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The Farmacom publishing house and the editors of the “Świat Przemysłu Kosmetycznego” / World of the Cosmetic Industry / quarterly together with theHonorary Host - Nivea Polska Sp. z o.o. warmly invite you to attend our

to be held on 13–14 October 2011 at Novotel Centrum in Poznań.

This second edition of the Congress will be a continuation of the previous one, where the Honorary Hosts were Laboratorium Kosmetyczne Dr Irena Eris.

For this specialist industry meeting, devoted to the latest trends, technologies, machinery and equipment used in cosmetic manufacture, we invite: technology and automation specialists, heads of production, control and quality assurance, heads of logistics and procurement and heads of product development at cosmetic companies and representatives of firms dealing with and supplying the cosmetic sector.

The high standard of the material presented at the Congress will be assured by experts from cosmetic companies, higher educational institutions, and institutions and organizations associated with the cosmetic industry.

WE WARMLY INVITE YOU TO ATTEND THE CONGRESS!!!

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Editor-in-chief of the publishing house „Farmacom”

Programme Board Grzegorz Cessak – President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsAndrzej Szarmański – Wiceprezes Andrzej Szarmański – President of ISPE Poland, Quality Director at Polpharma SA Pharmaceuticals Irena Rej – President of the Polish Pharmaceuticals Chamber of Commerce Daniel Gralak – Director of GMP Inspection Department in Main Pharmaceutical Inspectorate dr Jarosław Jan Hołyński – Polish Pharmaceutical Association dr n. farm. Leszek Borkowski – EU expert of the matters of medicines, former President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products prof. dr hab. Zbigniew E. Fijałek – director of the National Medicines Institute Marcin Kołakowski – Vice President for Medicinal Products of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products Marek Gnyś – Chief technologist Polfa Warszawa

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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.

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contents

20

We invite you to subscribe!

Tabletting Vademecum

6

Maintaining a spore-free environment

in the cleanroom

14

20

Bet on the quality of the barcode

Tabletting Vademecum

22 Disintegrators 9

Fast dissolution for hard and unmistakable tablets

12

New solutions in FAIMS Technology

14

Bet on the quality of the barcode

16

Retrofitting Process Equipment

Achieves Containment

For A Range Of Manufacturing Operations

3/2011

– Disintegrant Substances Applied in Tablets

Efficiency Test. Pt. III

31

Edelmann Group

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June 16-17 2011 - Poznań

3 Congress

World of the Pharmaceutical Industry The third Congress of Pharmaceutical Industry World was held in Poznań on 13–14 June 2011.

The Poznań Herbal Company HERBAPOL S.A. was its honorary host.

34

32

Contract Logistics for Healthcare

Cold supply chain

34

Contract Logistics for Healthcare

Intelligent logistics in FIEGE

36

IT Technologies in Care of Adherence

to GDP Procedures

38

Electronic management for pharmacy

Identification of drugs in Europe – part IV

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Pharmaceutical contract manufacturing

and API sourcing

– why not Central and Eastern Europe?

44

3 Congress World of Pharmaceutical Industry

3/2011

6 | production

Maintaining a spore-free environment in the cleanroom Karen Rossington Marketing and Development Manager, Shield Medicare Ltd.

The manufacture of sterile pharmaceutical products is governed in the European Union by the requirements of EU Good Manufacturing Practice for Medicinal Products. The GMP guide gives very specific details on the environmental and microbial requirements for aseptic processing. However, little or no guidance is given on how to create and maintain the correct level of microbial contamination in the aseptic suite.

This article focuses on two important issues - creating and maintaining a spore-free environment and preventing spore contamination that may result from the use of disinfectants.

As a disinfectant manufacturer, Shield Medicare offers a useful

peroxide/peracetic acid blends are often toxic, irritant, corrosive, leave

perspective on the selection and use of disinfectants, as it has an in-depth

residues or need a long contact time.

knowledge of the products and also operates its own cleanrooms to the same cGMP standards as pharmaceutical manufacturers.

An alternative sporicide is available, which is not as aggressive. It is an alcohol-free blend of a quaternary ammonium compound and stabilised chlorine dioxide. It is non-corrosive, with a contact time of just five minutes

Control of Bacterial Spores One of the most difficult requirements in a life science cleanroom is

and its efficacy against spores is adequate for almost all environments.

A key decision, therefore, is what level of sporicidal activity is required.

the control of bacterial spores. They can enter the cleanroom on people

A log 5 reduction in spores is achievable but this has other implications.

and on components at a surprisingly high rate. Research has shown that

For most cleanroom users a log 3 reduction is usually more than adequate.

40% of consumables as they are taken from stores are contaminated

Check the manufacturers’ supporting data for your selected agents,

with bacterial spores1. The rest of the study showed that if the transfer

including sporicidal activity, as this will identify any additional testing that

disinfection procedure employed comprised of spraying solely with alcohol,

is required. Most disinfectants have efficacy data against standard tests,

only 27.6% of the spores would be removed. Annexe 1 of Good Manufac-

BS EN 1276 (bactericidal), BS EN 1650 (fungicidal), BS EN 13704:2002

turing Practice (GMP) states that “Transfer of materials into and out of the

(sporicidal) efficacy data.

unit is one of the greatest potential source of contamination� 2.

The main problem with spores is their resistance to many of the

However, these standard tests are suspension tests and consideration should also be given to surface testing. Some biocides, due to the manner

standard disinfectants that are used, including alcohol, and their ability

in which they work, will not perform well in suspension, but perform more

to lie dormant for long periods of time. Often a successful sporicide will

than adequately on a surface test. Currently no surface test method is

have disadvantages, as it may be dangerous to humans, or equipment,

available for sporicidal efficacy. A test methodology can be found in BS

or both. Hence the search for a non-hazardous but effective sporicide

EN 13697:2001 for surface testing against bacteria and fungi.

is very important.

Traditional disinfectants, such as alcohols, quaternary ammonium

It is useful however to test under laboratory conditions the sporicidal effectiveness of a disinfectant on a surface. In the absence of an EN surface

compounds, phenols and amphoteric surfactants are effective against

test for spores Shield Medicare has developed a Hard Surface Test3 based

bacteria in their vegetative state but useless against spores. Biocides that

on BS EN 13697 and the AOAC carrier test. A log 3 reduction against

have sporicidal activity, including aldehydes, hypochlorites and hydrogen

spores on a surface is generally accepted as a pass criteria for this test.

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Specification

Method of Application

Whilst efficacy is important it is also crucial to consider the final spe-

The application of the sporicide should be carried out to a validated

cification of the disinfectant. The user must ensure it can be transferred

procedure. The actual process of decontamination is the same for

easily into the cleanroom, that it meets the required standards for sterility,

both cleaning and disinfection. Disinfection does not replace cleaning,

and that for a product contact area it is diluted with Water for Injection.

as a heavily soiled surface may interfere with the effectiveness

Current GMP states that „disinfectants in Grade A and B cleanrooms

of a disinfectant. Cleaning should therefore usually be undertaken

should be sterile prior to use” 2.

prior to disinfection, or combined with it. A separate cleaning stage

Similarly, a disinfectant may require a range of presentations and methods

is more likely to be needed if there has been a spillage of a product

of application for different environments, large areas may require concentrates

or sample. If a detergent is used, a rinsing cycle must be included

for use with a mop and bucket system or a format suitable for fogging.

to remove any residue. Any detergent residue remaining will have an

Critical areas will need ready to use sprays or presaturated impregnated

adverse effect on any disinfectant used. Rinsing can be carried out

wipes. Presaturated wipes are especially useful in very critical areas, such as

with either Water for Injection (WFI), sterile purified or deionised water

isolators and laminar flow cabinets, which may have areas where liquid can

or sterile alcohol.

collect and is difficult to remove. Large, impregnated mop wipes also make short work of disinfecting cleanroom ceilings, walls and floors.

In all cases, the product must be supplied with essential batch

Due to the effect of biofilms, surface wiping is needed to assist in the removal of surface contamination. Wiping or moping should never be carried out in a circular motion as this causes the wipe/mop

documentation and certificates of sterility, irradiation and conformity where

in its dirtiest state to be passed over an area which has just been

applicable. It is also essential to review the standard operating procedures

cleaned. This point needs to be reinforced with operators, as a circular

to determine the implications that a particular biocide may have.

wiping pattern is the most comfortable and convenient according to Siegerman5.

Health and Safety Alongside the effectiveness and usefulness of agents, a health and

The correct technique is to wipe/mop, towards you, in straight horizontal lines, each time overlapping the previous one by 10-25%.

safety risk assessment is required as part of the validation process

A contaminated wipe/mop should not be passed over an area that has

of a new sporicide. Some excellent disinfectants, particularly sporicides,

just been wiped, unless in the case of a wipe it is folded and refolded

are harmful and difficult to use in cleanrooms. The occupational exposure

to provide a clean surface. Usually quarterly folds are recommended but

limits, the extra protective clothing or equipment required and the cost

must be validated with each operator concerned, as a quarterly fold can

have to be considered for each agent. Input from personnel who have

lead to confusion as to which surfaces of the wipe have been used.

to use the disinfectants can also prove invaluable in the final selection.

In this case wipes folded in half should be used. Surface wiping

Similarly, practical considerations such as on site storage and,

or mopping should be carried out from top to bottom, from back to front

increasingly, the waste disposal of chemicals or packaging materials,

and from cleanest to dirtiest. The wipe or mop itself should be constructed

can have major implications resulting in additional costs.

from a low particulate material.

Impact on the Cleanroom Environment

Preventing Spore Contamination from Disinfectants

Many disinfectants, especially sporicides, are oxidising agents and the environmental impact of using these in a cleanroom containing expensive

Maintaining the cleanroom integrity demands the safe delivery of

equipment has to be taken into account. A review of the available

the disinfectant: as mentioned previously, EU GMP Annexe 1 states that

corrosion data on materials used in cleanroom, isolators and laminar flow

“Disinfectants and detergents used in Grade A and B areas should be

cabinets should be a fundamental part of every validation programme.

sterile prior to use” 2.

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8 | production In most cases, disinfectants are delivered by either trigger sprays or aerosols. Trigger spray systems can offer significant advantages including: • an adjustable nozzle so liquid can be dispensed as a jet or a spray, enabling thorough wetting of the surface and ensuring that disinfection procedures are effective • they are environmentally friendly as they contain no propellants that require special disposal procedures • all of the liquid can be dispensed from a trigger spray, so there is no wastage, making them a cost effective solution compared with an aerosol.

However, there is a significant potential drawback with some trigger sprays, as contaminated air can be drawn back into the bottle, compromising the sterility of the liquid. Validation work in the licensed pharmacy unit of the Queen Elizabeth Hospital in Birmingham, UK, identified that a trigger spray alcohol, used to spray items into an isolator, had been contaminated with fungal spores only 8 hours after opening6.

Improvements in the Trigger Spray System Trigger spray systems are available which resolve this problem, providing a system with the benefits of a trigger spray whilst guaranteeing the integrity of the contents.

The new design operates as a closed system, preventing air being drawn back into the bottle and so eliminating the possible chance of contamination of the liquid. The liquid is held inside a medical grade bag --- the function of the bottle is simply to enclose and protect the bag in use. All points of entry into the bag, including the dip-tube, are completely sealed, thereby creating the closed system.

In order to validate that the sterility of the liquid was not compromised during use, a series of tests were carried out on 1 litre bottles filled with sterile liquid nutrient7. Half the nutrient was sprayed out and the bottles left with their spray nozzles open in a Grade D cleanroom. Samples were removed at set time periods. The media was then tested at an independent laboratory to see if the contents had become contaminated.

No growth was found in any of the samples, demonstrating that this design can protect the sterility of the contents for up to six months.

If all these areas are acted upon then it should be possible to maintain a spore free environment in the cleanroom.

References 1. Validation of liquid transfer disinfection techniques for transfer of components into hospital pharmacy cleanrooms: Hospital Pharmacist Sept 2001: MG Cockcroft, D Hepworth, JC Rhodes, P Addison, AM Beaney 2. MCA: Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2002.

3. Shield Medicare Technical Report Number TR0304R Test method for Shield Medicare Hard Surface Test for Sporicidal Activity.

4. Shield Medicare Technical Report Number TR0302R: Evaluation of the efficacy of Premier Klercide-CR Sterile Filtered Biocide B during the commissioning of a Medical Device cleanroom manufacturing facility 5. Wiping Surfaces Clean: Advancing Applications in Contamination Control April 2003: Howard Siegerman 6. Dr B Salvage: Contamination Control at your Fingertips: Pharmaceutical Manufacturing International, Autumn 1999 7. Shield Medicare Technical Report Number TR9903R: An investigation into the in-use shelf life of Premier KlercideTM 70/30 Sterile Alcohol Sprays, Aug 2000

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production | 9

Fast dissolution for hard and unmistakable tablets Almut von der Brelie, Roberto Ognibene, Leonard Ohrem Merck KGaA, Darmstadt

Direct tablet compression – the new option for applying Candurin® pearl effect colors

New studies on direct compression have been conducted with the mineral Candurin® pearl effect colors and Parteck® ODT and Parteck® SI functional ready-to-use excipients. According to the results, these inert excipients are perfectly compatible. Candurin® exhibited no influence on compression behaviors and dissolution time. The benefit for drug manufacturers? Without the need for additional film coating in production, drug manufacturing becomes both more time and cost effective.

Introduction

Application

The coloration of solid drug forms is a generally accepted and effective way to prevent medication errors and to increase the safety of drug use.

On July 13, 2009, the American Food and Drug Administration

Manufacturing and Blending: The excipients were blended with Candurin® (3%) and iron oxide yellow (0.25%) for 5 minutes in a Turbula® Shaker-Mixer. In this stage the API was also included in the drug

(FDA) presented the draft of the new guideline entitled „Incorporation

formu­lation. In a second blending step the lubricant Parteck® LUB MST

of Physical Chemical Identifiers into Solid Oral Dosage Form Drug

(magnesium stearate) was added. The blend­ing appeared to be straight

Products for Anticounterfeiting” [1]. The document describes the use of

forward. Homogeneity was achieved easily in 5 minutes.

physical chemical identifiers (PCIDs) in solid dosage forms and provides the recommendation for the use of molecular markers as, for instance, colorants and pigments that are meant to be identifiable by the dealer or

Compression: All tabletting mixtures were com­pressed on a Korsch EK 0 DMS single punch press (500 mg tablets /11 mm, 50 rpm, biconvex).

Since the coating requires an additional process step, formulators are

pharmacists. The objective is to make it more difficult for counterfeiters to

also seeking opportunities to give tablets an unmistakable appearance by

copy drug products [2].

dry blending only. Especially for orally disintegrating tablets (ODTs), it is not

Candurin® pearl effect colors are a unique range of mineral food and pharmaceutical colors developed and manufactured by Merck KGaA.

possible to use coatings because this would interfere with the required fast disintegration.

Based on a natural silicate (mica) combined with titanium dioxide and/or

The direct compression of Candurin® was tested in powder blends

iron oxide, the colors have been widely applied in tablet coatings and in

with Parteck® SI 400 and Parteck® ODT, developed and manufactured by

capsules.

Merck KGaA.

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10 | production

Fig. 1. Pearlescentgranulate with Parteck® SI 400, Candurin® Gold Lustre and iron oxide yellow

Fig. 2. Morphology of granulate containing Parteck® ODT

and Candurin® Gold Sheen

Fig. 4. Pearlescent tablets exhibiting a shiny surface with homogeneous and uniform golden color.

Fig. 3. Morphology of granulate containing Parteck® Si 400, Candurin® Gold Lustre and iron oxide yellow.

Fig. 2, 3. Platelets are fixed by the rough surface structure of the polyols excipient particles.

Parteck® is a family of products featuring specially designed particle qualities for solid dose formulations. Based on spray-granulated mannitol, Fig. 5.

Excellent compression profiles of placebos with Parteck® ODT and Candurin® Gold Sheen

Parteck® ODT has been developed as a ready-to-use excipient system for fast disintegration [3].

Parteck® SI 400 is also a directly compressible excipient consisting of pure sorbitol.

The use of the excipients in uncoated tablets has been evaluated in placebo tablets and in a drug formulation containing Ibuprofen as a model drug substance.

The compression profile has been measured with a placebo formulation containing Parteck® ODT and Candurin® Gold Sheen. The tablet hardness was deter­minated by an Erweka TBH 30 MD tablet tester.

Dissolution: To study the dissolution behavior

Fig. 6.

Good dissolution performance for Ibuprofen tablets with Parteck® ODT and Candurin® Gold Sheen.

according to USP method, a formulation containing 200 mg Ibuprofen and Parteck® ODT was used with and without Candurin® color. The final tablet weight was 500 mg.

Results A homogenous, yellow golden granulate was obtained by blending Parteck® SI 400, Candurin® Gold Lustre and iron oxide yellow (fig. 1) even in a

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production | 11

Przedsiębiorstwo Handlu Zagranicznego FOREIGN TRADE ENTERPRISE 92-221 Łódź – Poland ul. Nowogrodzka 2 B Fax 0 42 678 74 79 Tel. 0 42 678 70 96 e-mail: biuro@yagra.com.pl

short blending time of 5 min. The SEM pictures show the micro structure

Conclusion

and the distribution of the flat shaped Candurin® platelets on the excipient

The study results show the perfect compatibility of the inert excipients

particles (fig. 2-3). The platelets are fixed by adsorption onto the rough

- Parteck® ODT and SI and Candurin® pearl effect colors - with other

surface structure of the polyols excipient particles. This supports a good

formulation ingredients while yielding an excellent direct compressibil­ity for

content uniformity throughout the tabletting process. The resulting tablets

cost-effective production of rapidly disintegrating oral tablets.

exhibit a shiny surface with a homogeneous, uniform golden color (fig. 4).

According to the hardness determination results, the use of Candurin®

The direct compression is a new option for applying Candurin® pearl effect colors with no need for additional film coating. The unmistakable

did not lead to a significant change in the compressibility. Extreme tablet

luster helps to prevent medication errors and makes it more difficult for

hardness of more than 300 N was achieved in any case (fig. 5). Further­

counterfeiters to copy drug products.

Dla przemysłu farmaceutycznego oferujemy najwyższej jakości wyroby .

more, no influence of Candurin® on the in vitro dissolution profile was

detected (fig. 6). This combination of high tablet hardness and fast disso­

Acknowledgement

lution is exceptional and results from the large structured surface area of

We thank Biogrund GmbH for the cooperation.

the Parteck® excipient particles. These surfaces interlock very intensively

·Tkaniny i włókniny techniczne do filtracji mokrej i suchej dla wszystkich urządzeń stosowanych w przemysłowych procesach technologicznych .

at low compression forces. As the binding is performed by the needles

References

on the surface of the particles, only the needles have to be dissolved to

1. Federal Register, Vol. 74, No. 33, 34021-34022 / July 14, 2009.

disintegrate the tablets. Especially in ODT applications, it is beneficial to

2. R. Eicher, European Compliance Academy (ECA), GMP News August

·Włókniny filtracyjne do odpylania agresywnych gazów , filtracji mokrej i ochrony środowiska .

have such a fast dissolution of nearly 100% within 5 minutes.

The mineral, non-artificial Candurin® pearl effect colors are compatible

5, 2009.

3. H. L. Ohrem, R. Ognibene, Pharmaceutical Technology Europe,

with other colors and characterized by excellent stability. They are also

September 2009.

·Gotową konfekcję techniczną na urządzenia filtracyjne wg potrzeb i życzeń odbiorców np. : gotowe worki do wirówek , przegrody do pras itp.

ideal for pediatric nutritional formulations for which some defined synthetic

4. Regulation (EC) No 1333/2008,AnnexV, Official Journal ofthe European

colors have to be labeled with a warning label in the EU [4].

Union, L 354/16-L354/33.

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We provide finest quality products for the pharmaceutical industry: · Technical woven and non-woven fabrics designed for wet and dry filtration for all devices used in industrial technological processes. · Non-woven filtration fabrics for dust removal from aggressive gases, wet filtration and environmental protection. · Ready-made technical fabrics for filtration equipment tailored to customers' needs and wishes, e.g. ready-to-use bags for centrifugal dryers, filter media for presses, etc.

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12 | production

New solutions in FAIMS Technology Ewa Korbiel, Kornelia Golik Irtech

FAIMS is a new technology capable of separation of gas-phase ions at atmospheric pressure and at room temperature. FAIMS can be operated over a wide range of pressures and has been tested above 1500 torr. FAIMS will operate at lower and higher temperatures.

FAIMS Technology Overview FAIMS exploits the properties of gas phase ions in an oscillating field at atmospheric pressure. Ion mobility changes non-linearly with

the strength of the electric field and is dependent on the charge and collisional cross section of the ion. In FAIMS, a stream of gas-phase ions is passed through a narrow gap between two electrode plates (in the case of the Thermo FAIMS, the two electrodes are concentric cylinders). The electric field between these two electrodes oscillates between a high voltage of one polarity and a low voltage of the opposite polarity. The term „asymmetric” in High Field Asymmetric Waveform Ion Mobility Spectrometry refers to the fact that the high-field portion of the waveform has a significantly shorter duration and greater magnitude than the opposite polarity low-field portion.

The result is that a gas-phase ion will migrate toward one electrode during the high-field portion of the wave form and toward the opposite electrode during the negative portion of the waveform, but the distance travelled will differ between the high-field and low-field portions depending

Fig. 1. An example of an asymmetric waveform

on the ion’s mobility in the conditions within the FAIMS unit.

Fig. 2.

Oscillation of ions between the electrodes

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Oscillating in this fashion, only ions with certain characteristics entering

As ions move through the device an electric field is applied, which

the FAIMS unit will avoid colliding with one electrode or the other and

filters the ion of interest from the background mixture. Ions with the

actually exit to pass on to the mass spectrometer. An additional parameter,

correct mobility ‘fingerprint’ pass through the device and are detected.

a DC potential referred to as compensation voltage (CV) applied to the

Conventional FAIMS technologies have a single filter gap, which requires

electrodes allows the user to tune the FAIMS unit and select which types

very high voltages and reduces sensitivity. Innovative design has a series

of ions will be filtered out and which will be allowed to pass through.

of filter electrodes connected in parallel, which results in a significant

Innovative Microchip solution

increase in sensitivity and a further ability to detect chemicals at very low concentrations.

The heart of innovative FAIMS detection technology is a microchip sized spectrometer. The device is fabricated using processes similar to those in the semiconductor industry, enabling a highly integrated ‘dime’ sized detector. The parallel, batch fabrication process results in economies of scale, which dramatically reduces unit cost.

Using microfabrication techniques it is possible to make the parallel gap filter structure extremely small. In addition to making the device small it also reduces the voltage required to operate the sensor, thus simplifying the system in its entirety. It becomes possible to fit all the electronics on another microchip, reducing the size, cost and power consumption. At Chemicals enter the detector and are ionized, which means they can be moved by an electric field. Ionization detection methods are among the

these lower voltages we can generate “cleaner” signals which improves resolution and reduces the false positive rates.

most sensitive available, easily achieving detection limits as low as one part per billion. This allows the detection of chemicals at very low thresholds, a key requirement across the whole range of detection applications.

Ions are then drawn into the sensor for analysis. Innovative design incorporates a drive electric field to ‘pump’ ions through the device.

Conventional FAIMS technologies use mechanical pumps which are power hungry and bulky. Innovative design is integrated to greatly reduce size and complexity. The power consumption is reduced by a factor of a thousand, which means the detector can be used in battery portable applications that demand long operational life.

It is necessary to heat FAIMS sensors to reduce deleterious effects due to changes in environmental conditions, minimise decontamination time and improvedetection of “sticky” substances such as explosives. Heating convetional FAIMS technologies requires a lot of energy, which reduces battery life. New solutions include an “intrinsic” heater. Due to small size of sensor it heats up rapidly with low power consumption making it more suitable for portable applications.

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3/2011

14 | production

Bet on the quality of the barcode Tomasz Dragan HIT – Kody Kreskowe

Quality of 1D and 2D barcodes lately be or not to be for supplieres. Among several ways of assuring good quality the most reliable way is varification with equipment especially designed for that purpose and certified with apropirate ISO standards.

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production | 15

Aparently it may seem that the effects arising from the incorrect reading of barcodes which do not meet the standards are marginal problem. But research conducted by Institute of Logistics and Warehousing indicate different conclusions. In 2007 r. around 35% of barcodes didn’t meet the standards, and 2-3,5% was completely unreadable. Average reading time of barcode from the package at cash point is 2,6 s (minimal time is little longer than a second), whereas manual entry item no. when the barcode is illegible take 6,1 s. That gives the average losses of working time in 24/7 system, of 10 hours a day, that is, 130 days a year! And these are only losses caused when reading a barcode. Considering the losses of time and costs incurred due to lack of ability to read barcodes while, among others. return delivery from the customer at our expense or delay in the supply chain at the stage of issue and receipt of goods, losses are even greater.

Some people being reluctant to invest in quality control of barcodes,

quality of a bar code already in the process of manufacturing and labeling.

claiming that since their Bar Code Reader is able to read the code,

Appropriate quality of barcodes on each label during the manufacturing

it means that the quality of the barcode is correct. Nothing could be further

process can be provieded by on-line verifier. Dedicated software in such

from the truth, this solution assures only the correct reading of the barcode

a solution can automatically stop the printing and application of labels

by this particular reader.

in the process immediately when it detects any non-compliance to the

Whereas equipment guaranteeing the code reading, by any reader

standard of quality codes. Verified can be all prints ordered, for example

is a barcode verifier, which check print parameters and their compliance

drug leaflets with barcodes or packaging. Very important element is the

with ISO standards. Conformity of data stored in the barcode in the

rapid ability to locate the defective barcode and incorrect printing, so that

pharmaceutical industry is especially important element. Therefore

it can replaced as soon as possible with correct one. Inaccuracy in the

pharmaceutical manufacturers often reach for a solution to verify the

numbering and content of the data on labels can lead to non-compliance,

in the manufacturer system and also in the subsequent distribution.

Therefore especially the pharmaceutical industry reaches for solutions that verify the quality of reading bar codes on-line. Additionally, the recorded history of readings in the software supplied with the verifier allows the archiving of data quality reports, readings of barcodes and enables quick information lookup on quality measurements carried out.

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16 | production

Retrofitting Process Equipment Achieves Containment For A Range Of Manufacturing Operations

Alan E. George

Adding new technology or features to existing equipment minimizes shutdown time and reduces interference in the production process.

Today’s marketplace and overall economy are putting more pressure than

equipment to meet these needs is a key element in the manufacturing

ever on decision makers in the pharmaceutical and biopharmaceutical

strategy.

industries. When asked, „What keeps you up at night?” feedback includes

This article provides a review of various innovative solutions, a

but is not limited to the following:

provocative thought process for customized installations if needed, and

• „I need to get a new product developed, and my schedule is too short

a look at a technology verified to reduce the overall cost of ownership for

to afford a long lead delivery of new process equipment.”

contained processing.

• „Money is tight, and I cannot get capital funding to expand my operations.”

• „I have existing equipment that is very functional, but I am now being asked to manufacture highly hazardous, potent compounds.”

• „My financial analysis of our business operations shows that we cannot continue to absorb high capital costs or the depreciation costs of new facilities and expensive containment equipment.”

What Is The Approach?

Retrofitting refers to the addition of new technology or features to older systems. This generic definition is somewhat basic but applies to enhancing process equipment and facilities.

The key objective is to apply proven containment technologies to minimize negative effects on productionwhile optimizing benefits to the organization. Minimizing shutdown time, reducing interferences or

Given these types of pressures, using innovative technologies to

impediments to production, and significantly reducing capital (as well as

achieve containment of highly hazardous compounds and current

the subsequent depreciation costs) are a few negative aspects that can be

Good Manufacturing Practice initiatives is crucial. Retrofitting process

turned into positives.

Alan E. George is the pharmaceutical product line manager for ILC Dover’s Containment Products. He has been actively involved in developing applications of flexible containment for various types of process equipment by working directly with pharmaceutical manufacturers and ILC’s engineering staff over the past 12 years. These designs are then manufactured

by ILC to support the production of potent compounds. George’s background over the past 28 years with ILC has ranged from design through management of programs and the introduction of new products for both Department of Defense and commercial uses where softgoods are designed to meet high reliability requirements such as those facing the pharmaceutical industry today. The designs being implemented are based on technologies developed through ILC’s roles for such products as all of the space suits used by NASA since Neil Armstrong first walked on the moon, airship and aerostat envelopes, and the landing impact bags for the Mars Pathfinder program.

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17 Additionally, organizations can maximize benefits with the ability to manufacture hazardous active pharma­ceutical ingredients (APIs) on

process. Figure 1 illustrates a portion of process characterization from projects performed with various pharmaceutical manufacturers.

existing process equipment as needed, within regulatory compliance, with

Figure 2 in this grouping shows an installation where raw materials

reduced cleaning and cleaning validation, in a manner that supports speed

are transferred from drums into a 700L DoverPac. While this operational

to market, and at safety levels to the nanogram protection range.

example sets up a contained transfer device, dispensing to weight is

Simply put, flexible containment is the application of films and fabrics integrated to process equipment via adaptive canisters, frames, and flanges — a system that supports product transfer and storage and consists of disposable components.

achieved by installing the system with a scale under the pallet (not shown in this application).

This process step is successfully demonstrating ongoing, contained dispensing in the BNL Limited warehouse in Dublin, Ireland. This repacka-

Flexible containment systems have been applied in a variety of processing equipment applications. The key to a successful flexible containment application is to engineer the retrofit around the process requirements and the process suite and specific piece of equipment already installed.

Paramount here are decisions centered around:

ging step is continually performed for a pharmaceutical end customer.

The only facility upgrade was the installation of a flexible wall room within the warehouse installed by Containment Service Providers, a local containment supplier in Ireland.

In this example, the DoverPac is transported to the end manufacturer and

• Containing the entire piece of equipment versus separating the mechanical and processing areas

charged directly into a reactor.

Reactor charging of drummed materials directly to the vessel is shown

• Using containment only when it is needed, based on the compound being manufactured

in figure 3. This operation is being performed at a different manufacturer.

Here, materials are received ready for release to manufacturing. Drums are

• The containment level to be achieved

sent to the processing suite directly from the warehouse and then charged

• Minimizing expensive facility modifications

to the vessel. In this example, the only retrofit was the inlet canister attached to the existing valve on the reactor.

Bulk Pharmaceutical Manufacturing One way to evaluate the applicability of this technology for retrofit applications is to start with a step-by-step flow chart analysis of the

Receive raw Materials (drums, sacks, boxes)

Figure 2.

Dispensing to DoverPacs from drums

Received reasdy for manufacturing

Yes

No

Dispense to weight

Release to Manufacturing

Charge to Reactor

Figure 3.

Figure 1.

Partial pharma manufacturing process form

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Drum transfer system for charging reactors

Process & Pump Slurry to dryer

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3/2011

18 | production Receive materials

API

Excipients, lubricants, other

Is Milling required?

Dispense to weight or contained transfer device required?

Figure 5.

Mill containment system

Yes

No

Yes

No

Figure 6.

Blender enclosure Mill

Release to Manufacturing

Release to Manufacturing

Dispense

Transfer

Blend

Figure 7.

Transfer

Tablet press and deduster enclosure

Figure 4.

Compression

Oral solid dosage process flow

Transfer

Tablet Coating

Transfer

Packaging

Figure 8.

O’Hara Technologies LCM laboratory tablet coater

heat buildup, and other considerations. However, sometimes existing equipment provides no option other than to contain the entire kit.

Figure 5 and figure 8 are prime examples of containing the process part of equipment only. The mill containment depicted in figure 5 was completed for a fielded mill using the DoverPac system.

In fact, the unit shown was from rental equipment from Quadro.

Oral Solid Dosage Manufacturing Retrofits in oral solid dosage manufacturing are also readily achievable. Common applications range from material receipt through packaging. Figure 4 breaks down some of these typical process steps

A simple change of hardware and rerouting the existing interlock achieved nanogram containment levels, even during screen change-out operations.1 Figure 8 depicts a flexible enclosure on an O’Hara tablet coater.

and decisions made along the way. As before, typical examples from

Recently delivered for lab-scale oper­ations at an international

customer case studies are depicted in figure 5 through figure 8.

pharmaceutical manufac­turer, this installation takes the idea of retrofits

Of interest in these illustrations is the retrofit option of separating

to another level. Here, a new piece of equipment was needed, but the

the process and technical areas or addressingthem collectively. Se-

manufac­turer cut costs by modifying an existing design. The original

parating these parts of the equipment is preferred for ease of cleanup,

equipment manu­facturer added flanges to the unit, allowing the end

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production | 19 user to process contained when needed and to pro­c ess to existing procedures when containment is not required.

Figure 6 and figure 7 are part of an entire process train retrofitted for containment. These process steps required entire pieces of equipment to be enclosed due to the size and design of the older equipment in use. Because this is a lab-scale operation, the equipment runs on short intervals before changeover, which minimizes the concern of heat buildup. The containment was integrated to stainless steel tables and trays specifically built for the application, so that utilities can run to the equipment rather than through the flexibles.

Of note, no facility retrofits were needed for any of these installations.

Biopharmaceutical Manufacturing Disposables are readily accepted in the biopharmaceutical marketplace. This includes applications, such as media and buffer preparation and lypholization.

The use of powder transfer devices within existing buffer preparation processes — whether new or existing — is gaining momentum as well. Figure 9 illustrates an example during the factory acceptance test stage of the project at METO Corporation where dispense-to-weight operations were being trialed. Now that this is successfully completed,

Figure 9.

Factory acceptance test for dispensing to DoverPac SF

process installation efforts are underway.

Because this was a dispense-to-weight operation withina tightly controlled tolerance, the support frame and scale had to be separated from the drum inverter. Figure 10 shows how to achieve this by applying a flexible sleeve with molded sanitary flanges.

Why Retrofit With Flexible Containment?

As shown, flexible containment retrofit solutions are applicable in a range of manufacturing operations including bulk pharmaceutical, oral solid dosage, and biopharmaceutical. Processes addressed in this article include drum transfer of raw materials, reactor charging, milling, blending, table compression, tablet coating, and dispensing to weight.

When considering containment technology options, the economic benefits and other performance benefits must be evaluated. The

Figure 10.

Separation transfer sleeve

features and benefits of flexible containment solutions are shown in the chart below. In today’s economic climate, the benefits associated with

Reference

a „lean nature” of flexible containment cannot be overestimated.

1. Brady, V „Performance Verification Testing of an ILC Dover, LP Mill

The ability to reduce capital expenditures and rapidly convert assets for other functions, such as API processing, are significant.

Containment System for Underdrive Style Comills using Surrogate Air and Wipe Sampling with Lactose Monohydrate.

Features

Benefits

Validated containment technology

Nanogram to current Good Manufacturing Practice containment levels achiev ed

Clear film

Supports visibility for maintenance

Passive system

Docs not alTcct European Union ATEX and EX ratings

Flexible materials

Ergonomics maximized

Disposable components

Reduced cleaning and cleaning v alidation Low capital and operating costs Rapid implementation

Robust designs

Multiple manufacturing stages supported

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3/2011

20

Knowledge gained by pharmacists returns to them enriched with the elements of mechanics necessary for the process of proper tabletting.

The guide, that we plan to publish soon, will not bore you with the We invite you to subscribe!

We invite you to subscribe!

principles of mechanics. On the contrary, we want to provide you with the key results of mechanical tests performed on all kinds of substances that may be a part of a tablet and form its structure. Such information is extremely valuable and could often be of a critical importance, influencing the condition of an entire company. Results of such tests have been used successfully by this industry for over 20 years; however, it has been done on a small scale. Now we want to disseminate and develop the knowledge

profitable and top-quality technology for the future, despite the fact that it

based on this data. As formulation scientists, pharmacists, or chemists,

is sometimes perceived as difficult or impossible (mainly due to a lack of

you are experts in chemistry. However, a good tabletting process requires

knowledge about mechanics). The guide will also include information about

at least basic knowledge of mechanics. This process depends greatly

wet methods, especially fluidised methods. One of the objectives of our

on the nature of the substances used and on the final operations of the

guide is to inform you about testing/experimental techniques. We will help

manufacturer, such as grinding, drying, or crystallisation conditions, etc.

you to submit for registration only those formulations that are thoroughly

We will provide you with objective results of tests conducted on

tested pharmacologically and mechanically, as required for high-volume

substances chemically identical, but in different forms that result from

industrial processing. We do not underestimate the importance of chemical

the procedures of the producers. This is the main goal of our guide that

research, but we want to present you the current situation on the market

would become a kind of an overview catalogue. On a regular basis, we

of Active Pharmaceutical Ingredients (API) and auxiliary substances

will provide you with information on all commercially available starches,

in terms of tabletting. Presented results of mechanical tests will be

lactose, cellulose, polymers, phosphates, carbonates, and other specifics,

constantly updated to track new products introduced by manufacturers

with information about their manufacturer, supplier, and other commercial

of different substances. We will provide information that would enable you

data, including of course, their test-proven parameters. These tests will

to systematise your knowledge about individual tablet ingredients in order

always be conducted in identical conditions, fairly, and in an impartial

to facilitate profitable purchasing and efficient troubleshooting during the

manner. Having such knowledge, we will promote direct tabletting as a

production process.

We invite you to subscribe!

Tabletting Vademecum 3/2011

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We would like to offer you a subscription to the TABLETING VADE-

21

One A4 sheet will contain products from one group (APIs, lactose,

MECUM bulletin, published jointly by Farmaserwis and the Farmacom

starch, cellulose, etc.) – selected by us to begin with, and later according

publishing house.

to your suggestions. According to need, it will be possible to increase the

The bulletin is intended both for pharmaceutical companies (technology

quantity of monthly information. It is planned to expand the thematic scope

specialists, quality control departments) and suppliers of substances for

to include current matters relating to tableting technology, formula design

the pharmaceutical industry.

and the solution of difficult problems. We will be concerned mainly with

The results of each test will be presented in the following form, and will

direct tableting, but without excluding certain elements of wet granulation.

contain information about the manufacturer or supplier, obtained exclusiveWe invite you to subscribe!

ly from the source, namely from the supplier.

Kwas acetylosalicylowy Acetylsalicylic acid

29.03.2011

Obrazy (pow.

Images (magnified 40x) cząstek 40x) of particles pozostałych left on na sieves: sitach: 0,0 0.0

0,1 0.1

0,2 0.2

0,4 0.4

0,5mm

Tare wytarować Sito the sieve with z zawartością, contents, then następnie weigh empty record the result zważyćand puste i zapisać wynik bez znaku without the minus sign "minus".

0,7 0.7

on sieve sicie sieve sito na [mm]

[g]

1.5 1,5 0,7 0.7 0,4 0.4 0,2 0.2 0,1 0.1 0,0 0.0

0.016 0,016 3,722 3.722 2,670 2.670 0,724 0.724 0,170 0.170

9

Target: Cel: :

Farmaserwis

Remarks Uwagi: :

10.05.2011

Results: Wyniki:

1. Base Baza (Acetylsalicylic (Kwas acetylosalicylowy) acid) 2. MgSt

36,6

0,2 0.2 51,0 51.0

9,9

36,6 36.6 9,9 9.9 2,3 2.3

2,3

0,0

0,1

0,2

0,4

0,2

0,0

0,7

1,5

wielkość oczek sita [mm] sieve mesh size [mm]

100,0 100.0

Kwas acetylosalicylowy Acetylsalicylic acid + 0.05% + 0,05% MgStMgSt BAZA22for This is now tests, as ajako water-insoluble formula To jest terazBASE dofurther dalszych prób, formulacja nierozpuszczalna w wodzie.

Tu osiągnięto Here the greatest największe hardnesses twardości were achieved z wszystkich out próbek, of all samples, od zawartości from 3%3%MgSt MgSt content 30 [g] of[g] tablet tabl.Ø10R13 Ø10R13for dlathickness grub. 5mm 5 mm gdywhen 10kN:10 kN: 200 x P WeightCiężar 99,95 % 99,95 mg 99.95 99.95 19,990 g * 0.428 19.990 0,428 25 0,05 % 0,05 mg 0.05 0.05 0,010 g * Pressures 0.010 Naciski Siła Ej. ThickGru- TwarHard- DisinteCzas

¦

?

kN kN

100,00 mg 100.00

w w w.farmacom.com.pl

100,00 % 100.00

20,000 g 20.000

kN kN

2 5 10 20 30 40

daN daN

7,5 8,5 10,0 10,5 14,0 14,0

mm mm

5,2 5,1 5,0 5,0 5,0 5,0

time daN MM,ss MM,ss daN

3,0 4,5 5,1 6,2 5,9 5,1

0,400 0.400 5,18 5.18 0,386 0.386

?

prelim. wst. main gł. force wyp. -ness bość -ness dość -gration rozp.

Remarks: Uwagi: Znakomicie Forms tablets się tabletkuije, excellently;nawet even fractures are somewhat less inclined to cause detachment of outer surface. MgSt is clearly appropriate here.

Stearic acid gave inferior slide; it settles on the matrix and penetrates between the punch and the matrix. Large batch tests were performed separately, and give an optimum MgSt content of 0.03–0.09%.

d o w n l o a d *. p d f v e r s i o n :

% 0,0 0.0

7,302 7.302

Dezintegratory Disintegrators

51,0

99,99 99,99 99,99 99,99 99,99 99,99

20 15 10 5 0

0

10

Deformation Zgniot: 5,0 5.0% %

20

30

kN 40

Tabletkowalność: Tabletability: 0.480,48

3/2011

We invite you to subscribe!

We invite you to subscribe!

Farmaserwis

p remaining on sieve [%]

A

Analiza Sieve analysis sitowa of produktu: product:

Disintegration Badania rozpadów tests

22 | production Name

Tableting

Disintegrators – Disintegrant Substances Applied in Tablets Efficiency Test. Pt. III

Jerzy Lasota FARMASERWIS

The originally planned production of a ranking of disintegrants turned out to be impossible as nearly all of them can make a good disintegrant, depending on the conditions in which they are used.

These conditions are described in order to demonstrate how much can happen unnoticed in a tablet and in tableting. Certain phenomena are referred to which are not generally known and thus not always considered when designing formulations.

The first part, published in number SPF 1/2011,

substance was introduced, which is not water

contained tests of method resolution, error

soluble.

estimation, identification of base substances and

A little reminder to start this research part,

establishing the efficiency profile for the Vivastar P

and a review of the information already acquired.

disintegrant.

The situation is as follows:

In the second part, there was a thorough study

Parteck M100 serves as a simulation of

and explanation of the phenomenon of disintegration

a water soluble formulation. The second base

time extension, which occurs for very small amounts

substance, not water soluble, is acetylsalicylic acid,

of gelling disintegrant, depending on the amount of

aka aspirin. Produced in India, it is in the form of

free space in the tablet, i.e. on its porosity. It was

spherical particles up to 0.4mm (51%) in size, with

discovered that in a formulation with mannitol it is

disintegration as shown in the previous part – this

possible to find even 1 per mille of Vivastar P, results

information is important as the results of the

indicating the possibility of detecting even smaller

present research are strongly dependent on the

amounts. The efficiency profile of Polyplasdone Ultra

external form of the substance.

was established, showing one of the substance’s beneficial qualities – good cohesion. Another base

3/2011

The use of two bases, although deliberate to provide new observations, caused a doubling of

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production | 23

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3/2011

24 | production the amount of tests and results diagrams. In order to save space, not

of 5±0.1mm. This condition, met at the beginning of a given sample at

all auxiliary graphs are shown which present the dependence of the

tableting, holds for at least that sample, on the whole pressure scale.

disintegration time on the proportion of disintegrants and on the pressure

It is expressed in grams as the amount of the substance per tablet.

used. These graphs turned out to be useful for thickening out the

In these samples, the indicator of the tablets’ mass was the pure

measuring points while preparing weighed amounts, as shown in parts I

(without disintegrants) base substances.

and II. It is straight from these, containing the disintegration times came

For all the samples, current and previous, a gravitational tableting

with seconds converted to hundredths of a minute, that the efficiency

machine was used, calibrated according to the rotational: Kilian Tx-40,

profiles, which have all now been shown, came from. They were merged

operating with a speed of 100 thousand tabl/h. Most of the pressures

into two per diagram – for formulation with mannitol and for formulation

do not depend on the amount of substance added to the matrix.

with aspirin.

The efficiency profile is a function illustrating by what percentage the

In the research section, all the planned actions were carried out and, in addition, following the example of the previously mentioned Vivastar

tablets disintegration time is reduced (on the vertical axis) depending

and Polyplasdone, the results of mechanical testing for all the remaining

on the disintegrant content horizontal axis) and depending on pressure,

substances (tables) were made available. On the horizontal axis –

which is shown by coloured lines and which was one of the main aims

pressures in kilonewtons. The black line shows cohesion, the others

of this research.

in this case are less important. Although in the case of disintegrants

Pressures were applied from 5kN to 40kN, sometimes without using

used in small amounts the fact of having good cohesion is of no great

5kN, or occasionally 30kN, as it transpired that they give nothing new.

significance, it is worth knowing a little more about the substances which

40kN is the maximum permissible pressure for the Ø10R13 test tablets

use it, even if just to know exactly the consequences of an overdose

used.

while designing a formulation. For example, if we know that Polyplasdone

The priority for a test tablet is its thickness, and not its mass.

has good bonding properties then regardless of the amount used in a

Such a turnaround dispenses with the dependence on differences in

tablet there is no need to worry about the hardness being weakened, as

bulk diameter between substances, making it possible to standardise

often happens in the case of disintegrants without cohesion. Returning to

its thickness, which is vital in testing its hardness, pushing force and

the beginning, though, figures 1 to 7 show the results arranged in rising

disintegration time. The mass results from the condition that

order of bulk density. The lightest is Polyplasdone, with the test tablet

a Ø10R13 tablet pressed with a force of 10kN should have a thickness

weighing 206mg. The heaviest is Primojel, pressed in the same volume

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production | 25

DC formulation Laboratory. Subject: Testing disintegrant efficiency.

For company: own work

Date:

DC formulation Laboratory. Subject: Testing disintegrant efficiency.

Page:

Efficiency profile of

For company: Date: Page: own work Base formula: acetylsalicylic +0.05%MgSt

Vivastar P as a disintegrant

but weighing a whole 352mg. Nota bene: aspirin at this volume weighs

unt of this substance is, in this case, 5 – 15%. Significantly, in the case

even more - 426mg.

of aspirin the effective amount of this disintegrant is only 0.5 – 1.5%.

Before discussing individual cases, attention should be turned

Pressure of 5kN clearly spoils the positive picture, but these are the

to common features. So for all the formulations with aspirin, the

cases which are worth remembering, which is why account was taken

disintegration time is less dependent on pressures than for mannitol.

of the effects of forces when considering disintegration times. This may

Why? This is simply a result of the construction of aspirin molecules.

be due to the following: low pressures mean larger pores in the tablet,

They do not combine so easily as mannitol molecules, as demonstrated

and then there is enough gel from the disintegrant to block them, but not

by the lower hardness of the tablets and lower strain level. It should be

enough to disperse the particles. The opposite phenomenon, namely

remembered here that strain is the loss of height (thickness) of a tablet

shortening of disintegration time in spite of high pressures, is a result

due to pressure, calculated analogously with, for example, loss of mass

of the decrease in empty spaces which, without the proper cohesion

during friabilation. To put it simply, aspirin is less vulnerable to pressing

between particles, makes it easier to divide up the particles with the aid

forces, and is in this sense “hard” and relatively inflexible, so the spaces

of gel, this time enclosed in a smaller volume.

between the granules remain similar both for the lower and the greater pressures. In the case of disintegration of aspirin tablets containing small amounts of disintegrant, there occurs a phenomenon which may be

Ac-Di-Sol This very greatly extends the disintegration time (fig. 2) when there

called the last particle problem – namely that although the entire tablet

is very little of it, and when it is tableted with low pressures. This

disintegrates within, for example, a minute, the particles it forms take a

process does not take place in the case of aspirin (right hand graph),

long time to disintegrate, with the last sometimes surviving for over half

however starting from amounts greater than 4%, also clearly optimal

an hour. This means that the results obtained under such conditions are

for mannitol, there appears an increasingly strong dependence of the

not exact, which is worth bearing mind.

disintegration time on the pressures. This is due not only to the gel, but also to the great cohesion of the croscarmellose, which probably

POLYPLASDONE ULTRA As can be seen (fig. 1), there is a tendency towards extension of

bonds the aspirin particles. This case is worth investigating further in the future, studying which actions can be used to improve tablet

the disintegration time with mannitol, but at the moment we will not be

hardness –increasing the proportion of croscarmellose and decreasing

considering this part of the graph, bearing in mind that the effective amo-

the pressures, or the reverse.

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26 | production

DC formulation Laboratory. Subject: Testing disintegrant efficiency.

Tablet: Ø10R13 weight: 0.356g thickness: 5±0.1 (10kN) % in formulation Pressure force [kN]

For company: own work

Date:

Page:

Base formula: Parteck M100+3%MgSt

Efficiency, i.e. % decrease in disintegration time

Efficiency profile of

Prejel PA5 PH as a disintegrant

Perfectamyl D6 PH We also see an extension of the disintegration time (fig. 3), but once

mannitol, the gel formed diffuses to the dissolved granules of the base substance, thus bonding firmly to create a barrier against water. Smooth

again only for mannitol, for which this ingredient can be considered

surfaced aspirin granules, on the other hand, probably do not bond with

unsuitable as a content of 20% is certain to weaken the tablet, with

that gel but disperse it. This is a thick gel, too, practically insoluble in

the disintegration times still relatively long. Perfectamyl transpires to

water. The efficiency range of PREJEL is very narrow, however, as may

be a very good disintegrant for aspirin, as illustrated by the right hand

be expected and can be seen on the graph.

graph, which needs no commentary. The example shows a very good assessment of the usefulness of a disintegrant depending on the formulation in which it has been used.

STARCH 1500 Another case (fig. 6) where an ingredient which is difficult to accept as a disintegrant for a soluble formulation turns out to be excellent for

Vivastar P The damage which can be done using admissible amounts of disinte-

an insoluble one. During the research (right hand graph) an extreme was sought which would have positive effects in the range of a 5 – 10%

grants was described in a previous part, so here (fig. 4) the fragments of

content. This was sought for 7%, and then 6%. Here was achieved the

the graph heading down towards the figure of almost minus 600% have

shortest disintegration time regardless of the forces. An aspirin tablet

been omitted. Strictly speaking, it should be noted that such minimal

containing 7% Starch 1500 disintegrates in less than twenty seconds.

disintegrant contents, around 0.05%, are simply not used, but the effects

Further increasing the starch content slightly impairs disintegration (clear

are worth knowing. It is worth noting the clear extreme for the value of 1%

gelling) making it dependent on the strength of the pressing forces.

which occurs with aspirin. It can also be seen that increasing the content above 2% results in an admittedly slight extension of the disintegration time for each of the pressures applied. It is also significant that, for example, for a force of 40kN the extension is less than for a force of 20kN.

PRIMOJEL Use of this ingredient along with croscarmellose caused the failure of a certain formulation which unhappily reached industry from the scientists. This example has already been published many times as a

PREJEL PA5 PH A very interesting case (fig. 5). A substance completely ineffective for a non water soluble formulation. The reason seems clear – in the case of

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warning how not to design a formulation. The fault lay, of course, in a lack of research. This figure (fig. 7) shows that it is a substance which must be applied prudently. Used in a soluble formulation, it threatens to

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production | 27 extend the disintegration time, with the dependence of the disintegration

optimisation of formulations, both existing and designed from the basics,

on small pressures appearing quite interesting. For mannitol, this is not

ever more real. The author knows many cases of needless complication

the best choice, but for aspirin it is. What is more, it is the most effective

of the process and incurring of unnecessary costs. The latest one, last

of all the options considered here. A mere 2% of this ingredient is

year, involved production engineers using wet processing for a product

enough for an aspirin tablet to disintegrate in a moment, and causes no

with good dry cohesion, about which nothing was known. The matter

danger of overdosing. Decreasing to below 1.5% may cause lo efficiency,

concerns disintegrants, because they were being considered for use to

though, as shown in a 10:1 enlargement. There is practically no depen-

shorten disintegration time. Earlier, though, they had extended that time

dence of the disintegration time on the forces forming the tablet. This

at their own wish by using adhesive wet, because “that’s what everyone

example legitimises the decision to introduce a second base substance

does�. All it took was to remove the water and add the adhesive in dry

during the research. It should, however, be emphasised that this note

form, to eliminate the granulator and drier too and shorten disintegration

concerns a specific aspirin, known by its external appearance, from

to under ten minutes. At the same time the quality improved of the

screen analysis and from the entire, precise mechanical characteristics

tablets which previously had to be made deliberately weaker, which

shown in the previous part. This particular aspirin, produced in India,

required tableting to a fixed porosity, in other words with fixed pressures.

tablets very well with a content of only 0.05% magnesium stearate, and

This is only one example of the use of mechanical research applied to

disintegrates excellently, having a 2% Primojel content. This data should

pharmaceutical substances. Using them consistently enables the possi-

not be generalised to other aspirins without first conducting research as

bility of direct tableting in those cases where this had previously seemed

in the present article. This, of course, only concerns direct tableting, in

impossible. The application of mechanical research has a double aim.

other words without wet granulation.

Firstly, to lead to the development of direct technology, in which a major

There are many disintegrant substances, these have been chosen

role will be played by optimising composition and investigating the supply

as an example for research. Some of them are available on the market

opportunities. Secondly, to control purchases, broadening product

under changed names, but the methodology of the research remains

specifications to include mechanical criteria alongside chemical.

current. Worth noting is the use of pressures independent, both in rotary

It is worth ending with a reminder of the attempt made to decrease

machines and laboratory conditions, of the amounts of substance in

the size of granules in the tested formulation with disintegrator. Aspirin

the matrix, which spectacularly simplifies all tests The multiplicity of

with a small amount of disintegrator was tested, such that the tablets had

observations, including those not recorded in this short article, makes

broken into pieces within 30 seconds, before each part disintegrated

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28 | production

individually as in the already described last particle problem. Then the

problems which warn against abandoning expensive traditional methods

granules were decreased by more or less half by light crushing in a

of processing. There are, however, ways to resolve these problems,

mortar. The tablets formed from this formulation stopped disintegrating,

and this opens up the road to better and cheaper technology. It is

showing no reaction to water. Let us summarise with two pieces of

worth realising that the tableting process, regardless of the special aura

advice as conclusions:

attached to it by pharmacists and current legislation, is a thoroughly

The effective amount of disintegrator depends not only on the types of other ingredients (put simply, on their water solubility or lack thereof)

mechanical process and will remain so.

The attractive but not yet fully explored mechanical properties of

but also, as in the case of a glidant, on the size of the particles. This

pharmaceutical substances are still there for the taking, as long as they

means that in the event of a change in a substance’s granulation (e.g.

can be skilfully brought out and applied. Nobody can do this better

a different supplier or batch) a change could occur in the disintegration

than a mechanic collaborating with a pharmacist. Those wishing such

time of the tablet despite other parameters (such as pressures)

a collaboration may make use of the newly undertaken joint initiative by

remaining unchanged.

Farmaserwis and Wydawnictwo Farmacom, involving systematic delivery

In the event that a dependency of the disintegration time on

of current results of research on pharmaceutical substances (API

pressures is discovered, which should happen at the design stage of

and auxiliary) available on the market, in the form of their mechanical

the formulation, those parameters should be optimised from the very be-

characteristics. Many years of experience have shown that this is often

ginning, where the use of the chosen pressures is considered possible.

information of strategic importance, of the most secret and protected

Another major role is of course played by the diameter and shape of the

status, since the fate of entire companies sometimes depends on it.

tablets as parameters defining a punch’s resistance to pressures.

The series of research presented in three parts concerns only a narrow question which is rarely considered difficult by pharmacists.

Far more interesting, but also more difficult, are questions concerning cohesion and the search for the possibility of direct tableting. As we know, applying dry methods instead of wet granulation brings tablet manufacturers enormous benefits, but sometimes involves a wealth of

3/2011

Through the kindness of the editors, author is pleased to invite you to the training he runs in mechanical analysis of formulations intended for tableting, planned for 28 September (Wednesday) in Warsaw. Detailed information, programme, announcements: www.polfarmed.pl

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Polish industry | 31

Edelmann Group Robert Miller

Edelmann Poland Expansion: Edelmann Group to Increase Eastern-Europe Engagement

Heidenheim, 16 June 2011. The Polish subsidiary of Edelmann Group has expanded its site in Poland. A total of 4 million euros was invested in the modernisation of production facilities and a new company building at the Pruszkow site near Warsaw. This was one further step in Edelmann Poland’s strategy to further strengthen its position within the Group as a production site for folding cartons and leaflets. In the past year, the company already accounted for ten percent of the Group’s total production volume.

The expansion and modernisation of the site constitute a strategic step in the effort to strengthen its presence in Central and Eastern Europe.

Dierk Schroder, Spokesman of Edelmann management, stressed this point at the inauguration of the new production facility. He said investments of a total of 4 million euros had been earmarked to boost production capacity, optimize the production flow and modernize the machines and the building.

Edelmann Poland now uses an area of more than 8 000 square metres for production and sales. The capacity increase created by the new printing, cutting and folding machines has made the business a high-capacity site for folding cartons and leaflets. This enables the Edelmann Group to service the growing demand for leaflets and outserts in Central and Eastern Europe.

The site in Poland was the first to be opened as part of the EasternEuropean strategy of the Heidenheim-based packaging manufacturer.

Together with the Hungarian packaging manufacturer Zalai Nyomda,

Having started out as a sales office in 2002, Edelmann increased its enga-

which was acquired in late 2010, the Edelmann Group’s production sites

gement in 2005 by introducing on-site production of folding cartons. Today,

in Central and Eastern Europe offer its internationally-operating customers

Edelmann Poland is among the Top-10 of Polish packaging manufacturers,

a wide selection of products ranging from Health Care to Beauty Care.

having generated revenue of 40 million zloty in 2010 (over 10 million euros).

This allows the Group to act as a one-stop shop for Global Players,

The investments in the site’s expansion and modernisation have now

providing them with a locally-produced diversified brand mix that includes

provided a basis for the planned two-fold increase in revenue for Edelmann

folding cartons, leaflets, labels and blister cards.

Poland within the next five years.

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32 | logistics

Cold supply chain Anna Słaboń Key Clients Director Pharmalink Sp. z o.o. www.pharmalink.pl

The term „cold supply chain” refers to transportation at temperatures between 2 and 8oC, used in the case of sensitive products which are adversely affected by high temperatures. The term is used quite commonly in the pharmaceutical industry, although for each case it may mean a different form of distribution.

The most common form is transportation using insulated foam polysty-

will, in accordance with your assumptions, transport

rene boxes, which serve to keep medicines at the right temperature while

the package at an appropriate ambient temperature. The temperature

being transported. This is probably the oldest form of cold supply, which

of the vehicle’s load compartment can also have a significant effect

is now gradually being replaced by newer solutions. This method is often

on the time for which temperatures are maintained within the required

wrongly assumed to minimize the cost of preparing for shipping.

range, and on their stability.

So what do you need in order to properly prepare a package for this form of transport?

And what about the costs associated with preparing a refrigerated package for shipping?

You have to choose foam polystyrene containers and coolants of the

It is often the case that the thermally insulated foam polystyrene conta-

right quality, and also validate the entire process. Process validation is

iners are left with the end customer together with the product. This means

time-consuming and requires a great deal of care. Validation refers to ac-

that your supply of packages will quickly run down, and so you will need to

tions which serve to confirm, in a documented fashion and in accordance

keep stocks of them in the warehouse. It is possible to have the transport

with the set objectives, that the procedures, processes, devices, materials,

firm collect the packages back from the customer, but this is a paid service

actions and systems indeed lead to the planned results. You must thus

involving additional costs. You also have to provide sufficient warehouse

create appropriate conditions which will enable you to determine whether

space to store the containers, purchase freezers for the coolants, and keep

a given package will actually allow maintenance of the right temperature

checks on the process of return of packages, which ultimately leads to

conditions for a specified time. It is necessary to verify the distribution

an increase in warehouse work. A significant risk in the transportation

of temperatures within the container in case the ambient temperature is

of medicines in thermally insulated containers is that the goods will come

higher or lower than the assumed level. Of course, as well as the thermally

into contact with the frozen coolants, which maintain a negative temperatu-

insulated container itself, you need to select a specialist transport firm that

re for several hours. For example, dry ice reaches a temperature of around

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33

–80°C, which in case of contact with a product may cause it to freeze

Therefore, Pharmalink addresses problems with the freight of goods

or suffer other adverse low-temperature effects. Connected with this is

that must be kept at low temperatures by offering the latest and safest

the issue of determining who is liable if appropriate temperatures are found

solution that does not require isothermal containers and cartridges. This

not to have been maintained. It may prove difficult to prove whether

solution is refrigerated transport that is provided by specially prepared

a deviation in temperature was the fault of the sender or of the transport

vehicles that ensure that the required temperatures are maintained within

firm.

the range of 2 to 8°C. This kind of transportation is called the “cold chain”,

There are also other solutions on the market for protecting medicines

because the whole trailer of the vehicle is cooled. Vehicles are equipped

during transport, such as containers made of polyester-glass laminate or

with heating and cooling devices with forced internal air circulation.

polyurethane foam, supplied with electricity, etc. With every such container

The temperature during the transport is fully monitored. The cold chain

it is necessary to validate it and check that it functions properly. The main

guarantees the safety of transported products and the high-quality of

disadvantage with all containers is their limited capacity. The specific

transport without increasing the cost of freight.

parameters of containers may significantly restrict how goods can be packed, bearing in mind that every container needs a sufficient amount

Many successful shipments completed by Pharmalink using the „cold

of empty space to allow the free circulation of air. Here it may turn out that,

chain” have proved that this transportation method is the best logistics

instead of one cardboard box, you are forced to make up two or three

solution currently offered for the pharmaceutical industry, and it has

smaller packages – and pay the transport firm for the carriage of each one.

become very popular.

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34 | logistics In the past few years it has been noticed increasing interest of outsourcing logistics services for healthcare industry in Poland.

However, delivering services by the logistics providers for such companies is still in the early stage of development and only a few logistics providers have competences to offer cost-effective, highly specialized solutions for their customers.

Contract Logistics for Healthcare Intelligent logistics in FIEGE Agata Wydmańska Public Relations Manager FIEGE

Fiege takes advantage of the many years of delivering solutions to

hospitals. Since the St. Franziskus-Stiftung, has been working hand in

the European markets. In those countries Fiege offers value added

hand with the logistics company Fiege, the supply quality and economic

services tailored to the customers’ needs for the entire supply chain

efficiency have been in the best of health. The aim of this project is to

spectrum such as co-packing, system handling, call centers, etc. Moreover

generate more time for the care and treatment of sick people by way

Fiege also offers centralised services for the hospitals and pharmacists,

of efficient supply chain solutions. It has been very successful on the

offering them logistic services like sterilisation, laundry, in – hospital

German market and lets us think about introducing such services on the

logistic, and in Holand evn the logistics of radioactive materials

polish markets.

Cost advantages are realized at many points of the supply chain

More than 15,000 items are stocked, picked and packed and supplied

process but it also brings additional opportunities and benefits from the

directly to the ward by the logistics provider at the MOC - from pain killer to

well modeled supply chain.

cannula to hip implants. The MOC acts as the hospital dispensary, central

Fiege Group aims in creating innovating solutions for this extremely

sterilization and central warehouse all in one for the affiliated hospitals. By

demanding industry. In 2009 Fiege has implemented The Medical Order

merely merging supply chain flows, a crucial potential for rationalization has

Center (MOC) project in Ahlen in Germany. The modern services centre

been developed, in addition to buying advantages achieved via product

dedicated to hospital logistics has been design for the group of 20 catholic

standardization and converged order volumes.

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35

Hospitals have noticed the savings of 20 - 25% of logistics costs.

freeing the hospital’s nursing

Optimization of range of products has brought savings 5% due to the

staff of the duties that have

procurement logistics and 10 % due to the standardization.

nothing to do with the care of

The range of services consists of many processes: incoming goods,

patients. Missing quantities are

order picking, outgoing goods, returns handling, batch tracing and

balanced just-in-time within 24

liquidation of stocks. The expired products are separated (in system, and

hours. The charge carriers are a

due to requirements also physically – in order to prevent and block them

sophisticated system of basket

from distribution) and then scrapped by authorized company – what brings

modules which saves material

additional perks for the hospitals.

and simplifies the handling.

The instant effects for the buying process and logistics are added

Surgeries are supplied with sets

by potential savings that equal a plus in the quality of the services.

that facilitate the preparation of

In co-operation with Fiege, the hospital developed an innovative pharma-

the impending treatment while

ceuticals supply concept which allows all affiliated hospitals to close their

reducing set-up times, as the

in-house dispensary. The customer is in control of the pharma portfolio,

necessary consumables are

which was co-ordinated with the clinics via access to the MOC pharmacy.

compiled virtually in advance

The centralization of the pharmaceuticals logistics to a single location has

with the nursing staff and doctors.

entailed the optimization of the spectrum of medicaments, combined with

The online order via the Web shop not only simplifies the order pro-

a high availability and fast delivery. The electronic order platform works as

cess. Even the traceability of the order history is available: from the order to

the standardized, largely automated warehousing processes at the MOC.

the supplied materials, to the cost centre invoice. Integrated online analysis

A hierarchy concept assigns user-defined catalogues to doctors as well

tools enable a daily updated evaluation and ensure cost transparency in

as nursing staff. This means that prescription medicine can only be

times of ambulant flat rate payments. The dimensions are quite impressive:

ordered by doctors who are authorized to do so.

Up to 120,000 items per month are ordered via the MOC’s order platform.

Deliveries are carried out as ordered. A tour schedule stipulates

The Medical Order Center project was honored in Idea Contest in

firmly defined supply times for the affiliated hospitals. For express and

Germany. It was chosen as one of the „365 Landmarks in the Land

emergency supplies, Fiege refers to so-called „Blitz” transports that

of Ideas” among over 2,000 applications. The idea contest titled „365

deliver instantly. Transportation needs to be organized in a dedicated way.

Landmarks in the Land of Ideas” is organized by the federal initiative

Requirements for logistic services dedicated to pharmaceutical products

of the German government in co-operation with the German business

are extremely restrictive and relate to the fulfillment of a number of strict re-

community, called „Germany - Land of Ideas”.

gulations to ensure the safety of pharmaceutical products. All drivers have

The prize was awarded in recognition for the innovative concept in

been trained to handle ADR hazardous goods and have their professional

healthcare logistics as well as for setting new trends in building a better

drivers’ qualifications.

health system.

The storage and delivery, however, form only one part of Fiege’s

The most important evidence for the functioning of this system is the

hospital logistics. An important link between the ward and the Medical

satisfaction of the hospital staff to provide high quality services and the

Order Center are the so-called supply assistants – Fiege employees

patients who most benefit from relieving the nursing and medical staff.

who take care of the entire material flow - from the ramp all the way to

From our experience we learned that the demands of hospitals more

the cabinet at the ward - as a constant partner on site. They assume as

or less are the same in the whole Europe. Therefore, it makes us think

„in-house logistics provider” the inventory control, check the picking and

optimistic about introducing those solutions to the polish markets as well.

replenishment trays, keep an eye on the products’ shelf life – thereby

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36 | logistics

IT Technologies in Care of Adherence to GDP Procedures Marta DÄ…browska Consafe Logistics

Good Distribution Practices (GPD) provide very rigorous requirements for people responsible for logistics in pharmaceutical companies. Maintaining right temperature and humidity in warehouses and shipping vehicles, stability and reliability of supply chain or inventory management are just a part of processes, where every error or accidental mistake could lead to serious legal consequences and, more importantly, cause health risks. Due to these reasons pharmaceutical goods manufacturers and logistics operators increasingly decide to invest in advanced warehouse management systems (WMS) and mobile solutions that allow monitoring of drugs storage and shipment on every stage of the process.

Safe and Cost Effective Storage Warehouse management systems and mobile solutions connect all

levels. These data allow for easy and effective prevention of delays and immediate reaction to critical situations, such as temperature change or

the processes related to flow of goods through a warehouse. In case of

goods damage. Product traceability system, providing information about

consignment warehouses they are responsible not only for effective and

product history, including its components, becomes invaluable when

timely collection of medicines batches and preparing adequate documen-

a defect is detected in a particular medicine batch and it is required to

tation to this extent but also for 24h monitoring of appropriate temperature

withdraw it from sale.

and humidity of rooms and handling of identification labels and expiry

An important aspect of warehouse management system in a com-

dates. How does a drugs supply chain coordinated by WMS look like then?

pany’s IT structure is its impact on work efficiency increase and planning

The first stage is the receipt of goods into a warehouse, including product

specific tasks based on current needs. Tasks are determined by a program

identification and registering complex data into the system, batch check

prioritizing individual orders – in the first order employees will receive tasks

and automatic choice of storage localization. This last part is especially

related to handling of shipments with closest deadlines. Another factor

important due to storage conditions required by the pharmaceutical law for

analyzed during task allocation is current employee localization. Employees

different kinds of medicines. When defining storage localization the system

are given tasks in the zones closest to them. One example of such ware-

also takes into account optimal warehouse space usage and forklift truck

house management solution is Astro WMS by Consafe Logistics, allowing

routing, allowing companies to generate significant savings in the area of

warehouse partitioning into time and functional zones, thus simplifying

operational processes.

routing optimization, partitioning of inventory levels and order picking. It

Continuous inventory monitoring guarantees that stock levels indicated

allows to allocate tasks based not only on task priority but also on routes

by the system are consistent with the real levels. This allows to eliminate

of forklift trucks. This way pharmaceutical companies not only can be sure

situations where there is shortage of life-saving drugs, which could cause

that orders will be picked and delivered to wholesalers and pharmacies

serious social and legal consequences. Additionally warehouse manager

in timely manner, but also can notice increased work efficiency and better

has access to a dashboard showing current operations and inventory

sales results and also growing number of satisfied customers.

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37

Loading Under Control

shipping containers with medicines. All deviations are communicated by

Good Distribution Practices define strict requirements for loading and

special alert in the terminal version of application or directly to the shipping

shipment of pharmaceutical goods. Besides protection from damage and

agent. Such solution allows full control of shipping conditions and ensures

contamination of products and providing optimal temperature, logistics

to the end user that goods were stored in appropriate conditions. The

operator has to take care for identification of the product and its consigner

impact of system mobility on higher shipping quality proves itself also in

and consignee. In operations managed by WMS solution complete orders

managing emergency situations. In case of irregularities related to shipping

are verified in the shipping zone and data are sent also to ERP or CRM

medicines batch (e.g. vehicle failure) shipping agent is immediately notified

system. In case of Astro WMS it’s also possible to use functions for weight

of the problem. Contact with employee allows immediate interventional

calculation and cubing during order picking and choose appropriate

action and effective prevention of delay in order shipment.

boxes filling level. Software is also responsible for preparation of shipping documents and printing identification labels.

Mobile solutions ensure also that drugs will be delivered to the right recipient and facilitate order registration required by the pharmaceutical law. Shipment can be delivered only to the person defined in the shipment

Mobile Shipment Protection Whereas in warehouse pharmaceutical goods storage is continuously monitored, shipment of drugs by vehicles in case of traditional solutions

documents. The recipient signs electronically on the terminal screen and immediately receives printed invoice and shipping agent receives Proof of Delivery.

doesn’t allow for delivery tracking and alerting about exceeded tempera-

Benefits of mobile tools being used by logistics operator are also

ture limits. The only exception are vehicles equipped with mobile solutions

valued by owners of pharmacies and wholesalers because online access

automating many operations related to medicines distribution. An example

to an application showing order status allows them to more accurately

of such mobile solution responsible for maintaining appropriate shipping

notify patients about drugs availability and even more versatile inventory

conditions is ControlTransport developed by Consafe Logistics. This solu-

management.

tion allows for integration with temperature monitoring systems in vehicles

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38 | logistics

Electronic management for pharmacy Identification of drugs in Europe – part IV Anna Kosmacz-Chodorowska Institute of Logistics and Warehousing Research Institute – GS1 Polska

Efficiently solutions for the pharmaceutical industry in the field of e-economy with making use of bar codes and electronic data interchange, our Readers have already known partially from previous articles in this series. For making use of efficient solutions throughout the supply chain, in order to improve business – process with manufactures, in warehouse, pharmacies and hospitals, it is essential to use global identifiers by the global GS1 System. Let’s consider how these global symbols for identification of medical products are used in various European countries, including Poland.

Why GS1 identifiers should be used The GS1 system is a set of international standards facilitating effective management of global supply-chains involving very many sectors by the unique identification of products, freight transportation, resources, location

The GS1 system includes: standards for bar-codes – used in the process of automatic identification and data collection and electronic communication as transaction – documents to change by electronic way.

The basis of the system constitutes identification numbers GS1,

and services. In the world this system is managed by GS1 with the base in

including numbers GTIN (Global Trade Item Number), identifying unambi-

Brussels (Belgium) and in Princeton (USA). It is estimated that over 7 billion

guously on the world’s scale every product including medicaments.

transactions per day carried out on the basic of the GS1 system.

Within the country the right to give permission for using global stan-

About the dynamic development of the unique universal international

dards GS1 (previous name: EAN.UCC), including numbers GTIN and using

and intersectoral system shows the fact that when Poland was admitted to

GS1 bar codes, including EAN 13 code, has only the national organization

the system, we were 47th country – its participant.

GS1, which, in Poland, is the Institute of Logistics and Warehousing (ILiM)

Currently it is used by more than 1 million and 300 thousand companies – participants from over 150 countries all over the word.

The GS1 system plays an integral role in health care an independent

in Poznan (in every country in the world, hence in UE countries only one national organizations GS1 is possible).

Each of manufacturers and the owner of trademark to mark their

body merging entities from the same branch. GS1 solutions are going

products, including healthcare products must be an active participant in

more and more recognition and now are recommended by such institu-

the national organization GS1.

tions as the European Commissions, EFIPA, EUCOMED, FDA, and Ministry

GTIN numbers on on products are used by bar codes on retail

of Health in the UK, New Zealand, Australia, France, Japan, Canada and

packages, bulk-trade and logistic units, if they have homogenous content,

Turkey.

and then also in electronic documents as order or electronic invoice.

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39 • So called NTIN (National Trade Item Number), that is GTIN but not created by manufacturer, but for example, by the Ministry of Health according to the principles of GS1 • And the national ID number Considering what was said above, currently all countries can be divided into 3 groups depending on identifiers for registered drugs used by them: • Countries where GTIN is accepted currently comprise that largest part of the world – see: in the Figure 1, countries marked in green.

• Countries where, so called NTIN number according GS1, in required, at the moment consist mainly of, so called, old western Europe. USA, Mexico and Japan see: in the Figure 2, countries marked in yellow.

• Countries where that national number ID is required and mainly china and 4 countries in Western Europe: Belgium, Germany, Portugal and Italy – see: Figure 1 countries marked in red.

Identification of medical products GTIN number consists of 4 parts: • GS1 prefix on national organization which is given by the global

Blue colour indicates the countries from which we have no conclusive data.

organization GS1 • Number of company which is given by the national organization GS1 • Product number which is given by the trademark owner or manufacturer entity taking responsibility • Lat digit is the check digit, calculated according to the algorithm GS1 There are 3 departures from the above mentioned rules: • Publications (books and magazines) • Groceries with a changeable number in retail packages • And registered healthcare-industry products • Which, if they are subjected to the national registration in particular countries, the agreements regarding their coding are concluded between the industry – government institution (in Poland between the Ministry of Health) and the national organization GS1 (in Poland: ILiM) Where the colours mean:

Identification of medical products in the world.

Some healthcare-products, including medicines are in every

Green – the country where GTIN is accepted Yellow - the country where NTIN according GS1 is required

country centrally recorded, and therefore, these products in particular

Red - the country where the national number ID is required

country may have different identifiers, so called national identifiers. Mot

Blue – no data

national solutions were worked out for the purpose of refund checks.

National identifiers are therefore, useful for the unambiguous identification neither on the European scale nor on the world scale. Because

Identification of medicinal products in Europe Currently in Europe the vast majority of countries, as many 17, use

of this, particular countries, especially those which have been using

GTIN numbers. The list of European countries where the identification

bar codes for a long time, in order to improve trade turnover (including

of medical products is entirely, compatibles with Global GS1 system

the most frequently codes that do not belong to the global standards,

and identifiers of drugs are given by the manufactures / entity

like a code 39 or a code 128) gradually, in the place of their national

responsaible, shown in Table 1. As it shows, there are mainly the new

identifiers, introduce such ones so that they will be useful in trade and,

EU countries that have not applied barcodes according to the national

in general in business on a wider scale than only within their country

solutions earlier. That is way introducing them, immediately applied

and will be able to be presented in barcodes of GS1 system.

global solutions as a target.

In practice three basic ways of identifying registered drugs are used in

Poland did likewise when was admitted to the system, that is from

the world – global numbers

March 1990. However, in 1998 Poland converted to NTIN numbers

• GTIN

according GS1, also known as GTIN numbers.

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40 | logistics

GTIN

NTIN (13-digit structure code is in line with the global GS1 system)

(format, structure and code entirely compatible with GS1, number given by manufacturer) Alabama

GTIN

Lithuania

GTIN

Austria

NTIN

Iceland

NTIN/GTIN

Bulgaria Croatia

GTIN

Malta

GTIN

Denmark

NTIN/GTIN

Norway

NTIN/GTIN

GTIN

Netherlands

GTIN

Finland

NTIN/GTIN

Poland

NTIN

Cyprus

GTIN

Rumunia

GTIN

France

NTIN

Slovenia

NTIN

Czech Republic

GTIN

Serbia

GTIN

Greece

NTIN

Switzerland

NTIN/GTIN

Sweden

NTIN/GTIN

Estonia

GTIN

Slovakia

GTIN

Spain

NTIN

Hungary

GTIN

UK

GTIN

Total countries

12

Ireland

GTIN

Turkey

GTIN

Latvia

GTIN

Total countries

17 krajów

Table 1. List of European countries, where the identification of medicinal is entirely compatible with the Global system of GS1

Table 2. List of European countries, where the identification of medical products is in line with the global GS1 system

started using the GS1 code markings, but not only EAN 13 in which only GTIN – 13 number or NTIN – 13 can be presented. France went a step

The second group of countries, also numerous in the group of 12 coun-

further. At once implements the GS1 Data Matrix codes, which together

tries which use NTIN numbers, with 6 of them only using NTIN numbers

with GTIN or NTIN number may present also additional information, on

and the other 6 countries using both GTIN numbers given by the national

retail – packaging, too.

institution registering NTIN as also typical GTIN given by manufactures.

List of European countries, where the identification of medical products

There are such information, as for example, date and series – but this is a topic for a separate article.

is in line with the globalGS1 system, and identifiers of drugs are given by the national registering institution is presented in Table nr 2. As it

Therefore, we can distinguish even the third group of countries that use both GTIN and NTIN numbers. Poland will soon join to this group.

shows, they are mostly the old European countries which previously used

The fourth group consist of four countries: Belgium, Germany, Portugal

barcodes according to the national solutions and gradually transforming

and Italy. In that countries the national ID number is still required and they

into the target global solutions. Also they remained an element of the

haven’t managed to peas to the GS1 global standards yet. The reason is a

national register. Poland has belonged to them since 1999.

very long and costly process.

France is one country with the shortest work experience in the GS1

• Belgium uses 16 – digit national marking, so called ABP

system in the field of registered drugs. France brought the national number,

• Germany uses 7 - digit national marking, so called PZN

so called CIP, into the global number NTIN according GS1 not until 2010.

• Portugal uses 7 - digit national marking,

Passing on formational solutions, as one of the few countries, immediately

• Italy 9 – digit national marking, so called AIC

Figure 2. Identification of medical products in Europe with the term of identifier

3/2011

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logistisc | 41 However, all producers in the countries, if their goods are to be also

Bioudes Products (UR), on the Registration Certificate. The Certificate is

exported, have an obligation to mark them according to the system GS1

currently known as the license for each product during its registration or

that is required by consumers.

registration or as an appendix.

All European countries can be, therefore, divided into 4 groups,

Bar code EAN 13, which shows the number, should be put on the

depending on which identifiers for registered drugs use:

package within 1 year from the date of the Certificate of Registration issue.

• GTIN

In 2004 the Agreement with the Ministry of Health was updated, modifying

• NTIN

the coding-rules of registered drugs in accordance with GS1.

• NTIN and GTIN • National number ID

In connection with the new act concerning the Registration of Medical Products Office, Medical products and Biocides Products (UR), which has

Identification of medicinal products in Europe according to the basic types of marks with the term of identifier is show in Figure 2.

become low since 1st of May 2011, on the 19th of July 2011 there was a tripartite meeting at the seat of the Registration Office. The meeting had varied programme but, above all its purpose was to sort out the formal

Identification of medicinal products in Poland: yesterday, today and tomorrow In Poland, since the beginning of join us to the system EAN functioning

issues connected with cooperation between MZ, UR and ILiM and taking into consideration changes in drug-registration.

The main change is return to giving GTIN numbers for medical

at that time – it means since March 1990, drug – producers used to

products by the producers of commercial brands. It means that UR goes

give GTIN numbers in the same way as the other producers from other

away from giving numbers from the quota granted the Ministry. Economic

industries. However, in 1998 the Ministry of Health, following the example

entities submitting be medicinal products for registration in UR should

of some western countries, in order to take into account in GTIN number

write GTIN numbers given from their own quote of numbers, which were

also national number form a register, under the agreement with ILiM

obtained thanks to the contract with the national organization GS1 (in

achieved the number of coding –until and started giving GTIN numbers (in

Poland from ILiM – GS1 Poland). Those numbers UR will be introducing

the figure identified as NTIN). These numbers (so called EAN codes) are

on license and take into account in the published lists. Further detailed

placed by the Ministry of Health (MZ). At present they are placed through

arrangements in this respect and regarding other industry – products will

the Registration of Medicinal Products Office, Medical Products and

be presented our Readers directly after tripartite approval.

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3/2011

plans raporty, projects, plany, projekty 42 | raports,

Pharmaceutical contract manufacturing and API sourcing – why not Central and Eastern Europe?

Agnieszka Stawarska Head Pharmaceutical Market Analyst PMR Publications

At present only a few companies based in Central and Eastern Europe (CEE) emphasise their production for contract manufacturing and API1 sourcing. There is quite strong competition from companies not only from the Far East but also from Western Europe. On the other hand, the potential of the region seems to be considerable, with Poland and the Czech Republic being still the most attractive locations. In others, e.g.

Russia, API production is scarce but slowly developing.

Higher production costs but higher quality Although companies in the CEE are usually unable to compete with

ceuticals, dietary supplements, semi-finished products and biotechnology products. Within the area into question, the most attractive countries for

Indian and Chinese manufacturers, given the production costs, there are

pharmaceutical contract manufacturing and API sourcing are Poland and

several region advantages over Far East, including:

the Czech Republic.

• Legislation based on EU standards or simultaneously being harmoni-

There are numerous companies which specialise in API production

sed with EU in Serbia and Croatia, which aim to join the EU.

in the Czech Republic in comparison with other countries in the region.

• Relatively wide application of ISO (International Organisation for

Contract manufacturing services pertaining to finished dosage forms in

Standardisation) and GMP (Good Manufacturing Practice) standards.

• Most CE companies can cooperate within the tariff-free trade framework of the EU. • A rapidly developing biomanufacturing industry.

the country focus primarily on the production of dietary supplements. This is associated with a long tradition of dietary supplement production in the Czech Republic.

In Poland there are not many API producers at present and most companies do not produce API for their own needs. With regard to

It must be however admitted, that there is a much more limited choice

contract manufacturing, there are several Polish companies with a long

of companies which offer contract manufacturing services and/or API in

tradition of pharmaceutical manufacturing. Also there are many companies

CEE in comparison with India and China.

which specialise in the production of dietary supplements or/and natural

According to the European Directorate for the Quality of Medicines & Healthcare, India and China are also progressing as non-European users

based raw materials used in the production of pharmaceuticals, dietary supplements or cosmetics.

of EDQM Reference Standards.

Poland and the Czech Republic the most attractive According to our analysis, Central and Easetrn European countries

Russia: production scarce but slowly developing Over the past few years a trend toward slow development has been observed on the part of producers of pharmaceutical substances in

offer possibilities of manufacturing not only APIs, other specialty chemicals

Russia. Domestic manufacturers of substances have broadened the range

and plant raw materials, but also various finished dosage forms of pharma-

of manufactured substances. However, API production in Russia is still not

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43

a particularly substantial component of the business of pharmaceutical

Union should carry out regular inspections at the API supplier’s manufac-

companies. It has been estimated that only 15% of API consumed in

turing facility to ensure that the company is not violating GMP standards

Russia are produced on the domestic market. Interestingly, however,

and present a written declaration confirming the quality. If such regulations

the differences between China and the other countries have become

came into force, they may weaken the position of API manufacturers

significantly less substantial over the last three years – in 2008 exports

outside the EU. Indian API manufacturers fear that the procedure could

from China cost half as much as those from the cheapest country in

lead to unnecessary, in their opinion, delays in export consignments.

Central and Eastern Europe but they have been becoming more expensive

At present, API suppliers to the EU need only to obtain a Certificate of

in recent years.

Suitability of European Pharmacopoeia monographs (CEPs) issued by the

The implementation of GMP standards by Russian manufacturers is slow, and the deadline has been moved several times. However, all

European Directorate for the Quality of Medicines & Healthcare.

In its 2015 Roadmap, the draft of which was published in January 2011,

companies in Russia must comply by January 2014. Many small Russian

the European Medicines Agency highlighted the quality of APIs manu-

companies which currently produce APIs at very low prices will have to

factured outside the EU as an area of concern, because the international

stop production if they do not succeed in implementing GMP rules before

sourcing of active pharmaceutical ingredients makes it possible for

the deadline. At the same time, knowledge of GMP rules is limited.

substandard material to enter the supply chain.

The Federal Target Programme (FTP) “Strategy for the development of the pharmaceutical industry of the Russian Federation between now and 2020” (Pharma 2020) is designed to encourage the transition of Russia’s

Contract manufacturing to become a must?

Substantial changes in manufacturing infrastructure started only a few

pharmaceutical industry to an innovative development model. Approxima-

years ago, and the global contract manufacturing market, including the

tely RUB 36bn (€900m) is to be spent on this, and the construction of abo-

CEE area in question, will still be growing rapidly in subsequent years.

ut 200,000 m² of facilities will be funded to produce sterile and non-sterile

Market growth will be accelerated by the expiry of patents on several

pharmaceuticals. Russian companies might, therefore, be more attractive

blockbusters in the next few years. This will compel large multinational

partners in the future. In all, to achieve the goals government has promised

companies, whose revenues are expected to decline significantly, to look

that RUB 120bn (€3bn) from the federal budget will be invested before

for savings.

2020 in the modernisation of the Russian pharmaceutical industry. Private

Companies may also be compelled to reduce their costs as a result

investments by Russian and international drug producers could come to

of uncongenial legislation introduced by governments. This includes,

as much as RUB 68bn (€1.7bn). The government strategy also envisages

for example, the Reimbursement Act in Poland, which will require

the production of domestic substances sufficient for the production of 50%

pharmaceutical companies to take part in a payback mechanism. It

of all drugs in terms of value, along with an eightfold increase in exports in

also introduces fixed margins and prices for reimbursed products. In

comparison with those of 2008. This might encourage foreign companies

Hungary the government has decided to increase the 12% tax payable by

to produce their drugs in Russia through local companies.

pharmaceutical manufacturers on revenues from reimbursed drugs to 20% from 1 July 2011 onwards.

EU to fight with poor-quality APIs Because of the questionable quality of some APIs exported into the European Union, in April 2010 the European Commission proposed that the drug regulator in the country which exports its APIs to the European

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This article is based on information contained in the PMR reports “Pharmaceutical contract manufacturing and API sourcing in Central Europe and the Balkan states 2011” and „Pharmaceutical contract manufacturing and API sourcing in Russia, Ukraine and the Baltic states 2011” published in 2011.

3/2011

44 | conferences, fairs, training

June 16-17 2011 - Poznań

3 Congress

World of the Pharmaceutical Industry The third Congress of Pharmaceutical Industry World was held in Poznań on 13–14 June 2011.

The Poznań Herbal Company HERBAPOL S.A. was its honorary host.

This year’s Congress was a continuation of the previous two editions, whose honorary hosts were the pharmaceutical company Polfa-Łódź S.A., and the medicines manufacturer and distributor Sanofi-Aventis Sp. z o.o. of Rzeszów.

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conferences, fairs, training | 45

HONORARY HOST:

HONORARY PATRONAGE

The high standard of the content of the Congress was assured by experts from pharmaceutical companies, universities, institutions and organisations operating in the pharmaceutical industry, including Dariusz Lipiak of Brenntag Polska Sp. z o.o., Mirosław Popieluch of StatSoft Polska, Marcin Weksler of the

PATRONAGE SUBSTANTIVE

MEDsynC Skotnicki Weksler partnership, P.P.H. FORMIKA Sp. z o.o., Professor Lucjusz Zaprutko – Head of the Department of Organic Chemistry at Poznań University of Medical Sciences, Jerzy Lasota of Farmaserwis, Mariusz Drozd of Kates Polska Sp. z o.o., Magdalena Mikołajczyk of Sartorius Stedim, Mariusz Kolbuszowski of DONSERV, Izabela Wachowiak, Anna Ryszczuk – Head of the Production Conditions Supervision Department at the Central Pharmaceutical Inspectorate, Andrzej Hantz of Radwag Electronic Scales, Dr Izabella Milczarek of Patpol, Daniel Gralak – Director of the Production Inspection Department at the Central Pharmaceutical Inspectorate, Dr Robert Królicki – Analytical Laboratory Director at Selvita Group, Elżbieta Napierała, Dr Anna Wachnik Święcicka – Centralised Procedure Coordinator at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Unilogo Sp. z o.o.

Sp. k., Arkadiusz Jaśniewski of Intrex, Wiktoryna

MEDIA PARTNER:

Kolado of COBRO, Dominika Kozioł of Pacplast Thermoform Polska Sp. z o.o., Andrzej Janczur of Trade&Consult Ltd. Sp. z o.o. Sp. k., Elżbieta Napierała, Anna Kosmacz-Chodorowska of the Institute of Logistics and Warehousing, Michał

ORGANIZER:

Witczak of ISL, and Jarosław Mazur of Potraf.

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46 | conferences, fairs, training

The first day of the Congress consisted of lectures, and concluded with a festive Gala. There were messages of thanks, a prize draw, a performance by the Hrabi comedy group, and fun lasting until the late hours.

On the second day, Congress participants had the opportunity to visit the production departments of the Poznań Herbal Company HERBAPOL S.A. Another edition of the Congress will be held next year.

You are warmly invited.

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