinions about it from already implemented projects are important. It is also important that the company is able to look objectively for the entire investment and it should carry qualification project independently from the executive company.

Sum up Still growing awareness of the effects of medicinal products on the health of the patient causing growing pressure on the provision of high quality and safe medicines. In order to prove that the process carried out within a set range of parameters and effectively carried out repeatedly, enabling the manufacture of a medicinal product which satisfies the requirements set out in the specification, a validation process. A precondition for the validation process is the qualification of all systems, installation and equipment affecting the quality of the process and product. Within the framework of qualifications should, however, focus only on critical aspects of verified systems, installations and equipment, leaving the attributes of non-practitioners acceptance (commissioning). Identification of components criticality should be based on risk analysis, supported by a careful process and product knowledge. Supervision of satisfying the requirements of GMP in the course of implementing the pharmaceutical investment is crucial for the subsequent process of manufacturing. Lack of control at this stage, can cause delays with production and increase costs of object adoption to GMP requirements. To avoid these dangers the external validation team should be already introduced at the early stage of investment process.

References •

Rozporządzenie Ministra Zdrowia z dnia 2 października 2006 r. w sprawie wymagań Dobrej Praktyki Wytwarzania (Poland).

Dyrektywa Komisji Wspólnot Europejskich 2003/94/EC z dnia 8 października 2003 r. ustanawiająca zasady i wytyczne dobrej praktyki wytwarzania w odniesieniu do produktów leczniczych stosowanych u ludzi oraz produktów leczniczych w fazie badań stosowanych u ludzi (Poland).

ISPE Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities: Volume 5, Commissioning and Qualification. March, 2001

ICH Topic Q8 Note for Guidance on Pharmaceutical Development, EMEA/CHMP/167068/2004

ICH Topic Q8 Annex to Note for Guidance on Pharmaceutical Development, EMEA/CHMP/518819/2007

ICH Q9 Quality Risk Management, Step 4, 09.11.2005

ICH Topic Q10 Note for Guidance on Pharmaceutical Quality System EMEA/CHMP/214732/2007

Chew, E. Robert, Petko, David: Commissioning and Qualification: A New ASTM Standard – GMP Regulations. Pharmaceutical Engineering, November/December 2007, Vol. 27, No.6

A White Paper on Risk-Based Qualification for the 21st Century. ISPE, 9 March 2005, Rev.2.

ISPE Baseline Guide Biopharmaceuticals, Industry Review Draft December 2002.

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in EU countries

– myth or reality?

Polish industry

Counterfeit medicines Zbigniew Fijałek

National Medicines Institute

In recent years there have been increasingly frequent reports in the world’s media about documented patient deaths caused by the use of counterfeit medicines, medical devices and diet supplements. They also warn of a huge increase in the quantity of such products available on certain markets and via the Internet. In this paper we try at least partially to answer the question of whether such a danger realistically exists in European Union countries, including of course Poland. However, in order to properly analyse the current situation, it is first necessary to define the types of products which we are encountering ever more frequently, consciously or unconsciously, when we do our shopping not exclusively through legal networks of distribution.

C

ounterfeit medicines are most often illegally marketed medicines; this includes traditional medicines, herbal products, medicines containing undocumented active pharmaceutical ingredients (APIs), and carrying inaccurate information about their origin, effects or use. There does not exist a universal definition of a counterfeit medicine. The most commonly used is the World Health Organization (WHO) definition, which states that “a counterfeit medicine is a medicine deliberately, and with intent to mislead, improperly marked as to its composition and/or source. Such a medicine may

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contain proper active substances, improper substances, an incorrect quantity of active substances, a significant quantity of contaminants, and possibly fake inner or outer packaging.” Also present on the market are “substandard” medicines, which are original products that do not meet all quality requirements, fail to comply with a specification or pharmacopeial requirements, or are repackaged to conceal their true expiry date.

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Polish industry

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All official sources of information emphasize the great difficulty and complexity of estimating the extent of this problem. Detailed figures on counterfeit medicines are hard to access and troublesome to interpret and publish. How can one make estimates regarding what is by its nature an informal and illegal market, and how can one present any material evidence when the medicine has already been swallowed by the patient? Apart from the huge differences between regions of Europe, very wide differences may occur also within a country – between urban and rural areas, between one city and another, and even depending on the season and on changing demand for a specific class of medicines. An additional obstacle is the fact that the counterfeiters and their collaborators, knowing that they are committing an offence, take aggressive steps to prevent it from being discovered. They form organized criminal groups in order to conceal their identity and in order that the main organizers always remain in the shade. They register nonexistent manufacturing and transport firms which provide cover for their true activity. They take advantage of any lowering of vigilance at the border controls, caused for example by certain national governments’ declared campaigns to promote international trade. They use falsified documents to gain access to key pharmaceutical ingredients or devices so as to manufacture and package counterfeit medicines and to sell them on a selected market or through a legal distribution network. All in all these criminal activities make it extremely difficult to discover and publicize real information about counterfeit medicines. The pharmaceutical industry itself, though it complains of losses in the billions, is unwilling to take action against illegal competition. Many firms do not wish news about the faking of their products to spread, and fail to warn patients, the pharmaceutical inspectorate or the police, for fear that this would have an unfavourable effect on their own sales. In attempting to analyse this problem it should also be remembered that, although the phenomenon of drug faking is as old as the history of medicine, it was only in 1985 that it was presented for the first time at an international conference, and in 1988 that WHO announced its first resolution concerning the combating of this problem. In the last decade growing dangers to public health from counterfeit, illegal and substandard medicines have become ever more evident, causing a significant increase in illness and death rates and a marked decrease in the effectiveness of medical care, particularly in developing countries. In 2006 two international conferences were devoted to these issues: the first in Rome called Combating Counterfeit Drugs: Building Effective International Collaboration sponsored by the WHO, and the second in Moscow in October, Europe Against Counterfeit Medicines, sponsored by the Council of Europe. Having regard to the global extent of the problem, the Rome Declaration of 2006 obligated the WHO and Council of Europe to establish an international group appointed to combat the faking of medical products: the International Medical Products Anti-Counterfeiting Taskforce (IMPACT), which brought together government, non-government and international institutions in order to

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propagate socially valuable information among patients, organizations and other entities, and in order to prepare the legal ground and create mechanisms for collaboration in combating medicine counterfeiting. This collaboration is based on written procedures, clearly defined roles of appropriate government departments, and effective administrative and operational tools. The first meeting of the members of IMPACT took place in November 2006 in Germany, and Dr Valerio Reggi from the WHO became its coordinator. Since 2007 the activities of IMPACT have been increasing in visibility, international cooperation has become tighter, and recommendations for individual government departments have been produced (including Draft Principles and Elements for National Legislation Against Counterfeit Medical Products and A Guidance to Investigating Counterfeit Medical Products and Pharmaceutical Crime). Particularly noteworthy is a poster circulated by IMPACT, providing an excellent illustration of the problem and capable of being understood by any potential purchaser of medicines or decision-maker.

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Polish industry

It is very hard to assess the worldwide scale of the problem, and so any such assessments are unreliable. Experts from WHO and the FDA (Food and Drug Administration) estimate that counterfeit products may account for approximately 10% of the world market in medicines (with a value of around $35bn in 2005 and $75bn in 2010), ranging from about 1% in developed countries to 10–30% in certain states of Africa, Asia and South America. They also warn that the risk of death as a result of taking counterfeit medicines is nowadays greater than the probabilities of dying from malaria and AIDS combined. International associations of pharmaceutical manufacturers and distributors, as well as pharmaceutical concerns themselves, have for many years been carefully analysing particular markets (naturally only in terms of their own products). The leading role here is played by the Pharmaceutical Security Institute (PSI-IFPMA), which works together with national drug registration agencies, customs authorities and Interpol. Unfortunately most incidents uncovered lead only to the confiscation of the counterfeit items, and further investigations are as a rule discontinued at the manufacturer’s request. PSI experts have discovered the greatest number of cases of sale of counterfeit medicines at Internet pharmacies; out of 3100 pharmacies studied only four had VIPPS (Verified Internet Pharmacy Practice Site) accreditation, a standard introduced in the US, Canada and Australia by the National Association of Boards of Pharmacy (NABP). On its website, NABP explains how to buy medicines safely over the Internet and makes it possible to check the legality of Internet pharmacy sites (http://www.nabp.net/). Another website worthy of recommendation is www.safemedicines.org, which provides consumers with an eight-step method for verifying the authenticity and safety of medicines (“An 8-Step Check List for Medicine Safety”). Unfortunately the rules presented are designed for the American medicines market and cannot be fully applied in Europe.

Fig. 1. WHO/IMPACT poster warning against counterfeit drugs

Counterfeit medicines Number of cases Number of countries involved with incidents All cases, including theft and illegal re-import

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In Europe a major role in combating pharmaceutical crime is played by the Council of Europe and the European Commission. In view of the increasing seriousness of the problem, 2005 saw the publication of the Council of Europe Counterfeit Medicine/Pharmaceutical Crime Report, in which the phenomenon is pictured as “another potential Pharmageddon Scenario”. However a report of 2007 states that on the EU’s borders in the years 2005 –2006 there was a rise of as much as 384% in quantities of confiscated counterfeit packages and illegal medical products (including anti-infectious, cardiac, psychotropic and

2006

2007

% change

1216 100 1412

1513 112 1759

+ 24% + 12% + 25%

Tab. 1.

Discovery of counterfeit medical products by PSI

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Polish industry

prostate cancer drugs). In 2001–2005 in EU countries there were discovered 27 cases of counterfeit medicines in legal distribution networks and 170 cases in illegal networks. In the UK, between 24 May and 12 July 2007, four counterfeit products were discovered in legal distribution: Zyprexa 10 mg (3 batches), Plavix 75 mg (5 batches containing 42–83% of active substance), Casodex 50 mg (1 batch), and Sensodyne Original and Sensodyne Mint toothpaste (containing diethylene glycol). At the request of the European Commission specialist programmes have been launched to study the water-tightness of distribution channels for medicines (2006–2008) and medical devices (2007–2009) and the safety of medicines in parallel import. Furthermore in May 2008 a document was published entitled Public consultation in preparation of a legal proposal to combat counterfeit medicines for human use, on the basis of which a steering committee is to draft a European Convention on Pharmaceutical Crime, classifying the counterfeiting of medicines as a Expensive

Tab. 2.

Counterfeit medical products discovered in Germany in 2003–2007

Sandimmun Locol Stavudin Zerit Trizivir Corpormon Somatogenum Norditropin UFT

Cheap (generic) Acenorm Amoxicillin Atenolol Rhinopront

serious pharmaceutical crime. Particular attention is paid within the EU to active pharmaceutical ingredients. It is currently accepted that a medical product can be safe only if the API meets all requirements described in the approved MA/DMF/CEP documentation, if there is a fully identifiable path from the API manufacturer, and if the API is produced in accordance with the cGMP requirements (ICH/Q7). The need to impose such requirements is made especially clear by two cases – in the year 2000 the use of counterfeit gentamicine as an ingredient led to more than a dozen deaths and several hundred serious adverse effects, while in 2007–2008 the FDA recorded 81 deaths caused by the use of heparin 40% contaminated with over-sulphated chondroitin sulphate and dermatan sulphate. The investigation showed with high probability that this was due to deliberate faking of the active ingredient using a similar biological product which is a hundred times cheaper. The heparin case was particularly hard to detect, since the ingredient batches imported from China complied with all of the requirements laid down in the specification. Only by applying methods for which the specification did not provide, such as NMR and capillary electrophoresis, was it possible to fully identify the problem. In the study of illegal, counterfeit and substandard medicines a very important role is played by the European Network of Official Medicines Control Laboratories (OMCLs), which is organized and

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supervised by the European Directorate for the Quality of Medicines (EDQM) in Strasbourg. Within the framework of this activity, in 2007 the network’s laboratories prepared 108 reports containing, among other things, descriptions of developed and applied analytic methods (such as NMR, HPLC-MS-MS, capillary electrophoresis, NIR, ICP-MS and X-ray diffraction) and of established content levels of active substances and contaminants. In just the first half of 2008 there were 93 such reports, which may indicate a significant growth in the danger to public health in the European Union. Poland still lacks official data relating to the scale of this phenomenon, even though it is classified in Europe as a highrisk country as regards organized crime and the counterfeiting of various products (such as computer software, DVDs and CDs, cosmetics and clothing). According to WHO and Interpol experts, the danger comes chiefly from the neighbouring former Soviet countries, known for easy access to counterfeit medicines and dietary suplements (at least 20% of Small market Berodual Roxithromycin Enalapril Lisinopril Berotec Urospasmon Fraxiparin Agopton Orfiril Ditec

Large market Aclinda Amoxilat Clav Amiodaron Blopress Innohep Doxazosin Ciprofloxacin

“Lifestyle” Fluoxetin Movate Sigra Power Love Sterydy anaboliczne Finegra Viagra i klony Cialis i klony Levitra i klony

the medicines market), which translates into easy expansion through illegal sources to the Polish market and onward to other EU countries. A partial picture of the situation in Poland may be given only by the report by the Finance Ministry that 1350 packages of counterfeit medicine were confiscated on the country’s borders in 2007, and that in the same year the National Medicines Institute (a member of the OMCL Network) prepared for prosecutors, courts, police and customs authorities a total of 182 opinions relating to 310 products, while in the first half of 2008 it issued 34 opinions relating to 300 illegal products. To conclude it should be emphasized that, according to declarations of the Council of Europe and WHO, the counterfeiting of medical products, at every stage from their production to their administration to patients, is a serious criminal offence which endangers human life and damages the credibility of systems of healthcare. In order to combat this practice effectively and ensure the safety of patients, it is necessary for a new international convention against medicine counterfeiters to be signed, and for appropriate provisions to be introduced into national and international law. It must also be remembered that no doctor or pharmacist, let alone a patient, is in a position to distinguish a good fake from the original product, and this fact gives additional encouragement to criminals to make and sell counterfeits. Usually only when suspicious symptoms appear or patients suffer long-term illness or death does the suspicion arise that there may have been something wrong with the medicines.

www.farmacom.com.pl

2008-09-05 21:41:20


Polish industry

HAZOP

in pharmaceutical industry?

Why not? Marzena Sokołowska, Pat Swords PM Group Poland

During works on the project of a pharmaceutical plant modernization or the construction a new plant, the safety operation of it should be considered as one of the top priorities. Why?

B

ecause an appropriate and safe functioning of all processes is the deciding of the stable production output, its repeatable quality, safety of the site surrounds (the natural environment, the neighborhood) and in particular the health and welfare of the staff remaining on its area. In addition this leads to significant financial savings – lower costs of insurances for the sake of risk control and reconstruction costs, less unexpected processes shut-downs and compensation fees, which usually occur in case of serious failure. Is it possible to plan, program and execute in a systematic way the actions which increase the safety level in designed and existing pharmaceutical facilities? One technique, which is commonly in used in chemical, petrochemical and pharmaceutical industries, is HAZOP. For many years PM Group has been supporting their business partners in their attempts to reduce the risk on all of the possible project stages. The experience of the company was gained during the HAZOP reviews for Ireland, UK, France, Poland and Romania based food, cosmetics and especially pharmaceutical industries. This enables the authors to extract the expedient conclusions and present them further below.

Marzena Sokołowska-Żołnierczyk Has studied the Chemical and Process Engineering at the University of Technology in Warsaw. Marzena has over ten years experience in pharmaceutical process engineering. In PM Group Poland is in charge of the Process Engineering Team. Currently she develops the process designs for local Polish and Multinational companies in accordance with the GMP requirements. Is the expert in the assessment of the pharmaceutical, cosmetics and food projects risks related to the explosion protection and hazardous processes. Marzena was working for the multinational companies in Poland and abroad (Germany, Italy, Russia, Ukraine, Lithuania and in Iran).

Pat Swords Is a Fellow of the Institute of Chemical Engineers with twenty years of experience with the PM Group in the design of pharmaceutical, chemical and general industrial facilities. He has specialised in particular in the regulatory aspects providing cost effective solutions to meet EU legislative requirements in Environment, such as Integrated Pollution Prevention and Control (IPPC) and Health and Safety, such as Control of Major Accident Hazards (Seveso II) and ATEX (Explosive Atmospheres). In the last nine years Pat has spent considerable time in Eastern Europe on EU Technical Assistance projects implementing the Seveso II and IPPC legislation and providing technical assistance to PM Group Poland.

What HAZOP means? A HAZOP comes from the words a HAZard and Operability. A HAZOP study consists in analysing by an experienced team what faults can arise with the design or existing process and if sufficient safeguards are in place. The reasons for which one should consider carrying the audit out were discussed in the introduction. Other good reasons are:

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Polish industry

Even the best of engineers can overlook issues, even under supervision. They may be focused on designing their section of the plant and forget how it is going to be maintained or cleaned. They may not fully understand how it interacts with the process interfaces to plant sections designed by others. Accidents do happen in the process industries. As part of the EU legislation on control of majoraccident hazards involving dangerous substances (Seveso II Directive), a database is maintained on reported accidents. The vast majority of accidents notified, over 95% of the accidents in which the causes are known, could have been foreseen early and consequently prevented by the proper application of existing experience and disseminated knowledge. Far too often analysis of accidents in the above databases has shown the concept of ‘drift’, defined as the ‘systematic organisational performance deteriorating under competitive pressure, resulting in operation outside the design envelop where preconditions for safe operation are being systematically violated’. Frequently also accidents are actually re-occurrences of previous events, which means that we are possibly not learning sufficiently from the investigative work of others. The EU is clear in that risk assessments of the work place are required, see the Framework Directive on Occupational Safety and Health 89/391/EEC, which requires the employer to implement the following general principles of prevention: Avoiding risks, Evaluating the risks which cannot be avoided, Combating the risks at source, Adapting to technical progress). The same principles are enshrined in all Member State safety legislation. In Poland decisions of the 89/391/EWG Directive were considered in appropriate acts.

HAZOP Technique in Pharmaceutical Industry Initially invented by Imperial Chemical Industries (ICI) but only started to be widely used in the chemical process industry after the Flixborough disaster, a chemical plant explosion that killed 28 people in the UK in 1974. The technique was promoted by the UK Chemical Industries Association and was widely adopted by petroleum industry, followed by the food and water industries in circumstances where the potential for hazards is great. Experience gained by PM group personnel during the long-term work for big and medium sized pharmaceutical companies in Western Europe and Asia has shown that a design team is often under pressure to complete project on schedule which can lead to errors and oversights. A HAZOP has proven itself as a valuable tool for correcting such oversights before changes become impossible or too expensive at a later stage. It is now perhaps the most widely used aid to loss prevention. There is a HAZOP application guide available as a British and International Electrotechnical Commission Standard: BS IEC 61882:2001. Furthermore

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the Institution of Chemical Engineers’ popular HAZOP Guide to Best Practice has recently been updated (April 2008) and is available from their website: www.icheme.org . A HAZOP is usually based around a Process and Instrumentation Drawing (P&ID), although the technique can also be applied to a batch record sheet or a functional design specification for a control system (CHAZOP). Not every P&ID needs a HAZOP. If similar equipment modules are present, review one and check the others for difference. If a standard package is being purchased, i.e. reactor for the work with organic solvents, this will be proven technology with a risk assessment and CE marking provided by the vendor. Although you may consider a HAZOP review for your interfaces, i.e. for connection point the reactor to another installations. The design team should ensure that the design is advanced enough for the review but not so advanced that it is too expensive to incorporate changes. For example information about type of the pump, what it is peristaltic, rotodinamic or positive-displacement pump is sufficient. Information about the actual manufacturer’s model is unnecessary. The information included in the design should never leave issues to ‘be resolved’ in the HAZOP. The design team should be confident that their proposed design is safe in normal operation and will pass scrutiny. A HAZOP study is fundamentally based on the skills of the HAZOP team, the HAZOP assumes that the competency necessary is participating. It is assumed that however carrying out the HAZOP and the participation in the review are most important. A HAZOP chairman is appointed who is independent of the design team, yet understands the technology concerned and has sufficient experience to lead the review. Other attendees include the process design engineer, the automation engineer, representatives from production and maintenance and possibly a safety engineer or a representative from an equipment supplier. A junior engineer is often used to record (scribe) the meeting, recording the agreed content on one of the commercially available software packages, often projecting the text onto a screen using a ‘beamer’ so that the participants can see the content.

Attention! HAZOPs are mentally tiring. Experience has shown that two sessions per day lasting for at the most three hours every session is optimal. In the sequence of the week effectively it is possible to carry three sessions out. The design is broken into suitable sections, called Nodes. For each node: • Guidewords are applied to stimulate discussion on Deviations from the intended design. For example; No Flow, Reverse Flow, More Flow, or for a batch process, More Material Added / Added too Fast. • Causes are reasons why the deviation might occur, e.g. an oversized valve leading to More Flow.

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• •

The Consequences are then examined without consideration of the Safeguards, e.g. uncontrolled pressure rise. The Safeguards are then considered, e.g. pressure alarms and pressure relief. If the Safeguards are not considered adequate then an Action is generated. It is important not to try and redesign the system in the HAZOP, the design team should be requested to review or consider other options, e.g. a throttling valve to prevent the material being added too fast. For each Action there must be a person assigned to ensure it is carried out – Responsibility.

In August 1993 a fire and explosion occurred at the Hickson PharmaChem plant in Cork, Ireland. Fortunately there were no fatalities but more than €25 million in damage occurred. The company was prosecuted successfully by the Irish Health and Safety Authority (HSA). The cause of the explosion was a distillation unit for

Polish industry

Some companies take the process one step further. Risk is the likelihood of a specific event occurring within a specified period or in specific circumstances. Risk = Likelihood of an event (probability) x Severity of outcome (consequences). Risk can be assessed using a risk matrix in which likelihood and consequences are inputted using criteria chosen by the company, e.g. Severe may a single fatality or a major financial loss.

It was indeed highly fortunate that the major explosion and fire that occurred in the Buncefield petroleum storage depot north of London in December 2005 lead to no fatalities. However, the fire raged for days and the groundwater underneath the site to a distance of 2 km is severely contaminated with both hydrocarbons and fire fighting foams.

A Typical Risk Matrix

Probability

RISK MATRIX

CONSEQUENCES Severe

Serious

Significant

Minor

Bardzo prowdopodobne

Intolerable

Intolerable

Substantial

Moderate

Prawdopodobne

Intolerable

Substantial

Moderate

Tolerable

Nieprawdopobne

Substantial

Moderate

Tolerable

Tolerable

Bardzo nieprawdopobne

Tolerable

Tolerable

Tolerable

Tolerable

Intolerable: Discontinue operation or do not start until risk has been reduced to Moderate or Tolerable. Risks control measures need to be based primarily on engineering controls with high reliability. Substantial: Corrective actions should be taken with urgency to reduce risk to Moderate or Tolerable. Risk controls need to be based on engineering controls and maybe supplemented by administrative controls. For the proposed work, do not start until the risk has been reduced. Moderate: Initiate efforts to reduce risk. Implement measures within a short time period. Monitoring is required to ensure that available controls are maintained. Tolerable: No action or additional controls required.

If there is one thing that must be learnt from a HAZOP is that: “All actions must be closed before the plant goes into service and the plant / process must not be modified without reviewing the assessment.”

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recovery of Isopropyl Alcohol. The residues were known to be potentially unstable and the design intent was that these would be cleaned out at the end of the batch. In reality this was not happening and residues were building up, which upon start-up after a shut-down lead to the explosion. The Director of the Irish HSA concluded; “in relation to this major accident, the company can be criticised for not having a fully documented process safety analysis for either the single distillation process or the multiple distillation process...Hickson PharmaChem were not in a position to show that the risks associated with the process had been fully evaluated”. For more information see: www.pmg.pl

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J.S. Hamilton Poland Ltd. is a professional partner for pharmaceutical industry as an independent testing laboratory specialized in chemical, physical and microbiological analysis of medicines and other pharmaceutical products. Laboratories offers a broad range of analytical services during product development as well routine analysis for - APIs, excipients, additives, intermediate products, finished products and packing materials. Services offered include: Development of analytical methods: • Assay • Identity testing • Dissolution testing • Disintegration testing • Microbiological preservation efficiency testing

J.S. Hamilton Poland Ltd. Laboratories

4_2008_spf.indd 52

ul. Indyjska 13 81-336 Gdynia, Poland

Validation of analytical methods: • Impurities • OVI (Organic Volatile Impurities) • Assay disintegration products • Stability studies according to ICH • Methods in compliance with ICH, EP, FP, USP or in-house validated Implementation analytical methods: • Optimization • Qualification pharmacopeial methods • Implementation • Transfer methods Laboratory has permission for production of pharmaceutical products from the Chief Pharmaceutical Inspectorate in Warsaw (No. GIF-IW-4000/25/05/06).

tel. +48 58 660 2763 fax +48 58 621 9810

www.hamilton.com.pl pharma@hamilton.com.pl

2008-09-05 21:42:01


Polish industry

FSP GALENA API producer Piotr Didkowski GALENA

There are currently few producers of Active Pharmaceutical Ingredients in Poland, and it seems that this tendency is not going to change in the nearest future. Moreover, the medicinal boom appears to discourage pharmaceutical companies from developing in different directions.

I

t should be noted, however, that the convenience of non-obligator y GMP certification for API will soon come to an end. Both the customers, and some of the institutions, already treat GMP as the basic document certifying the quality of the produced substance. Also the REACH Regulation, in force since 1 June 20 07, introduced obligator y registration of chemical substances (which is quite expensive), while simultaneously exempting manufacturers of medicinal products from this obligation. This might discourage some entrepreneurs from investing in this branch of industr y. It is worth mentioning that, apart from a few obstructions that caused by mandator y implementation of EU regulations, several benefits appear. The fact that the Polish API producers meet the majority of EU requirements may be a significant advan-

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tage (facilitation of transport, unified documentation, etc.), appreciated by the customers (especially from memberstates). In addition to the above-mentioned aspects, API manufacturers should also consider the purely technical matters (connected with specific and often dangerous production processes). Paradoxically, it is in this niche technology that I see the chance for Polish companies to develop API production. Moderate demand for a given substance seems to discourage large companies who are interested in high-volume production. It appears that currently the best solution allowing for the maintaining of API production in Poland is a low-volume production of specific substances.

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Polish industry

So far, home-based producers of finished dosage forms aim at buying APIs from external sources and their physical processing (mixing, granulating, and compressing into tablets). Although such a solution has some unquestionable advantages, it should be remembered that it also poses certain threats. One of them is undoubtedly the monopolisation of the market by Asian suppliers and large pharmaceutical companies. Consequently, the producers may become dependent on a single source of API supply. A total abandonment of API production would also preclude a fast launch of domestic production in case of a possible economic crisis on world markets. Another advantage of domestic API production is the better ability to control the product quality, and consequently a decrease in the number of complaints, e.g. resulting from inappropriate transportation.

Their own production guarantees securing API in accordance with an appropriately prepared documentation, and with the use of fully qualified production machinery. Thanks to this approach, medicinal production at FSP “Galena” ensures thorough adherence to the firm’s Quality Policy. Due to its extensive experience, “Galena” successfully fulfils both the requirements imposed by the pharmaceutical law and by various regulations pertaining to the production of chemical substances. Furthermore, this profile of production allows for the increase in company flexibility, as well as the understanding for the distinctive nature of the production processes.

One of the companies producing APIs, both for sale and as ingredients of their own medicinal products, is the “Galena” Pharmaceutical Co-operative Society (Farmaceutyczna Spółdzielnia Pracy „Galena”) in Wrocław. Presently, it produces four APIs conforming to all requirements concerning chemical and microbiological purity (each batch of the product is subjected to microbiological examination). The substances produced by “Galena” include the following: • Calcium Dobesilate and Etamsylate – substances used in the production of antihaemorrhagic drugs, • Thiocol – used in the production of expectorants, and • Perazine – used in the production of psychotropic drugs.

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At this point, it may be noted that combining API production with the pharmaceutical branch might present some problems, particularly to this very distinctiveness of the production processes. As I have already mentioned, pharmaceutical companies focus on physical processing, and implementing a typical chemical production process may cause problems with understanding the mechanisms of the chemical processes. On the other hand, subordinating API production to the chemical industry may result in problems with implementing the regulations and requirements specific for the pharmaceutical branch. After all, maintaining API production seems justified. Apart from utilitarian reasons, there is also the “prestige” argument. Chemical synthesis is the measure of modernity and progress of the chemical industry. It is characteristic of highly advanced technologies, and it creates space for innovation and general development of the technical thought.

www.farmacom.com.pl

2008-09-05 21:42:25


Adamed in foreign pharmaceutical markets

Polish industry

Adamed, the leading Polish pharmaceutical company, strengthens its position in foreign pharmaceutical markets. Olanzapine produced in Adamed´s laboratories reached the Estonian and Lithuanian market. The total value of those markets is estimated at 600mln EURO.

Adamed Kamila Dobrowolska Director of the Foreign Projects Departments

W

arsaw, 29 July 2008. Adamed systematically puts products on the foreign markets. On January 2008 the company introduced new drugs on Turkish and Czech market and on July olanzapine was launched on Estonian market. Olanzapine – modern the second-generation antipsychotic drug with proved effectiveness in the treatment of positive and negative symptoms of schizophrenia. Launching of olanzapine in foreign markets is an element of Adamed´s export strategy. Currently olanzapine is the most important drug that has been produced in Adamed´s laboratories starting from active substance synthesis up to final drug formulation. Olanzapine – known under different trade names – Zolafren, Solazin, Caprilon, Zalepin, will gain the European markets. Adamed registered olanzapine in Lithuania, Estonia, Finland and Greece, so far. In cooperation with the local respectable economic partner drug accessed the Estonian market and in the nearest future will appear in warehouses and pharmacies in Lithuania. The next step will be supplies to Finland and Greece, where the sales beginning is expected in the third and fourth quarter of 2008 year. Olanzapine is very important product in Adamed´s trade offer, but not the only one. Simultaneously, we pursue intensive business activities to put on market other products from our portfolio – said Kamila Dobrowolska, Director of the Foreign Projects Departments in Adamed.

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Estonian and Lithuanian markets are attractive for Polish entrepreneurs. They have the relevant impact on the sales potential and with high growth dynamic they guarantee stable competitive conditions. In addition, geographic proximity, cultural similarity and above all EU membership determine the foreign sales direction. The key success factor is a quick reply to market´s needs and offering the newest high quality products. Adamed expands export activity meeting the global pharmaceutical trends. Particular countries are interested in high quality drugs lowering therapeutic costs. Such requirements give hope for high increase in export sales of Adamed.

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Polish industry

New board elected at Polfa Warszawa S.A. Polfa Warszawa S.A.

On 8 July 2008, the Regular Meeting of Stockholders of Polfa Warszawa S.A. approved the company’s annual report for 2007. Simultaneously, the meeting initiated the operation of the thirdterm Board, composed of Maciej Głowacki as its Chairman, Krzysztof Rebkowiec, as Member of the Board, and Adam Stępień, as the new Member of the Board representing the personnel.

Maciej Głowacki Chairman of the Board Polfa Warszawa S.A.

O

n 20 June 2008, an advertisement was published in the national press regarding the start of a competition for the posts of Chairman and Member of the Board. Within the prescribed time limit, i.e. until 30 June 2008, 11 applications were submitted. After a formal selection by the Polfa’s Supervisory Board on 1 July, six candidates were qualified for the next stage. On July 4, upon completion of the interviews, the Supervisory Board appointed Maciej Głowacki for the post of the Chairman of the Board, and Krzysztof Rebkowic for the post of the Member of the Board – i.e. the persons who had fulfilled these functions in the previous term. The new term of office of the Board began on the date of approval by the Regular Meeting of Stockholders of Polfa Warszawa S.A. of the 2007 annual report, on 8 July 2008.

“I feel happy that my qualifications have been appreciated. My re-election as Chairman of the Board assures me that our hitherto practised company management policy is correct, and that it is supported by the company owners” – said Maciej Głowacki.

Polfa Warszawa S.A. is one of Poland’s largest producers of medications. It manufactures more than 120 drugs from different therapeutic categories in many forms and dosages. It employs nearly 1400 people. In 2007, the company was the fourth best-selling Polish firm of the branch. Along with Polfa Tarchomin and Polfa Pabianice, Polfa Warszawa S.A. constitutes the Polish Pharmaceutical Holding (Polski Holding Farmaceutyczny, PHF S.A.). Polfa Warszawa S.A. has two subsidiary companies: Ipochem, engaged in research and the production of active pharmaceutical ingredients (API) and semi-finished products for the pharmaceutical industry and Sanfarm, responsible for the production of dry medicines. Polfa Warszawa S.A., while specialising in the production of prescription medications and medicines for hospital health service, it also offers non-prescription drugs (OTC). Apart from a high activity on domestic market, Polfa Warszawa S.A. exports its products to European, African, Asian, and South American markets. The most important importers of Warsaw’s Polfa are Russia and other ex-members of the Commonwealth of Independent States, as well as Hungary, Bulgaria, and South Africa.

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www.farmacom.com.pl

2008-09-05 21:42:29


Polish industry

Polpharma and Bioton together Robert Miller

On Friday August 15, Bioton announced in a press release that a contract had been signed “under which Prokom has agreed to sell to Windstorm Trading & Investments Limited (WT&I), a company controlled jointly with Polpharma, the whole of Prokom’s shareholding in the company”.

T

hus a 33.1% shareholding in Bioton will come into the hands of the fund Windstorm Trading & Investments Limited, which is a company under the joint control of the Polish medicines manufacturer Polpharma and Prokom Investments. In its press release, Prokom Investments announced that the sale of shares to Windstorm “provides very good prospects for Bioton’s expansion and for growth in value for all Bioton shareholders.” Bioton’s sale has come at a time when the company is disappointed by its results and its listed share price is falling. In the last 12 months the company has seen its value fall by as much as 62%. In the second quarter of this year Bioton made a loss of 15.7m zloty, while in the same period a year ago it had over 60m zloty profit. The company blames its poor result on the strengthening zloty (most of its output is exported), which meant that it has had to reduce its projected revenue for this year from 500m to 400m zloty. Last year too Bioton’s sales were lower than had been planned. It turns out that not only Polpharma was interested in Bioton. It is reported that interest was also shown by Sanofi-Aventis, one of the world’s largest pharmaceuticals concerns. Pharmaceuticals expert Tomasz Jędorowicz from PricewaterhouseCoopers believes that such

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a move should not surprise the market. “The insulin market, where Bioton is a player, offers very good prospects and in the long term will bring significant profits. Another possibility is that this acquisition is treated as a means of increasing the value of its portfolio in negotiations with another generic player.” According to Jerzy Starak, the two companies will function separately. They have different technologies and the nature of investment is also different. “It cannot be ruled out that the firms will cooperate in some area in the future, but there is nothing to discuss at the moment,” the investor declares. “We are just beginning a due diligence process for Bioton. I expect it to take about a month. If nothing unexpected comes up during the investigation, we will complete the contract. However I prefer to be cautious, because the split with Gedeon Richter, where negotiations were also at a very advanced stage, is still fresh in my memory,” Jerzy Starak points out.

Source: Parkiet, Gazeta Wrocławska, Puls Biznesu, Rzeczpospolita, Gazeta Wyborcza

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57 2008-09-05 21:42:34


Polish industry

Klopidogrel in the international market Adamed

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Adamed – Polish pharmaceutical company get the chance to launch in the international market clopidogrel, the modern drug used in the treatment of acute coronary syndroms, brain stroke and peripheral arterial diseases. In 2007 total income from the global sales of clopidogrel reached 7.4 bln USD and increased 21 percent over last year. Clopidogrel has already sprinted to the top ten of the global drugs best-seller list.

arsaw, 15 July 2008 – Adamed applied to the Ministry of Health, through the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, the competent reference agency, for the commencement of the Mutual Recognition Procedure (MRP). MRP enables the speedy authorization of medicinal product in several European markets simultaneously.

Within the framework of the MRP the product will undergo the national and international phase. Prepared by the Agency assessment report will be delivered to the member states, where the company is competing to get the registration. Within 3 months regulatory agencies must be provided with information and clarification in the event of doubt. MRP should be finalized within 6 months by the issue of authorization, in accordance with approved assessment report, Summary of Product Characteristic, labels and patient information leaflet. We would like to put clopidogrel on Central and Eastern European market. Our plans are to cover: Czech Republic, Estonia, Lithuania, Latvia, Romania, Slovakia, Slovenia, Bulgary and Hungary – said Kamila Dobrowolska, Director of the Foreign Projects Department in Adamed. We believe that in spite of an enormous amount of work related with the adjustment

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of registration documentation to EU requirements, the Office will smoothly carry out the MRP. This is the chance for us, as Polish pharmaceutical company to access the several markets simultaneously and impulse for the economic development as well. Clopidogrel – antiplatelet agent, tienopiridine derivative. Clopidogrel is indicated in prevention of thrombus formulation in patients with acute coronary syndroms with or without elevation of ST segment, in patients after ischemic brain stroke and with peripheral atherosclerosis. Clopidogrel is an inhibitor of ADP-induced platelet aggregation. Safety and effectiveness of clopidogrel in prevention of ischemic incidents was assessed e.g. in CAPRIE trial involving more than 19 thousands subjects. MRP – Mutual Recognition Procedure of pharmaceutical products. The legal basis of MPR is Directive 2001/3/ EU of 6 November 2001 on the Community code relating to medicinal products for human use and in the case of Poland on the basis of the Pharmaceutical Act of 6 September 2001.

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On 3–4 June 2008, Cooper Conferences organized an event in Warsaw under the name “Diet Supplements Workshops 2008: switch, notifications, upcoming changes”. Tomasz Butyński

alks were given by leading specialists from the bodies directly involved in the preparation of legal regulations for the diet supplements market, including Dr Elżbieta Wojtasik, chair of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Dr Janusz Ciok representing the Institute of Food and Nutrition, and Anna Starnawska-Oleńko, head of the Judgments Section of Warsaw’s Provincial Sanitary and Epidemiological Station. Two firms shared their legal expertise: Domański Zakrzewski Palinka, represented by attorney Marcin Flak, and CMS Cameron McKenna, represented by attorney Magdalena Wawrzyniak. Practical knowledge was provided by Iwona Kowalczyk and Grażyna Osęka from Foodie Sp.J. A talk on prospects for the dietary supplements market was given by Jacek Czarnocki from IMS Health Poland.

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Cooper Conferences had invited representatives of the National Supplements Council, the Provincial Pharmaceutical Inspectorate and PASMI to the event. The Polish Pharmaceuticals Chamber of Commerce was represented by Irena Rej. The two days of workshops enabled almost 40 representatives of firms active in this segment of the pharmaceuticals market to save the time they would have spent seeking this information individually. The chief moderator was Małgorzata Szelachowska, Provincial Pharmaceutical Inspector in Warsaw. Many legal questions relating to this market segment remain unresolved. Nutrition and health declarations are currently the subject of review. Action on new laws on diet supplements and nutrition is also being taken at EU level. Moreover it is also not precisely established what view is taken, from the legal standpoint, by the Chief Sanitary and Pharmaceuticals Inspectors regarding the sale of supplements at pharmacies. A further meeting is planned for early 2009. Changes relating to notification are expected in 2009–2010.

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conferences, fairs, training

Diet Supplements Workshops 2008

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conferences, fairs, training

Medicine Refunding 2008 The Law, Practice and the Future Tomasz Butyński

On 10–11 June this year, at Warsaw’s Sheraton hotel, Cooper Conferences organized a conference titled “Medicine Refunding 2008. The Law, Practice and the Future”. It was attended by more than 70 representatives of pharmaceuticals manufacturers and distributors.

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very manufacturer or distributor would be glad to see its product on the list of medicines which are subject to refunding, therefore there was great interest in the training sessions relating to the legal and economic aspects of this issue. Specially for the event Cooper Conferences had invited Piotr Błaszczyk, former director of the Medicines Policy Department at the ministry of health, and Bolesław Piecha, former deputy minister for health. Among those introducing the refunding process to conference participants were Artur Fałek, Director of the Medicines and Pharmacy Policy Department at the ministry of health, Prof. Jacek Spławiński from the Pharmacology Section of the National Institute of Medicines, Paweł Sztwiertnia, directorgeneral of INFARMA, Rafał Zyśk, director of the Medicines Management Department of the National Health Fund, Dr Wojciech Matusewicz, director of AOTM (the Medical Technology Assessment Agency), and experts from IMS Health, the Cameron McKenna law firm and Dr Marcin Czech representing the Polish Pharmaco-Economic Association. Artur Fałek explained a draft executive order of the Minister for Health concerning applications for refunding, and Piotr Kowalczyk from IMS Health Poland presented an overview of the Polish refunded medici-

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nes market. Agata Zalewska described both the changes made last year (Pharmaceutical Law) and the prospects for future changes and their consequences. These and many other talks dealing with the issue of refunding from various perspectives filled the two-day conference programme. The event ended with a panel discussion, with invited speakers Dr Marek Jędrzejczak, deputy chairman of the National Pharmacists’ Council, Andrzej Dziukała of Bayer, and Dr Zbigniew Król of AOTM.

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opportunity for greater competitiveness on the Polish pharma market PMR Publications

reports, projects, plans

Supply chain management

The Polish pharmaceutical market is slowly coming to resemble the analogous markets of Western Europe. The market conditions, which until recently were comfortable as typical for markets in early stages of development, have began to change. As a consequence of sector saturation, it is increasingly more challenging to note either high profitability or high revenue growth. To stay ahead, more firms are looking for new, “non-product” answers to enhancing their market appeal. Without a doubt, well-modelled supply chain cooperation is one such solution.

Existing solutions cannot keep pace with market changes Research conducted for PMR Publications’ newest report “Supply chain management1 in the pharmaceutical industry in Poland 2008” uncovered a strategic gap in the use of SCM applications in the Polish pharmaceutical sector. Beyond around a dozen global companies that are constantly on the lookout for new sources of an edge on an exceptionally demanding field of rivalry, entities active on the Polish pharma market have not noticed the fact that internal enhancements (in logistics and manufacturing) and – even more so – an external supply chain can be a great source of competitive advantage. When the rising market competition, increasing client and consumer demands in logistics support and pricing terms are juxtaposed against the business strategies Polish pharma players most often use – focused on quality (GMP and other quality assurance systems) or on simple restructuring or on intensifying marketing activities, it is apparent that pharmaceutical firms in Poland are not aptly prepared either for the changes taking place right now or for the ones which will affect their market soon. In order to curtail a drop in profitability typical amidst the mentioned market conditions, a company can very quickly downsize employment, raise prices, lower the quality of consumer service, or slim down its product assortment; yet all those actions comprise reactive measures, often implemented by a firm experiencing losses, in an atmosphere of defeat.

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AstraZeneca – pioneer of direct distribution in Poland It is clearly better (for profitability as well as for market image and workplace atmosphere) to employ preventative measures, thus those which prevent or, at worst, limit the negative consequences of changes. Based on the experiences of other sectors, which have gone through similar “difficult” times or have “awaited” such times, organised supply chain cooperation implemented through a defined period and with heavy involvement can limit the consequences of the mentioned dangers and improve the security of those firms which leverage it as a business innovation. Direct distribution, now considered by moreand more pharma firms worldwide, represents one such solution. As the Polish Office for Competition and Consumer Protection (UOKiK) noted in a report on drug distribution released in 2006, even then in Poland increasingly more companies entered into contracts with chosen warehouses for exclusive trade in some products or product groups, i.e. niche or innovative drugs.

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reports, projects, plans

In addition, unofficial information has been meandering on the Polish market for some time about the plans of some pharma concerns to implement a model of exclusive distribution of the entirety of their product assortments. AstraZeneca was the first to officially confirm such market rumours. As reported by Gazeta Prawna, the firm announced that between the third and the fourth quarter of this year it intends to finalise a tender to select a firm with which it will establish such an exclusive partnership. Most likely, AstraZeneca will select several entities – wholesalers with greatest market reach in Poland. According to manufacturers, the execution of a contract for exclusive distribution would streamline supply chain management and would reduce problems related to counterfeit drugs. Representatives of wholesalers and pharmacies have also stated that such a move would help manufacturers to avoid losses which they incur when they have to import products within the framework of parallel imports (a legal mechanism entailing the import of a drug from one EU member state in which it costs less than in the target country, and then selling it at the lower price than the drug of the same manufacturers available in the target country).

Distributors as the most advanced The objective of the research conducted for the report among companies active on the Polish pharmaceutical market was, among its other aims, to diagnose the supply chain of the Polish pharma market. Based on the responses obtained through the survey and direct interviews, the key characteristics of Polish SCM include: • varying level of SCM awareness among the different members of the supply chains: with distributors (representing foreign manufactures) as the most aware, through select manufacturers and logistics operators, to medical institutions which are the least SCM-aware • strong impact of regulations imposed by government institutions, which significantly complicate and limit the possibility of efficient and effective flow of information, products and cash along supply chains • increasingly more visible influence of logistics operators on the form of the flow of tangible medicinal products through the supply chain.

Sector initiatives a must for SCM development The key factors material to the development of SCM in the Polish pharma sector include: • government’s policy relating to the establishment of strategic alliances or other types of closer cooperation, characterised by SCM • nature of social capital2 of a given country, which shapes the level of trust among business partners • extent of consolidation of the manufacturing and distribution sector, which affects the negotiating leverage of the individual trade partners in a supply chain

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• •

technological and infrastructural conditions which feed process improvement in SCM establishment of sector-specific and multi-sector (e.g. national) initiatives to promote and support this type of projects.

As found in the survey conducted for this report, among conditions comprising the greatest barriers to the functioning of SCM within the pharma sector in Poland are: • relatively low level of trust in business relations • lack of sector initiatives promoting SCM • still insufficient development of the sector of specialist logistics operators • restrictive drug manufacturing and distribution legislation. As backdrop phenomenon for the development of SCM in the pharmaceutical sector in Poland, only the state’s restrictive sector policy and low level of social capital defining the degree of trust among business partners are outside the sphere of influence of entities active on the pharmaceutical market. Undoubtedly pharma companies can play a role in changing some factors blocking the implementation of the SCM idea in the sector, such as the lack of organisational support, as well as coordinated efforts and promotion of SCM initiatives in the sector. Meanwhile, as far as the development of a sector of specialist logistics operators in Poland is concerned, in the opinion of survey respondents, this sector will soon evolve in the direction conductive to the SCM concept. For more information on supply chain management, see PMR Publications’ latest report “Supply chain management in the Polish pharma sector 2008” authored by Anna Baraniecka, PhD, and Bartłomiej Rodawski, PhD.

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Supply Chain Management (SCM)

2

According to Coleman’s definition, peoples’ ability to work with others within a group and organisation in order to realise common goals, referring to such characteristics of social organization as trust as well as norms and relations, which can improve effectiveness of a society by facilitating coordinated actions.

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Świat Przemysłu Farmaceutycznego 4/2008 EN